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NCCN Follicular Lymphoma Recommendations

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					                                                                                                                                                                                                                           NCCN Guidelines Index
                                                                                                                                                                                                                            NHL Table of Contents
                                                                                                                                                                                                                                       Discussion




                          NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™)



                                                         Non-Hodgkin’s
                                                          Lymphomas
                                                                                                              Version 3.2011



                                                                                                              NCCN.org


                                                                                                                   Continue


Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Printed by Eric Kirkendall on 7/17/2011 6:41:14 PM. For personal use only. Not approved for distribution. Copyright © 2011 National Comprehensive Cancer Network, Inc., All Rights Reserved.



                                                                                                                                                                                                                              NCCN Guidelines Index
                                                          NCCN Guidelines™ Version 3.2011 Panel Members                                                                                                                        NHL Table of Contents
                                                          Non-Hodgkin’s Lymphomas                                                                                                                                                         Discussion

   * Andrew D. Zelenetz, MD, PhD/Chair † Þ                                                         Leo I. Gordon, MD ‡                                                              Barbara Pro, MD † Þ
     Memorial Sloan-Kettering Cancer Center                                                        Robert H. Lurie Comprehensive Cancer                                             Fox Chase Cancer Center
                                                                                                   Center of Northwestern University
      Jeremy S. Abramson, MD † ‡                                                                                                                                                 * Nishitha Reddy, MD ‡ x
      Massachusetts General Hospital Cancer Center                                              * Nancy Lee Harris, MD ¹                                                           Vanderbilt-Ingram Cancer Center
                                                                                                  Massachusetts General Hospital Cancer
   * Ranjana H. Advani, MD †                                                                      Center                                                                            Lubomir Sokol, MD, PhD † ‡ Þ §
     Stanford Comprehensive Cancer Center                                                                                                                                           H. Lee Moffitt Cancer Center & Research
                                                                                                   Richard T. Hoppe, MD §                                                           Institute
      C. Babis Andreadis, MD ‡                                                                     Stanford Comprehensive Cancer Center
      UCSF Helen Diller Family Comprehensive Cancer                                                                                                                                 Lode Swinnen, MB, ChB ‡
      Center                                                                                    * Steven M. Horwitz, MD † Þ                                                         The Sidney Kimmel Comprehensive Cancer
                                                                                                  Memorial Sloan-Kettering Cancer Center                                            Center at Johns Hopkins
      Nancy Bartlett, MD †
      Siteman Cancer Center at Barnes-Jewish Hospital                                              Christopher R. Kelsey, MD §                                                      Christina Tsien, MD §
      and Washington University School of Medicine                                                 Duke Cancer Institute                                                            University of Michigan Comprehensive Cancer
                                                                                                                                                                                    Center
      Naresh Bellam, MD, MPH ‡                                                                   * Youn H. Kim, MD v
      University of Alabama at Birmingham                                                          Stanford Comprehensive Cancer Center                                             Julie M. Vose, MD ‡ x
      Comprehensive Cancer Center                                                                                                                                                   UNMC Eppley Cancer Center at The Nebraska
                                                                                                * Ann S. LaCasce, MD †                                                              Medical Center
      John C. Byrd, MD † Þ                                                                        Dana-Farber/Brigham and Women's Cancer
      The Ohio State University Comprehensive Cancer                                              Center                                                                            William G. Wierda, MD, PhD ‡
      Center - James Cancer Hospital and Solove                                                                                                                                     The University of Texas M. D. Anderson
      Research Institute                                                                           Auayporn Nademanee, MD † ‡ x                                                     Cancer Center
                                                                                                   City of Hope Comprehensive Cancer Center
      Myron S. Czuczman, MD † ‡                                                                                                                                                     Joachim Yahalom, MD §
      Roswell Park Cancer Institute                                                            * Pierluigi Porcu, MD ‡ Þ                                                            Memorial Sloan-Kettering Cancer Center
                                                                                                 The Ohio State University Comprehensive
      Luis Fayad, MD † ‡ Þ                                                                       Cancer Center - James Cancer Hospital and                                          Nadeem Zafar, MD ¹
      The University of Texas M. D. Anderson Cancer                                              Solove Research Institute                                                          St. Jude Children's Research Hospital/
      Center                                                                                                                                                                        University of Tennessee Cancer Institute
                                                                                                   Oliver Press, MD, PhD †                                                       NCCN
      Martha J. Glenn, MD † ‡ Þ                                                                    Fred Hutchinson Cancer Research
      Huntsman Cancer Institute at the University of                                                                                                                             Mary Dwyer, MS
                                                                                                   Center/Seattle Cancer Care Alliance                                           Hema sundar, PhD
      Utah
                                                                                                                                                          † Medical Oncology                                   x Bone Marrow Transplantation
      Jon P. Gockerman, MD † ‡                                                                                        Continue                            ‡ Hematology/Hematology                              ¹ Pathology
      Duke Cancer Institute                                                                                                                                oncology                                            Þ Internal medicine
                                                                                                                                                          § Radiotherapy/Radiation                             v Dermatology
   NCCN Guidelines Panel Disclosures                                                                                                                       oncology                                            * Writing Committee Member

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Printed by Eric Kirkendall on 7/17/2011 6:41:14 PM. For personal use only. Not approved for distribution. Copyright © 2011 National Comprehensive Cancer Network, Inc., All Rights Reserved.



                                                                                                                                                                                                                              NCCN Guidelines Index
                                                          NCCN Guidelines™ Version 3.2011 Table of Contents                                                                                                                    NHL Table of Contents
                                                          Non-Hodgkin’s Lymphomas                                                                                                                                                         Discussion

   NCCN Non-Hodgkin’s Lymphoma Panel Members                                                                                                                                                     Clinical Trials: The NCCN
   Summary of the Guidelines Updates                                                                                                                                                             believes that the best management
                                                                                                                                                                                                 for any cancer patient is in a clinical
   Chronic Lymphocytic Leukemia/
                                                  Use of Immunophenotyping and Genetic                                                                                                           trial. Participation in clinical trials is
    Small Lymphocytic Lymphoma (CSLL-1)                                                                                                                                                          especially encouraged.
                                                  Testing in Differential Diagnosis of Mature B-
   Follicular Lymphoma (FOLL-1)
                                                  Cell and T/NK-Cell Neoplasms (NHODG-A)          To find clinical trials online at NCCN
   Marginal Zone Lymphomas (MZL-1)                                                                member institutions, click here:
                                                  Tumor Lysis Syndrome (NHODG-B)
     Gastric MALT Lymphoma (MALT-1)                                                               nccn.org/clinical_trials/physician.html
                                                  Response Criteria for Non-Hodgkin’s
     Nongastric MALT Lymphoma (NGMLT-1)
                                                  Lymphoma (NHODG-C)                              NCCN Categories of Evidence and
     Nodal Marginal Zone Lymphoma (NODE-1)                                                        Consensus: All recommendations
                                                  Monoclonal Antibody Directed at CD20 and
     Splenic Marginal Zone Lymphoma (SPLN-1)                                                      are Category 2A unless otherwise
                                                  Viral Reactivation (NHODG-D)                    specified.
   Mantle Cell Lymphoma (MANT-1)
                                                  Principles of Radiation Therapy (NHODG-E) See NCCN Categories of Evidence
   Diffuse Large B-Cell Lymphoma (BCEL-1)
                                                                                                  and Consensus
   Burkitt Lymphoma (BURK-1)
   Lymphoblastic Lymphoma (BLAST-1)
   AIDS-Related B-Cell Lymphoma (AIDS-1)                                                         Classification and Staging (ST-1)
   Primary Cutaneous B-Cell Lymphoma (CUTB-1)
   Peripheral T-Cell Lymphoma, Noncutaneous (TCEL-1)
   Mycosis Fungoides/Sezary Syndrome (MFSS-1)
   Adult T-cell Leukemia/Lymphoma (ATLL-1)
   Extranodal NK/T- Cell Lymphoma, nasal type (NKTL-1)
   Post-Transplant Lymphoproliferative Disorders (PTLD-1)


   Primary CNS Lymphoma (See NCCN CNS Guidelines)
   Waldenström’s Macroglobulinemia/Lymphoplasmacytic Lymphoma (See NCCN WM/LPL Guidelines)
     The NCCN Guidelines™ are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to
     treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of
     individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network ® (NCCN ®) makes no
     representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in
     any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Network ®. All rights reserved. The NCCN Guidelines and the
     illustrations herein may not be reproduced in any form without the express written permission of NCCN. ©2010.
   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.
Printed by Eric Kirkendall on 7/17/2011 6:41:14 PM. For personal use only. Not approved for distribution. Copyright © 2011 National Comprehensive Cancer Network, Inc., All Rights Reserved.




                                                           NCCN Guidelines™ Version 3.2011 Updates                                                                                                                            NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Non-Hodgkin’s Lymphomas                                                                                                                                                        Discussion

   Summary of the changes in the 3.2011 version of the Non-Hodgkin's Lymphoma guidelines from the 2.2011 version include:
   MS-1
   · The following sections of the Dicussion were updated to reflect the changes to the algorithm:
     > CLL/SLL                             > Lymphoblastic lymphoma                           > Mycosis fungoides and Sezary syndrome
     > Follicular lymphoma                 > AIDS-related B-cell lymphoma                     > Adult T-cell leukemia/lymphoma
     > Diffuse large B-cell Lymphoma       > Primary cutaneous B-cell lymphoma                > Extranodal NK/T-cell lymphomas, nasal type
     > Burkitt lymphoma                    > Peripheral T-cell lymphoma                       > Post-transplant lymphoproliferative disorders

   Summary of the changes in the 2.2011 version of the Non-Hodgkin's Lymphoma guidelines from the 1.2011 version include:
   FOLL-B 1 of 3                                                                MFSS-A 1 of 4
   · Footnote “f” was modified by adding, “Updates as of 2010 suggest a         · Footnote g, “Patients with large cell transformed (LCT) MF and stage IV
     trend towards an increased risk of MDS with RIT treatment”.                  non-Sezary/visceral disease may present with more aggressive growth
   MANT-A 1 of 3                                                                  characteristics. In general, agents listed in SYST-CAT C are preferred in
   · Induction therapy,                                                           these circumstances” is new to the page.
     > “Alternating RCHOP/RDHAP (rituximab, cyclophosphamide,                   NKTL-2
        doxorubicin, vincristine, prednisone) / (rituximab, dexamethasone,      · Induction therapy,
        cisplatin, cytarabine)” was added as a suggested treatment regimen        > “Combined modality therapy with 50 Gy RT” was changed to
        under aggressive therapy.                                                    “Concurrent chemoradiotherapy”. (Also for NKTL-B)
     > “Bendamustine ± rituximab” was changed to “bendamustine +                  > Stage I, no risk factors present, “clinical trial” was added as an option
        rituximab”                                                                   and the “RT alone” dose was changed from 54 Gy to ³ 50 Gy.
     > “CHOP ± rituximab” was changed to “CHOP + rituximab”                     NKTL-3
     > “CVP (cyclophosphamide, vincristine, prednisone) ± rituximab” was        · Post RT response assessment, stage I with or without risk factors,
        changed to “CVP + rituximab”                                              additional therapy, for both PR and refractory disease, “candidate for
   · Footnote b, “These regimens include first-line consolidation with high       transplant and non candidate for transplant” were removed.
     dose therapy and autologous stem cell rescue (HDT/ASCR)” is new to           > For PR, the therapy was changed to “Hematopoietic stem cell
     the page.                                                                       transplant, if eligible”
   · Footnote, “There are no prospective randomized comparative trials            > For refractory disease, the therapy was changed to “salvage
     with induction therapy regimens for mantle cell lymphoma” was                   chemotherapy or best supportive care” and after salvage chemotherapy,
     removed.                                                                        “Hematopoietic stem cell transplant, if eligible”.
   TCEL-B 1 of 2                                                                NKTL-B
   · “Romidepsin” was added as a suggested treatment regimen for                · Suggested treatment regimens, “or in sequence with chemotherapy” was
     second-line therapy.                                                         added to “radiotherapy alone” and recommended tumor dose was
   MFSS-6                                                                         changed from 54 Gy to ³ 50 Gy.
   · For primary treatment of generalized extent tumor, transformed and/or      PTLD-2
     folliculotropic disease, a link to the systemic therapies in category C on · Polymorphic, systemic disease, “rituximab” was added a primary
     MFSS-A was added.                                                            treatment option.
   MFSS-8
   · Footnote dd, “Patients with stage IV non-Sezary/visceral disease may
     present with more aggressive growth characteristics. If there is no
     evidence of more aggressive growth, systemic therapies from SYST-
     CAT B are appropriate. If aggressive growth is seen, then agents listed
     in SYST-CAT C are preferred” is new to the page.                                                                                    Continued on next page
   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.       UPDATES
Printed by Eric Kirkendall on 7/17/2011 6:41:14 PM. For personal use only. Not approved for distribution. Copyright © 2011 National Comprehensive Cancer Network, Inc., All Rights Reserved.




                                                           NCCN Guidelines™ Version 3.2011 Updates                                                                                                                            NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Non-Hodgkin’s Lymphomas                                                                                                                                                        Discussion

   Updates to the 1.2011 version of the Non-Hodgkin's Lymphoma guidelines from the 1.2010 version include:
   New Guidelines                                                                                                                      CSLL-5
   NKTL-1                                                                                                                              · Moved statement from footnote to a subbullet of clinical trial, “17p
   · Extranodal NK/T-cell Lymphoma, nasal type is a new guideline.                                                                       deletion is associated with low response rates with all treatments and
   PTLD-1                                                                                                                                there is no standard treatment, clinical trial is recommended”.
   · Post-transplant lymphoproliferative disorders is a new guideline.                                                                 · Footnote r, “ Patients with low positivity should be retested due to
   Principles of Radiation Therapy                                                                                                       chance of false positive results” is new to the page.
   · Principles of radiation therapy is new to the guidelines and links to this                                                        CSLL-A
     page were added throughout the guidelines.                                                                                        · Footnote b , “ IGHV rearrangements involving VH3-21 carr y a poor
   Global change                                                                                                                         prognosis even if mutated” is new to the page.
   · Clinical follow-up was modified as “Clinical follow-up every 3-6 mo for                                                           · Percentages were added to outcome association for flow cytometry.
     5 y then yearly or as clinically indicated” throughout the guidelines.                                                            CSLL-C
   · Workup sections, “MUGA scan/echocardiogram” was modified by                                                                       · Sinopulmonary was added to recurrent infections.
     adding “if anthracycline or anthracenediones-based regimen is                                                                     · Recurrent sinopulmonary infections, 2nd subbullet was modified to
     indicated” which was previously in a footnote.                                                                                      “...nadir level of approximately 500 mg/dl”.
   Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma                                                                             · Antiinfective prophylaxis, alemtuzumab subbullet was modified by
   · A new algorithm for CLL with deletion of 11q on CSLL-6 and the                                                                      adding, “Clinicians must be aware of the high risk of CMV reactivation.
     corresponding suggested regimens on CSLL-D 3 of 5 were added.                                                                       The current appropriate management is controversial, some use
   CSLL-1                                                                                                                                ganciclovir (oral or IV) prophylactically if viremia present, others only if
   · Diagnosis, the section title “informative for prognostic determination”
                                                                                                                                         viral load is rising. CMV viremia should be measured by PCR
     was modified as “informative for prognostic and/or therapy                                                                          quantitation at least every 2-3 wks. Consultation with an Infectious
     determination”.                                                                                                                     Disease expert may be necessary.”
   CSLL-2                                                                                                                              · Autoimmune cytopenia, PRCA, “and bone marrow evaluation” was
   · Workup, Hepatitis B testing bullet was modified as “ if CD20
                                                                                                                                         added.
     monoclonal antibody contemplated.”                                                                                                · Vaccination, p neumococcal vaccine was modified by adding “Prevnar
   · Workup, “PET scan is generally not useful in CLL but can assist in
                                                                                                                                         preferred”
     directing nodal biopsy if Richter's transformation is suspected” was                                                              · Blood product support, “i rradiate all blood products” was modified by
     added.                                                                                                                              adding “to avoid transfusion associated GVHD”.
   CSLL-3                                                                                                                              CSLL-D 1 of 5
   · Evaluate for indications for treatment, “Progressive” was added to
                                                                                                                                       · CLL without del (11q) or del (17p)
     bulky disease.                                                                                                                      > First-line therapy, a ge ³ 70 y or younger patients with co-morbidities
   · Footnote ‘j’ was modified by adding “... unless above 200- 300 x 10 9/L                                                                7 Vincristine was removed from combination with CP ± rituximab.
     or symptoms related to leukostatsis.” Also for CSLL-5.                                                                                 7 “+ rituximab” was added to bendamustine.
   · Footnote ‘m’ was modified by adding, “... FISH [ t(11;14); t(11q;v); +12;                                                              7 Cladrabine was added.
     del(11q); del(13q); del(17p)] is necessary to direct treatment.”                                                                    > First-line therapy, age < 70 y or older patients without significant co-
   · Footnote n, “ In addition to the regimens listed in BCEL-C ,
                                                                                                                                            morbidities
     R-HyperCVAD has also been used in this setting” is new to the page.                                                                    7 Bendamustine + rituximab was added.
   CSLL-4                                                                                                                                   7 “Alemtuzumab, chlorambucil, bendamustine, fludarabine” as
   · CLL without a deletion 11 q was added to the page.
                                                                                                                                              monotherapies were removed.
   · Age ³ 70 y, “or younger patients with co-morbidities” was added as a
                                                                                                                                         > Relapsed/refractory therapy, short response < 2 y for age ³ 70 y:
     qualifier.                                                                                                                             7 Chlorambucil ± prednisone, “if used first-line” was added as a qualifier.
   · Footnotes ‘o’ and ‘p’ are new to the page.                                                                                             7 Alemtuzumab ± rituximab was added.              Continued on next page
   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.       UPDATES
Printed by Eric Kirkendall on 7/17/2011 6:41:14 PM. For personal use only. Not approved for distribution. Copyright © 2011 National Comprehensive Cancer Network, Inc., All Rights Reserved.




                                                           NCCN Guidelines™ Version 3.2011 Updates                                                                                                                            NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Non-Hodgkin’s Lymphomas                                                                                                                                                        Discussion

   Updates to the 1.2011 version of the Non-Hodgkin's Lymphoma guidelines from the 1.2010 version include:
   Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (cont)                                                                   Gastric MALT Lymphoma
   CSLL-D 2 of 5                                                                                                                    MALT-1
   · CLL with del (17p)                                                                                                             · Workup
     > First-line therapy                                                                                                             > “Endoscopic ultrasound (if available)” was moved to essential with
        7 “± rituximab” was added to alemtuzumab and ‘rituximab” was                                                                     endoscopy.
          added to bendamustine.                                                                                                      > “SPEP” was added to useful under certain circumstances. (Also for
     > Relapsed/refractory therapy                                                                                                       NGMLT-1)
        7 “± rituximab” was added to bendamustine and high-dose                                                                     MALT-2
          dexamethasone and corresponding footnote g, “Rituximab should                                                             · For Stage I E2 or Stage II E, initial therapy of currently accepted antibiotic
          be added unless patient is known to be refractory to rituximab” was                                                         therapy for H. pylori followed by evaluation for H. pylori eradication with
          added.                                                                                                                      endoscopy was added.
        7 Footnote f, “This is not effective in patients with lymph nodes                                                           · Footnote h, “Involvement of submucosa or regional lymph nodes are much
          > 5 cm” was added to ofatumumab.                                                                                            less likely to respond to antibiotic therapy. If there is persistent disease after
   Follicular Lymphoma                                                                                                                evaluation, RT may be considered earlier in the course” is new to the page.
   FOLL-1                                                                                                                           MALT-3
   · Diagnosis, useful under certain circumstances, “ Paraffin section                                                              · Footnote q, “If patient originally had clinical Stage I E2 or Stage II E early RT
     immunohistochemistry: Ki67” and corresponding footnote f, “There                                                                 should be considered if there is no response to antibiotics” is new to the
     are reports showing Ki67 proliferation fraction of > 30 % may be                                                                 page.
     associated with a more aggressive clinical behavior but no evidence                                                            MALT-4
     this should guide treatment decisions” were added.                                                                             · Restage after RT was changed from 3 mo to 3-6 mo.
   FOLL-2                                                                                                                           · For lymphoma positive and H. Pylori negative or positive, “locoregional RT,
   · Stage I, II locoregional RT (preferred) was modified as “IFRT                                                                    if not previously treated” was removed and directed to follicular lymphoma.
     (preferred for clinical stage I or contiguous stage II)”.
   · Bulky Stage II or abdominal disease was modified as “Stage IIX”.                                                               Nongastric MALT lymphoma
   · Footnote q, “Consider clinical trials appropriate for patients on                                                              NGMLT-1
     observation” is new to the page.                                                                                               · Workup, useful in selected cases, “SPEP” was added. Also for NODE-1.
   FOLL-B 1 of 3
   · First-line therapy, “bendamustine + rituximab” the category was                                                                Nodal Marginal Zone Lymphoma
     changed from a category 2A to a category 1 designation.                                                                        NODE-1
   · First-line therapy for elderly or infirm, “± rituximab” was added to                                                           · Diagnosis, the section title “useful under certain circumstances” was
     single agent alkylators.                                                                                                         modified by adding “for clarification of diagnosis”.
   · First-line consolidation or extended dosing, “rituximab maintenance”
     the category designation was changed from category 2B to a
     category 1 and “up to 2 y” was added as a qualifier.
   · “Hi gh dose therapy with autologous stem cell rescue” and
     “allogeneic stem cell transplant for highly selected patients”and
     “rituximab maintenance” were added to a new section titled
     “Second-line Consolidation or Extended Dosing”.
                                                                                                                                                                                                                     Continued on next page


   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.       UPDATES
Printed by Eric Kirkendall on 7/17/2011 6:41:14 PM. For personal use only. Not approved for distribution. Copyright © 2011 National Comprehensive Cancer Network, Inc., All Rights Reserved.




                                                           NCCN Guidelines™ Version 3.2011 Updates                                                                                                                            NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Non-Hodgkin’s Lymphomas                                                                                                                                                        Discussion

   Updates to the 1.2011 version of the Non-Hodgkin's Lymphoma guidelines from the 1.2010 version include:
    Splenic Marginal Zone Lymphoma                                                                                                     Diffuse Large B-Cell Lymphoma
    SPLN-1                                                                                                                             BCEL-1
    · Diagnosis, essential, “peripheral blood, bone marrow, or tissue” was                                                             · Subtypes included with DLBCL were added:
      added to “cell surface marker analysis by flow cytometry”.                                                                         > Intravascular large B-cell lymphoma
    · Footnote ‘a’ is new to the page.                                                                                                   > DLBCL associated with chronic inflammation
    · Workup, useful in selected cases, “direct Coombs test” was added.                                                                  > ALK positive DLBCL
    SPLN-2                                                                                                                               > EBV positive DLBCL of the elderly
    · Hepatitis C, “assess” was added as a first decision in management and if                                                           > T-cell/histiocyte rich large B-cell lymphoma
      no symptoms, then “observe” was added.                                                                                           · Subtypes not included with DLBCL were added:
    · Footnote, “Splenectomy is preferred in patients who are able to tolerate                                                           > Primary DLBCL of the CNS
      it” was removed and footnote e, “Vaccination should be performed at                                                              BCEL-3
                                                                                                                                       · Stage I - IV, “RCHOP 6 or 8 cycles” was revised to “RCHOP 6 cycles”. Also
      least 2 weeks before splenectomy” was added to the page.
    Mantle Cell Lymphoma                                                                                                                 for follow-up on BCEL-5.
    MANT-1                                                                                                                             · Stage I, II, “locoregional RT” was changed to “RT”.
    · Footnote c, “Ki67 proliferation fraction of < 30% is associated with a                                                           · Stage II, IV, “preferred” was removed from “clinical trial”.
                                                                                                                                       · Footnote ‘k’ was modified by adding, “See AIDS-2 for HIV-positive DLBCL.”
      more favorable prognosis. However, it is not used to guide treatment” is
                                                                                                                                       BCEL-4
      new to the page.
                                                                                                                                       · Partial response, “± RT pre- or post-transplant” was added to “High dose
    · Footnote ‘e’ was modified by adding, “essential for confirmation of stage
                                                                                                                                         therapy with autologous stem cell rescue” and “Clinical trial (may include
      I- II diseaese”.
    MANT-2                                                                                                                               allogeneic stem cell transplant.”
                                                                                                                                       · For completion of planned course of treatment after a complete response,
    · Bulky Stage II or abdominal disease was modified as “Stage IIX”.
    · Stage IIX, III, IV, for induction therapy with suggested treatment                                                                 the algorithm has been directed to “clinical followup every 3-6 mo...” rather
      regimens, “± RT” was removed.                                                                                                      than “end of treatment restaging.”
    · Footnote ‘i’ is a new reference.                                                                                                 BCEL-5
    MANT-A 1 of 3                                                                                                                      · For stage III, IV, interim restaging was changed from “after 3-4 cycles” to
    · Induction therapy,                                                                                                                 “after 2-4 cycles”.
      > Aggressive therapy, “CALGB regimen (rituximab + methotrexate with                                                              · After completion of treatment with a complete response, “Observation
          augmented CHOP [cyclophosphamide, doxorubicin, vincristine,                                                                    (preferred)” and “For high risk patients, high dose therapy can be
          prednisone])” and “Sequential RCHOP/RICE (rituximab,                                                                           considered (category 2B)” were added as further options.
          cyclophosphamide, doxorubicin, vincristine, prednisone)                                                                      BCEL-C 1 of 3
                                                                                                                                       · First-line therapy for patients with poor left ventricular function, “RCEOP ”
          (rituximab,ifosfamide, carboplatin, etoposide)” were added as
          treatment options.                                                                                                             was added as a treatment option.
                                                                                                                                       · Second-line therapy “for candidates for high dose therapy with autologous
      > Less aggressive therapy,
          7 “CVP ± rituximab” was added as an option.                                                                                    stem cell rescue” was clarified as “For patients with intention to proceed to
          7 Cladribine was changed from “± rituximab” to “+ rituximab”.                                                                  high dose autologous stem cell rescue.”
    · Second-line therapy                                                                                                              · Second-line therapy for patients who are non-candidates for high dose
      > “± rituximab” was added to lenalidomide.                                                                                         therapy,
      > Cladribine was changed from “± rituximab” to “+ rituximab”.                                                                      > “CEOP ± rituximab” and “GDP ± rituximab” and “GemOx ± rituximab”
      > “Temsirolimus” and “thalidomide + rituximab” were removed.                                                                          were added.
                                                                                                                                         > “± rituximab” was added to lenalidomide.
                                                                                                                                       · Footnote ‘e’ is new to the page.                Continued on next page
   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.       UPDATES
Printed by Eric Kirkendall on 7/17/2011 6:41:14 PM. For personal use only. Not approved for distribution. Copyright © 2011 National Comprehensive Cancer Network, Inc., All Rights Reserved.




                                                           NCCN Guidelines™ Version 3.2011 Updates                                                                                                                            NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Non-Hodgkin’s Lymphomas                                                                                                                                                        Discussion

   Updates to the 1.2011 version of the Non-Hodgkin's Lymphoma guidelines from the 1.2010 version include:
   Burkitt Lymphoma                                                                                                                   Primary Cutaneous B-Cell Lymphoma
   BURK-1                                                                                                                             · “Locoregional RT” was clarified as “local RT” in the primary cutaneous
   · Diagnosis, useful under certain circumstances, for additional                                                                      B-cell lymphoma guidelines.
     immunohistochemical studies to establish lymphoma subtype, “Frozen:                                                              CUTB-1
     kappa/lambda” and “Paraffin panel: TdT; kappa/lambda” were removed.                                                              · Diagnosis, useful under certain circumstances, “Assessment of
   · Workup, “flow cytometry of cerebrospinal fluid” was moved from useful                                                              surface IgM and IgD expression (to further help in distinguishing
     under certain circumstances to essential. (Also for BLAST-1)                                                                       DLBCL, leg type from FCL)” was added.
   BURK-2                                                                                                                             · Statement was added, “ NOTE: A germinal (or follicle) center phenotype
   · “Second line chemotherapy followed by high dose chemotherapy with                                                                  and large cells in a skin lesion is NOT equivalent to DLBCL but is
     HSCT in selected patients” was added as a treatment option for relapse                                                             consistent with primary cutaneous germinal/follicle center lymphoma. ”
     after a complete response in the low risk category and after                                                                     · Workup, peripheral blood flow cytometry, “if CBC demonstrates
     consolidation in a clinical trial for the high risk category.                                                                      lymphocytosis” was added.
   BURK-A 1 of 2                                                                                                                      · Footnote ‘c’ with the typical immunophenotype was added.
   · For “dose-adjusted EPOCH” in both low and high risk combination                                                                  · Footnote ‘d’ was modified, “Rule out drug-induced cutaneous
     regimens, a statement, “data is for patients without CNS disease” was                                                              lymphoid hyperplasia”.
     added.                                                                                                                           CUTB-2
   · “Second line therapy options for relapse for select patients with                                                                · Solitary/regional, initial therapy, “preferred” was added to local RT.
     reasonable remission” was added with the following regimens:                                                                     · Generalized disease, initial therapy:
     > Dose-adjusted EPOCH                                                                                                              > “intralesional steroids” was added. Also for CUTB-3.
     > R-IVAC if have not received previously                                                                                           > palliative chemotherapy, ‘± rituximab” was added to “chlorambucil”.
     > RGDP                                                                                                                               Also for CUTB-3.
     > HDAC                                                                                                                           · Footnote j, was modified by adding “There are case reports showing
                                                                                                                                        efficacy of topicals which include...”. Also for CUTB-4.
   AIDS-Related B-cell lymphoma                                                                                                       CUTB-4
   AIDS-1                                                                                                                             · For solitary/regional and generalized disease with a complete
   · Workup, “stool guaiac, if anemic” was removed.                                                                                     response after initial therapy, “observe” was added until relapse.
   AIDS-2                                                                                                                             · Solitary/regional, secondary therapy, “local RT” was modified by
   · Statement regarding antiretrovirals was added, “Antiretrovirals can be                                                             adding “to previously unirradiated tumor”.
     administered safely with chemotherapy, however some regimens have
     recommended discontinuation. Any change in antiviral therapy should
     be done in consultation with infectious disease specialist.” (Also for
     AIDS-3)
   · For lymphoma-associated with Castleman's disease, DLBCL, and
     Primary effusion lymphoma, “For DLBCL relapse, see BCEL-6” was
     added.
   AIDS-3
   · For primary CNS lymphoma, “For select patients with good performance
     status and on HAART, see NCCN CNS Guidelines- Primary CNS
     Lymphoma” was added.
   · Footnote g, “Management can also apply to HIV negative plasmablastic                                                                                                                                           Continued on next page
     lymphoma” was added to the page.
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                                                           NCCN Guidelines™ Version 3.2011 Updates                                                                                                                            NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Non-Hodgkin’s Lymphomas                                                                                                                                                        Discussion

   Updates to the 1.2011 version of the Non-Hodgkin's Lymphoma guidelines from the 1.2010 version include:
   Peripheral T-Cell Lymphomas                                                                                                        MFSS-4
   TCEL-1                                                                                                                             · Stage IA, for primary treatment, “If B1 blood involvement, consider
   · Diagnosis, useful under certain circumstances: “PD1” and “ b F1 and                                                                primary treatment for Stage IIIB B1 (category 2B)” was added. Also for
     CD279” were added.                                                                                                                 IB-IIA on MFSS-5.
   TCEL-3                                                                                                                             MFSS-6
   · Induction therapy for “ALCL, ALK positive” subtype was added.                                                                    · “and/or histologic evidence of folliculotropic or large cell transformation
   TCEL-4                                                                                                                               (LCT)” was added with “stage IIB.”
   · Partial response, follow-up therapy, “± RT” was added to “high dose                                                              · Limited extent tumor, primary treatment with local RT for limited extent
     therapy with stem cell transplant” and “clinical trial (may include                                                                tumor, transformed, and/or folliculotropic disease, “+ skin-directed
     allogeneic stem cell transplant”.                                                                                                  therapies” was removed and “± skin-directed therapies” was added to
   TCEL-B 1 of 2                                                                                                                        “systemic therapies ± RT”.
   · First-line therapy, the following list of “Other regimens that can be                                                            · Footnotes s, “Rebiopsy if suspect large cell transformation” is new to
     used” were added:                                                                                                                  the page.
     > CHOEP                                                                                                                          · Footnote t, “Histologic evidence of LCT often, but not always corresponds
     > CHOP every 2 or 3 wks                                                                                                            to a more aggressive growth rate. If there is no evidence of more aggressive
     > CHOP followed by ICE
                                                                                                                                        growth, choosing systemic therapies from category A or B are appropriate.
     > CHOP followed by IVE
                                                                                                                                        If aggressive growth is seen, then agents listed in category C (SYST-CAT C)
     > HyperCVAD alternating with high-dose methotrexate and cytarabine
   · Footnote b, “Standard induction for PTCL remains undefined with the
                                                                                                                                        are preferred” is new to the page.
                                                                                                                                      · Footnote u, “For non-radiated sites, see Stage I-IIA. After patient is rendered
     exception of ALCL, ALK + for which CHOP remains the standard.
                                                                                                                                        disease free by RT, may consider adjuvant systemic biologic therapy (SYST-
     Clinical trial is preferred for all other subtypes” is new to the page.
   · Footnote c, “In AITL, pralatrexate has limited activity” is new to the page.
                                                                                                                                        CAT A) after RT to improve response duration” is new to the page.
                                                                                                                                      · Footnote y, “The role of allogeneic HSCT is controversial. See discussion
   · Footnote e, “With close follow-up of renal function” is new to the page.
                                                                                                                                        for further details” is new to the page. Also for MFSS-7 and MFSS-8.
   Mycosis Fungoides/Sezary Syndrome                                                                                                  MFSS-7
                                                                                                                                      · Footnote cc, “Alemtuzumab can be administered by IV or
   MFSS-1
   · Workup, useful in selected cases: “Rebiopsy if suspicious of large                                                                 subcutaneously. Lower doses administered subcutaneously have shown
     cell transformation” was added.                                                                                                    lower incidence of infectious complications” is new to the page. Also for
   · Workup, essential, “chest x-ray” was removed from imaging studies.                                                                 MFSS-8.
   · Footnote ‘a’ was modified by adding “clinically or histologically non-                                                           MFSS-8
     daignostic cases”.                                                                                                               · For primary treatment of non sezary or visceral disease, a link to the
   · Footnote ‘c’ was modified by adding “demonstration of identical                                                                    new category C treatment options for systemic therapies was added.
     clones in skin, blood and/or lymph node may be helpful in selected                                                               MFSS-A 1 of 3
                                                                                                                                      · Systemic therapies, a new group titled “Category C” was added with
     cases”.
   MFSS-2                                                                                                                               corresponding footnote g, “Combination regimens are generally
   · Footnote ‘g’ was modified as “...defined as a clonal rearrangement of                                                              reserved for patients with relapsed/refratory or extracutaneous
     the TCR in the blood (clones should be relevant to clone in the skin)                                                              disease.”
     and either 1000/mcL or increased CD4 or CD3 cells with CD4/CD8 of
     10 or more or increase in CD4 cells with an abnormal phenotype (40%                                                                                                                                             Continued on next page
     CD4/CD7 or 30% CD4/CD26).”

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                                                           NCCN Guidelines™ Version 3.2011 Updates                                                                                                                            NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Non-Hodgkin’s Lymphomas                                                                                                                                                        Discussion

   Updates to the 1.2011 version of the Non-Hodgkin's Lymphoma guidelines from the 1.2010 version include:
    Adult T-cell Leukemia/Lymphoma
    ATLL-1
    · Diagnosis, useful under certain circumstances, “ Molecular analysis HTLV-1 clonal
      integration is encouraged in all cases of mature T-cell lymphoma/leukemia in HTLV-1
      seropositive individuals: Southern blot or inverse PCR ” was removed.
    ATLL-2
    · Chronic/smoldering subtype, after persistent or progressive disease “discontinue
      treatment” was removed and “clinical trial or best supportive care” were added as
      additional treatment options.
    ATLL-3
    · Acute subtype, after complete response “consider allogeneic stem cell transplant” was
      added as an additional treatment option.
    · Both acute and lymphoma subtypes, after persistent or progressive disease “best
      supportive care” was added as an additional treatment option.

    Use of Immunophenotyping/Genetic Testing in Differential Diagnosis of Mature B-cell
      and T/NK-cell Neoplasms
    NHODG-A
    · Footnote c, “Rare cases of both cyclin D1 and t(11;14) negative MCL have been reported.
      This diagnosis should be made with extreme caution and with expert consultation” was
      added.

    Tumor Lysis Syndrome
    NHODG-B
    · High risk features for tumor lysis syndrome were added.
    · Indications for rasburicase use were added.




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                                                            NCCN Guidelines™ Version 3.2011                                                                                                                                   NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                            CLL/SLL a                                                                                                                                                                     Discussion

   DIAGNOSIS
   ESSENTIAL:
   · Hematopathology review of all slides with                                             · Adequate immunophenotyping to establish
     at least one paraffin block representative of                                           diagnosis b,c
     the tumor, if the diagnosis was made on a                                               > Recommended panel for paraffin section                                                                                                 See Workup
     lymph node or bone marrow biopsy.                                                         immunohistochemistry: CD3, CD5, CD10,                                                             CLL/SLL                              for CLL/SLL
     Rebiopsy if consult material is                                                           CD20, CD23, cyclin D1                                                                                                                  (CSLL-2)
     nondiagnostic.                                                                            or
   · An FNA or core needle biopsy alone is not                                               > Cell surface marker analysis by flow
     generally suitable for the initial diagnosis of                                           cytometry: kappa/lambda, CD19, CD20, CD5,
     lymphoma. In certain circumstances, when                                                  CD23, CD10
     a lymph node is not easily accessible for                                             · Absolute monoclonal B lymphocyte count d
     excisional or incisional biopsy, a
     combination of core biopsy and FNA                                                    INFORMATIVE FOR PROGNOSTIC AND/OR
     biopsies in conjunction with appropriate                                              THERAPY DETERMINATION: e
     ancillary techniques for the differential                                             · Cytogenetics and/or FISH to detect: t(11;14);                                                       Monoclonal B
     diagnosis (immunohistochemistry, flow                                                   t(11q;v); +12; del(11q); del(13q); del(17p)                                                         lymphocytosis (MBL)
     cytometry, PCR for IGHV and TCR gene                                                  · Molecular genetic analysis to detect:                                                               · Absolute monoclonal
     rearrangements, and FISH for major                                                      immunoglobulin heavy chain variable gene                                                              B lymphocyte count
     translocations) may be sufficient for                                                   (IGHV) mutation status                                                                                < 5000/mm 3                             Observe
     diagnosis. This is particularly true for the                                          · Determination of CD38 and Zap 70 expression                                                         · All lymph nodes
     diagnosis of CLL/SLL.                                                                   by flow cytometry or immunohistochemistry f                                                           < 1.5 cm
   · Flow cytometry of blood adequate for
                                                                                                                                                                                                 · No anemia
     diagnosis of CLL/SLL (biopsy not required).
                                                                                                                                                                                                 · No thrombocytopenia

                                                                                                                                   c See
                                                                                           Use of Immunophenotyping and Genetic Testing in Differential Diagnosis of
   a CLL  = chronic lymphocytic leukemia; SLL = small lymphocytic lymphoma. Cases Mature B-cell and T/NK-cell Neoplasms (NHODG-A).
     diagnosed as B-PLL are excluded from this guideline.                           d Absolute monoclonal B lymphocyte count < 5000/mm 3 in the absence of
   b Typical immunophenotype: CD5+, CD23+, CD43+/-, CD10-, CD19+, CD20 dim,            adenopathy or other clinical features of lymphoproliferative disorder is monoclonal B
     sIg dim+ and cyclin D1-. Note: Some cases may be sIg bright+, CD23- or dim        lymphocytosis (MBL).
     and some MCL may be CD23+; cyclin D1 immunohistochemistry or FISH for          e See Prognostic Information for CLL (CSLL-A).
     t(11;14) should be considered in all cases and should be done in cases with an f Evaluation of ZAP 70 expression can be challenging and ZAP 70 is not
     atypical immunophenotype (CD23 dim or negative, CD20 bright, sIg bright).         recommended outside the setting of a clinical trial.
      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          CSLL-1
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                                                            NCCN Guidelines™ Version 3.2011                                                                                                                                   NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                            CLL/SLL                                                                                                                                                                       Discussion

    WORKUP

   ESSENTIAL:
   · Physical exam: attention to node-bearing areas, including
     Waldeyer’s ring, and to size of liver and spleen
   · Performance status                                                                                                                          SLL/Localized
   · B symptoms                                                                                                                                  (Ann Arbor Stage I)
   · CBC, differential, platelets                                                                                                                (See CSLL-3)
   · LDH
   · Comprehensive metabolic panel
   · Hepatitis B testing g if CD20 monoclonal antibody contemplated
   · MUGA scan/echocardiogram if anthracycline or anthracenediones-
     based regimen is indicated
   · Pregnancy testing in women of child-bearing age
     (if chemotherapy planned)

   USEFUL UNDER CERTAIN CIRCUMSTANCES:
   · Quantitative immunoglobulins
   · Reticulocyte count, hepatoglobin, and direct Coombs’ test                                                                                   CLL or SLL
   · Chest/abdominal/pelvic CT should be done prior to initiation of                                                                             (Ann Arbor Stage II - IV,
     therapy (particularly when peripheral adenopathy is present and                                                                             Rai Stages 0-IV)
     symptoms suggest bulky lymph nodes)                                                                                                         (See CSLL-3)
   · Beta-2-microglobulin
   · Uric acid
   · Unilateral bone marrow biopsy (± aspirate) at initiation of therapy
   · Discussion of fertility issues and sperm banking
   · PET scan is generally not useful in CLL but can assist in directing
     nodal biopsy if Richter's transformation is suspected




   g HepatitisB testing is indicated because of the risk of reactivation with immunotherapy + chemotherapy. Tests include hepatitis B surface antigen and core
     antibody for a patient with no risk factors. For patients with risk factors or previous history of hepatitis B, add e-antigen. If positive, check viral load and
     consult with gastroenterologist.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          CSLL-2
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                                                            NCCN Guidelines™ Version 3.2011                                                                                                                                   NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                            CLL/SLL                                                                                                                                                                       Discussion

   PRESENTATION
   SLL/Localized
                                           Locoregional                                                                                                                                       Consider prophylaxis for tumor
   (Ann Arbor                                                                                Observe
                                           RT (if indicated)                                                                                                                                  lysis syndrome (See NHODG-B)
   Stage I) h
                                                                              Evaluate for indications for                                                                                    Consider risk for CMV
                                                                              treatment: j                                                                                                    reactivation (See CSLL-C)
                                                                              · Eligible for clinical trial k
                                          SLL                                 · Significant disease-related                                           No
                                                                                symptoms:                                                             indication
                                          CLL                                   > Fatigue (severe)
                                          Rai Low (0)                           > Night sweats
                                                                                > Weight loss                                                                                                                                        CLL Without
                                          and
                                                                                > Fever without infection                                                                                                                            Deletion of
                                          Intermediate                                                                                                                                                                               11q or 17p
   CLL                                    (I-II) risk i                       · Threatened end-organ function
                                                                                                                                                                                                                                     (See CSLL-4)
   (Rai Stages                                                                · Progressive bulky disease                                             Indication
   0-IV)                                                                        (spleen > 6 cm below costal                                           present
   or                                                                           margin, lymph nodes > 10 cm)
   SLL                                                                        · Lymphocyte doubling time (LDT)                                                                                                                       CLL With
   (Ann Arbor                                                                   £ 6 mo                                                                                            · Evaluate FISH m                                  Deletion of
   Stages II-IV) h                                                            · Progressive anemia                                                                                · Imaging as appropriate                           17p (See
                                                                              · Progressive thrombocytopenia l                                                                                                                       CSLL-5)
                                          CLL
                                          Rai High (III-IV)
                                          Risk i                                                                                                                                                                                     CLL With
                                                                                                                                                                                                                                     Deletion of 11q
                                          Histologic transformation                                                                                                                                                                  (See CSLL-6)
                                                                                                        Manage as aggressive                                       Consider allogeneic stem cell
                                          to diffuse large-cell/ Hodgkin
                                                                                                        lymphoma (See BCEL-C) n                                    transplant (See BCEL-C)
                                          lymphoma
   h See   Supportive Care For Patients With CLL (CSLL-C).
   i See  Rai and Binet Classification Systems (CSLL-B).                                                                           l Plateletcounts >100,000 cells/mm 3 are typically not associated with clinical risk.
   j Absolute lymphocyte count alone is not an indication for treatment unless above                                               m Re-evaluation    of FISH [t(11;14); t(11q;v); +12; del(11q); del(13q); del(17p)] is
      200- 300 x 10 9/L or symptoms related to leukostatsis.                                                                         necessary to direct treatment.
   k Given incurability with conventional therapy, consider a clinical trial as first line of                                      n In addition to the regimens listed in BCEL-C, R-HyperCVAD has also been used in
      treatment.                                                                                                                     this setting.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.           CSLL-3
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                                                            NCCN Guidelines™ Version 3.2011                                                                                                                                   NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                            CLL/SLL                                                                                                                                                                       Discussion

   CLL WITHOUT DELETION OF 11q or 17p                                                                                                                                                                        Consider prophylaxis for tumor
                                                                                 FIRST-LINE                                   RESPONSE TO
                                                                                                                                                                                                             lysis syndrome (See NHODG-B)
                                   Frail patient,                                THERAPY                                      THERAPY p
                                   significant co-                               See Suggested                                                                               See Suggested                   Consider risk for CMV
                                   morbidity o (not                              Regimens                                                                                    Regimens q                      reactivation (See CSLL-C)
                                   able to tolerate                              (CSLL-D 1 of 5)                                                                             (CSLL-D 1 of 5)
                                   purine analogs)
                                                                                                                               Long response > 3 y,
                                                                                                                                                                             Retreat with first-line
                                                                                                                               repeat FISH, if del
                                                                                                                                                                             therapy until a short
                                                                                                                               (17p) see CSLL-5, or
                                                                                                                                                                             response
                                                                                                                               del (11q) see CSLL-6
                                   Age ³ 70 y or                                  See Suggested
                                   younger patients                               Regimens
                                   with co-morbidities o                          (CSLL-D 1 of 5)                              Short response < 2 y,                           See Suggested
   CLL without                                                                                                                                                                 Regimens                                      Consider allogeneic
                                                                                                                               repeat FISH, if del
   del (11q) or                                                                                                                                                                (CSLL-D 1 of 5)                               stem cell transplant,
                                                                                                                               (17p) see CSLL-5, or
   del (17p) h,j,k                                                                                                             del (11q) see CSLL-6                            (relapsed/refractory                          if without significant
                                                                                                                                                                               therapy)                                      co-morbidities p

                                                                                                                               Long response > 3 y,
                                                                                                                                                                               Retreat with first-line
                                                                                                                               repeat FISH, if del
                                                                                                                                                                               therapy until a short
                                   Age < 70 y or                                                                               (17p) see CSLL-5, or
                                                                                 See Suggested                                                                                 response
                                   older without                                                                               del (11q) see CSLL-6
                                                                                 Regimens
                                   significant
                                                                                 (CSLL-D 1 of 5)                                                                               See Suggested
                                   co-morbidities o                                                                            Short response < 2 y,
                                                                                                                                                                               Regimens
                                                                                                                               repeat FISH, if del                                                                          Allogeneic stem cell
                                                                                                                                                                               (CSLL-D 1 of 5)
                                                                                                                               (17p) see CSLL-5, or                                                                         transplant
                                                                                                                                                                               (relapsed/refractory
                                                                                                                               del (11q) see CSLL-6
   h See   Supportive Care For Patients With CLL (CSLL-C).                                                                                                                     therapy)
   j Absolute  lymphocyte count alone is not an indication for treatment unless above 200-300 x 10 9/L or symptoms related to leukostatsis.
   k Given incurability with conventional therapy, consider a clinical trial as first-line of treatment.
   o Salvi F, Miller MD, Grilli A, et al. A manual of guidelines to score the modified cumulative illness rating scale and its validation in acute hospitalized elderly patients. J Am
     Geriatr Soc 2008;56:1926-1931.
   p Keating M, Wierda W, Tam C, et al. Long term outcome following treatment failure of FCR chemoimmunotherapy as initial therapy for chronic lymphocytic leukemia.
     Blood (ASH Annual Meeting Abstracts) 2009;114:Abstract 2381.
   q If long response, treat with the same first line therapy. If short response, consider alternative first line therapy not used before.


      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.           CSLL-4
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                                                            NCCN Guidelines™ Version 3.2011                                                                                                                                   NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                            CLL/SLL                                                                                                                                                                       Discussion

   CLL WITH DELETION OF 17p

                                  FIRST-LINE THERAPY                                      RESPONSE TO
                                                                                          THERAPY
                           Consider prophylaxis for tumor                                                                                                                                                               Observe
                                                                                                                                                                                             CR s                       or
                           lysis syndrome (See NHODG-B)
                                                                                                                                                                                                                        Clinical trial
                           Consider risk for CMV
                           reactivation (See CSLL-C)                                                                                                                                                                    Observe
                                                                                                                                                                                                                        or
                                                                                                                 Candidate for                    Allogeneic stem                                                       Clinical trial
                                                                                                                                                                                             PR s                       or
                                                                                                                 transplant                       cell transplant
                                                                                                                                                                                                                        See Suggested Regimens
                                  · Clinical trial                                                                                                                                                                      (CSLL-D 2 of 5)
                                    > 17p deletion is
                                                                                       CR/PR s
                                      associated with low                                                                                                                                    No
                                      response rates with                                                                                                                                    response
                                      all treatments and
    CLL with                          there is no standard                                                                                                                                                              Clinical trial
    del (17p) h,j,r                   treatment, clinical
                                                                                                                Non- candidate                                                                                          or
                                                                                                                for transplant                                                                                          Relapsed/refractory
                                      trial is recommended.
                                  · See Suggested                                                                                                                                                                       therapy (See Suggested
                                    Regimens                                                                                                                                                                            Regimens CSLL-D 2 of 5)
                                                                                       No
                                    (CSLL-D 2 of 5)                                    response




   h See  Supportive Care For Patients With CLL (CSLL-C).
   j Absolute lymphocyte count alone is not an indication for treatment unless above 200- 300 x 10 9/L or symptoms related to leukostatsis.
   r Patients with low positivity should be retested due to chance of false positive results.
   s See Response Criteria: CLL (CSLL-E) or SLL (NHODG-C).

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          CSLL-5
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                                                            NCCN Guidelines™ Version 3.2011                                                                                                                                   NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                            CLL/SLL                                                                                                                                                                       Discussion

   CLL WITH DELETION OF 11q

                                            FIRST-LINE                                  RESPONSE TO
                                            THERAPY                                     THERAPY                                                                                                                          Observe
                                                                                                                                                                                             CR s                        or
                    Consider prophylaxis for tumor                                                                                                                                                                       Clinical trial
                    lysis syndrome (See NHODG-B)
                                                                                                                                                                                                                         Observe
                                                                                                                                                                                                                         or
                    Consider risk for CMV
                                                                                                                                                                                                                         Clinical trial
                    reactivation (See CSLL-C)                                                                 Candidate for
                                                                                                                                               Consider                                      PR s                        or
                                                                                                                                               allogeneic stem
                                                                                                              transplant                                                                                                 See Suggested Regimens
                                                                                                                                               cell transplant
                                                                                                                                                                                                                         (CSLL-D 3 of 5)
                                                                                                                                                                                             No
   CLL with del
                                                                                      PR s                                                                                                   response
   (11q) h,j
   · Outcomes are                                                                                                                                                                            No
     more favorable                         · Clinical trial                                                                                                                                 transplant
     in patients with                       · See Suggested                                                   Non- candidate
     11q deletion                             Regimens                                                        for transplant
     who receive                              (CSLL-D 3 of 5)                                                                                                                                                            Clinical trial
     regimens                                                                                                                                                                                                            or
                                                                                                                 Observe
     containing an                                                                                                                                                           Disease                                     Relapsed/refractory
                                                                                      CR s                       or
     alkylator.                                                                                                                                                              progression                                 therapy (See Suggested
                                                                                                                 Clinical trial
                                                                                                                                                                                                                         Regimens CSLL-D 3 of 5)



                                                                                      No
                                                                                      response



   h See Supportive Care For Patients With CLL (CSLL-C).
            lymphocyte count alone is not an indication for treatment unless above 200- 300 x 10 9/L or symptoms related to leukostatsis.
   j Absolute
   s See Response Criteria: CLL (CSLL-E) or SLL (NHODG-C).

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          CSLL-6
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                                                            NCCN Guidelines™ Version 3.2011                                                                                                                                   NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                            CLL/SLL                                                                                                                                                                       Discussion

                                                                                           PROGNOSTIC INFORMATION FOR CLL a


                                                 Immunoglobulin Variable Region (IGHV) Gene Mutation and Surrogates by Flow Cytometry

                                                                                                                                    Outcome Association
                                                                                                                                 Favorable      Unfavorable
                                                                           DNA sequencing b
                                                                            IGHV                                                 > 2% mutation                      £ 2% mutation

                                                                           Flow Cytometry
                                                                              CD38                                               < 30 %                             ³ 30 %
                                                                              Zap 70                                             < 20 %                             ³ 20 %



                                                                                                   Interphase Cytogenetics (FISH) c

                                                                         Unfavorable                            Neutral                                  Favorable

                                                                         del(11q)                               Normal                                   del(13q) (as a
                                                                         del(17p)                               +12                                      sole abnormality)




   a This table provides useful prognostic information relative to the time to progression where therapy is required and survival. The presence of del(11q) and/or del (17p)
     are associated with short progression free survival to chemotherapy and chemoimmunotherapy approaches. Alemtuzumab or high dose steroids have anecdotal
     response in del(17p) disease.
   b IGHV rearrangements involving VH3-21 carry a poor prognosis even if mutated.
   c Formal studies identifying the percentage of abnormal cells identified by FISH are ongoing although populations less than 10% appear to not have the clinical impact
     as noted in the table.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          CSLL-A
Printed by Eric Kirkendall on 7/17/2011 6:41:14 PM. For personal use only. Not approved for distribution. Copyright © 2011 National Comprehensive Cancer Network, Inc., All Rights Reserved.




                                                            NCCN Guidelines™ Version 3.2011                                                                                                                                   NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                            CLL/SLL                                                                                                                                                                       Discussion

                                                                                                            CLL STAGING SYSTEMS
                                                     Rai System a                                                                                                                        Binet System b

             Stage            Description                                                                 Risk Status                                   Stage                 Description


             0                Lymphocytosis, lymphocytes in                                               Low                                           A                     Hemoglobin ³ 10 g/dL and
                              blood > 15,000/mcL and > 40%
                                                                                                                                                                              Platelets ³ 100,000/mm 3 and
                              lymphocytes in the bone marrow                                                                                                                  < 3 enlarged areas

             I                Stage 0 with                                                                Intermediate
                              enlarged node(s)                                                                                                          B                     Hemoglobin ³ 10 g/dL and
                                                                                                                                                                              Platelets ³ 100,000/mm 3 and
             II               Stage 0-I with splenomegaly,                                                Intermediate                                                        ³ 3 enlarged areas
                              hepatomegaly, or both
                                                                                                                                                        Cc                    Hemoglobin < 10 g/dL and/or
                                                                                                                                                                              Platelets < 100,000/mm 3 and
             III c            Stage 0-II with hemoglobin < 11.0 g/dL                                      High
                                                                                                                                                                              any number of enlarged areas
                              or hematocrit < 33%


             IV c             Stage 0-III with                                                            High
                              platelets < 100,000/mcL




   a This  research was originally published in Blood. Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical
      staging of chronic lymphocytic leukemia. Blood 1975;46(2):219-234. (c) the American Society of Hematology.
   b From: Binet JL, Auquier A, Dighiero G, et al. A new prognostic classification of chronic lymphocytic leukemia derived from a
      multivariate survival analysis. Cancer 1981;48(1):198-206.
   c Immune-mediated cytopenias are not the basis for these stage definitions.


      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          CSLL-B
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                                                            NCCN Guidelines™ Version 3.2011                                                                                                                                   NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                            CLL/SLL                                                                                                                                                                       Discussion

                                                                                        SUPPORTIVE CARE FOR PATIENTS WITH CLL

                Recurrent Sinopulmonary                                       · Antimicrobials as appropriate
                Infections (requiring IV                                      · Evaluate serum IgG, if < 500 mg/dl
                antibiotics or hospitalization)                                 > begin monthly IVIG 0.3-0.5 g/kg,
                                                                                > adjust dose/interval to maintain nadir level of approximately 500 mg/dl

                Antiinfective Prophylaxis                                     · Recommended for patients receiving purine-analog and/or alemtuzumab during treatment
                                                                                and thereafter, if tolerated
                                                                                > Herpes virus (acyclovir or equivalent)
                                                                                > PCP (sulfamethoxazole/trimethoprim or equivalent)
                                                                              · Alemtuzumab: Clinicians must be aware of the high risk of CMV reactivation. The current
                                                                                appropriate management is controversial, some use ganciclovir (oral or IV) prophylactically
                                                                                if viremia present, others only if viral load is rising. CMV viremia should be measured by
                                                                                PCR quantitation at least every 2-3 wks. Consultation with an Infectious Disease expert may
                                                                                be necessary.

                 Autoimmune Cytopenias                                         · Auto-immume hemolytic anemia (AIHA): Diagnosis with reticulocyte count, haptoglobin, DAT
                                                                                 > AIHA that develops in setting of treatment with fludarabine, stop, treat, and avoid
                                                                                   subsequent fludarabine
                                                                               · Immune thrombocytopenia purpura (ITP): Evaluate bone marrow for cause of low PLT
                                                                               · Pure red blood cell aplasia (PRCA): Evaluate for parvo B19 and bone marrow evaluation
                                                                               · Treatment: Corticosteroids; rituximab; IVIG; cyclosporin A; splenectomy; eltrombopag or
                                                                                 romiplostim (ITP)

                 Vaccination                                                   · Annual Influenza vaccine a
                                                                               · Pneumococcal vaccine (Prevnar preferred) every 5 yrs
                                                                               · Avoid all live vaccines, including Zoster

                 Blood Product Support                                         · Transfuse according to institutional or published standards
                                                                               · Irradiate all blood products to avoid transfusion associated GVHD

   a In patients who have received rituximab, B-cell recovery occurs by approximately 9 months. Prior to B-cell recovery, patients generally do not respond
     to influenza vaccine and if given should not be considered vaccinated.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          CSLL-C
Printed by Eric Kirkendall on 7/17/2011 6:41:14 PM. For personal use only. Not approved for distribution. Copyright © 2011 National Comprehensive Cancer Network, Inc., All Rights Reserved.




                                                            NCCN Guidelines™ Version 3.2011                                                                                                                                   NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                            CLL/SLL                                                                                                                                                                       Discussion

                                                                                               SUGGESTED TREATMENT REGIMENS a
                                                                                                     (in order of preference)
                                                                                                  CLL without del (11q) or del (17p)
       Frail patient, significant co-morbidity                                  First-line therapy b                                                         Relapsed/Refractory therapy
        (not able to tolerate purine analogs)                                   · Age ³ 70 y or younger patients                                             · Long response > 3 y
       · Chlorambucil ± prednisone                                                with co-morbidities                                                          > Retreat as in first line therapy until short response
       · Rituximab (single)                                                       > Chlorambucil ± prednisone                                                · Short response < 2 y for age ³ 70 y
       · Pulse corticosteroids                                                    > BR (bendamustine, rituximab) d                                             > Chemoimmunotherapy d
                                                                                  > Cyclophosphamide, prednisone                                                 7 Reduced-dose FCR e
                                                                                    ± rituximab                                                                  7 Reduced-dose PCR
                                                                                  > Alemtuzumab c                                                                7 Bendamustine d ± rituximab
                                                                                  > Rituximab                                                                    7 HDMP (high-dose methylprednisolone) + rituximab
                                                                                  > Fludarabine e ± rituximab                                                  > Chlorambucil ± prednisone (if used first-line)
      See Monoclonal Antibody                                                     > Cladribine                                                                 > Ofatumumab
      Directed at CD20 and Viral                                                                                                                               > Alemtuzumab ± rituximab
                                                                               · Age < 70 y or older patients without
      Reactivation (NHODG-D)                                                                                                                                   > Dose-dense rituximab (category 2B)
                                                                                 significant co-morbidities                                                  · Short response < 2 y for age < 70 y or older patients
       See Suggested Regimens for                                                > Chemoimmunotherapy d
                                                                                   7 FCR (fludarabine, e                                                       without significant co-morbidities
       CLL with del (17p) (2 of 5)                                                                                                                             > Chemoimmunotherapy d
                                                                                     cyclophosphamide, rituximab)                                                7 FCR e
       See Suggested Regimens for                                                  7 FR (fludarabine, e rituximab)
                                                                                                                                                                 7 PCR e
       CLL with del (11q) (3 of 5)                                                 7 PCR (pentostatin,
                                                                                                                                                                 7 BR
                                                                                     cyclophosphamide, rituximab)                                                7 Fludarabine e + alemtuzumab
                                                                                   7 BR                                                                          7 CHOP (cyclophosphamide, doxorubicin, vincristine,
                                                                                                                                                                   prednisone) + rituximab
                                                                                                                                                                 7 HyperCVAD (cyclophosphamide, vincristine,
                                                                                                                                                                   doxorubicin, and dexamethasone alternating with
                                                                                                                                                                   high-dose methotrexate and cytarabine) + rituximab
                                                                                                                                                                 7 Dose-adjusted EPOCH (etoposide, prednisone,
   a See references for regimens CSLL-D 4 of 5 and CSLL-D 5 of 5.                                                                                                  vincristine, cyclophosphamide, doxorubicin) +
   b Antibioticprophylactic therapy for shingles and pneumocystis is recommended in purine                                                                         rituximab
     analog-based and/or alemtuzumab combination therapy.                                                                                                        7 OFAR (oxaliplatin, fludarabine, e cytarabine,
   c Less effective for bulky (> 5 cm) lymphadenopathy; monitor for CMV reactivation.
   d Monitor for myelosuppression.                                                                                                                                 rituximab)
   e Autoimmune hemolytic anemia (AIHA) should not preclude the use of combination therapy                                                                     > Ofatumumab
                                                                                                                                                               > Alemtuzumab ± rituximab
     containing fludarabine and patients should be observed carefully.
                                                                                                                                                               > HDMP + rituximab
      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                            CSLL-D
   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.           1 of 5
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                                                            NCCN Guidelines™ Version 3.2011                                                                                                                                   NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                            CLL/SLL                                                                                                                                                                       Discussion

                                                                                             SUGGESTED TREATMENT REGIMENS a
                                                                                                   (in order of preference)
                                                                                                                  CLL with del (17p)
         First-line therapy b                                                                                                       Relapsed/Refractory therapy
         · FCR (fludarabine, e cyclophosphamide, rituximab)                                                                         · CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) +
         · FR (fludarabine, e rituximab)                                                                                              rituximab
         · HDMP (high-dose methylprednisolone) + rituximab                                                                          · CFAR (cyclophosphamide, fludarabine, e alemtuzumab, rituximab)
         · Alemtuzumab c ± rituximab                                                                                                · HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and
         · Bendamustine d + rituximab                                                                                                 dexamethasone alternating with high-dose methotrexate and
                                                                                                                                      cytarabine) + rituximab
                                                                                                                                    · OFAR (oxaliplatin, fludarabine, e cytarabine, rituximab)
                                                                                                                                    · Ofatumumab f
                                                                                                                                    · Alemtuzumab ± rituximab
                                                                                                                                    · High-dose dexamethasone ± rituximab g
                                                                                                                                    · Bendamustine d ± rituximab g
     See Monoclonal Antibody Directed at
     CD20 and Viral Reactivation (NHODG-D)
     See Suggested Regimens for CLL without
     del (11q) or del (17p) (1 of 5)

     See Suggested Regimens for CLL with del
     (11q) (3 of 5)




   a See   references for regimens CSLL-D 4 of 5 and CSLL-D 5 of 5.
   b Antibiotic prophylactic therapy for shingles and pneumocystis is recommended in purine analog-based and/or alemtuzumab combination therapy.
   c Less effective for bulky (> 5 cm) lymphadenopathy; monitor for CMV reactivation.
   d Monitor for myelosuppression.
   e Autoimmune hemolytic anemia (AIHA) should not preclude the use of combination therapy containing fludarabine and patients should be observed carefully.
   f This is not effective in patients with lymph nodes > 5 cm.
   g Rituximab should be added unless patient is known to be refractory to rituximab.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                            CSLL-D
   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.           2 of 5
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                                                            NCCN Guidelines™ Version 3.2011                                                                                                                                   NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                            CLL/SLL                                                                                                                                                                       Discussion

                                                                                              SUGGESTED TREATMENT REGIMENS a
                                                                                                   (in order of preference)
                                                                                                    CLL with del (11q)
           First-line therapy b                                                                                   Relapsed/Refractory therapy
           · Age ³ 70 y or younger patients with co-morbidities                       · Long response > 3 y
             > Chlorambucil ± prednisone                                                > Retreat as in first line therapy until short response
             > BR (bendamustine, rituximab) d                                         · Short response < 2 y for age ³ 70 y
             > Cyclophosphamide, prednisone ± rituximab                                 > Chemoimmunotherapy d
             > Reduced-dose FCR (fludarabine, e cyclophosphamide,                         7 Reduced-dose FCR e
               rituximab)                                                                 7 Reduced-dose PCR
             > Alemtuzumab c                                                              7 Bendamustine ± rituximab
             > Rituximab                                                                  7 HDMP (high-dose methylprednisolone) + rituximab
           · Age < 70 y or older patients without significant co-morbidities              7 Chlorambucil ± prednisone (if used first line)
             > Chemoimmunotherapy d                                                     > Ofatumumab
               7 FCR                                                                    > Alemtuzumab ± rituximab
               7 BR                                                                     > Dose-dense rituximab (category 2B)
               7 PCR (pentostatin, cyclophosphamide, rituximab)                       · Short response < 2 y for age < 70 y or older patients
                                                                                        without significant co-morbidities
                                                                                        > Chemoimmunotherapy d
                                                                                          7 FCR e
       See Monoclonal Antibody Directed at CD20 and
                                                                                          7 PCR e
       Viral Reactivation (NHODG-D)
                                                                                          7 BR
       See Suggested Regimens for CLL without del (11q)                                   7 Fludarabine e + alemtuzumab
       or del (17p) (1 of 5)                                                              7 CHOP (cyclophosphamide, doxorubicin, vincristine,
                                                                                            prednisone) + rituximab
       See Suggested Regimens for CLL with del (17p) (2 of 5)                             7 HyperCVAD (cyclophosphamide, vincristine,
                                                                                            doxorubicin, and dexamethasone alternating with
                                                                                            high-dose methotrexate and cytarabine) + rituximab
                                                                                          7 Dose-adjusted EPOCH (etoposide, prednisone,
   a See references for regimens CSLL-D 4 of 5 and CSLL-D 5 of 5.
   b Antibiotic prophylactic therapy for shingles and pneumocystis is recommended in        vincristine, cyclophosphamide, doxorubicin) +
     purine analog-based and/or alemtuzumab combination therapy.                            rituximab
   c Less effective for bulky (> 5 cm) lymphadenopathy; monitor for CMV reactivation.     7 OFAR (oxaliplatin, fludarabine, e cytarabine, rituximab)
   d Monitor for myelosuppression.                                                      > Ofatumumab
   e Autoimmune hemolytic anemia (AIHA) should not preclude the use of combination      > Alemtuzumab ± rituximab
     therapy containing fludarabine and patients should be observed carefully.          > HDMP + rituximab

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                            CSLL-D
   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.           3 of 5
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                                                            NCCN Guidelines™ Version 3.2011                                                                                                                                   NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                            CLL/SLL                                                                                                                                                                       Discussion

                                                                                             SUGGESTED TREATMENT REGIMENS
                                                                                                      REFERENCES
    Alemtuzumab                                                                                                                             Chlorambucil + prednisone
    Lozanski G, Heerema NA, Flinn IW, et al. Alemtuzumab is an effective therapy                                                            Raphael B, Andersen J, Silber R, et al. Comparison of chlorambucil and
    for chronic lymphocytic leukemia with p53 mutations and deletions. Blood                                                                prednisone versus cyclophosphamide, vincristine, and prednisone as initial
    2004;103:3278-3281.                                                                                                                     treatment for chronic lymphocytic leukemia: Long-term follow-up of an Eastern
    Keating MJ, Flinn I, Jain V, et al. Therapeutic role of alemtuzumab (Campath-                                                           Cooperative Oncology Group randomized clinical trial. J Clin Oncol 1991;9:770-
    1H) in patients who have failed fludarabine: Results of a large international                                                           776.
    study. Blood 2002;99:3554-3561.                                                                                                         Cyclophosphamide, Fludarabine, Alemtuzumab, and Rituximab (CFAR)
    Hillmen P, Skotnicki AB, Robak T, et al. Alemtuzumab compared with                                                                      Wierda WG, O'Brien S, Ferrajoli A, et al. Combined cyclophosphamide,
    chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol                                                       fludarabine, alemtuzumab, and rituximab (CFAR), an active frontline regimen
    2007;25:5616-5623.                                                                                                                      for high-risk patients with CLL. Blood (ASH Annual Meeting Abstracts),
    Alemtuzumab + rituximab                                                                                                                 2007;110:Abstract 628.
    Faderl S, Thomas DA, O'Brien S, et al. Experience with alemtuzumab plus                                                                 CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)
    rituximab in patients with relapsed and refractory lymphoid malignancies. Blood                                                         Leporrier M, Chevret S, Cazin B, et al. Randomized comparison of fludarabine,
    2003;101:3413-3415.                                                                                                                     CAP, and CHOP in 938 previously untreated stage B and C chronic lymphocytic
    Bendamustine                                                                                                                            leukemia patients. Blood 2001;98:2319-2325.
    Fischer K, Stilgenbauer S, Schweighofer CD, et al. Bendamustine in                                                                      FCR (fludarabine, cyclophosphamide, rituximab)
    combination with rituximab (BR) for patients with relapsed chronic                                                                      Keating MJ, O'Brien S, Albitar M, et al. Early results of a chemoimmunotherapy
    lymphocyticleukemia (CLL): A multicentre phase II trial of the German CLL                                                               regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for
    Study Group (GCLLSG). ASH Annual Meeting Abstracts. 2008;112:330.                                                                       chronic lymphocytic leukemia. J Clin Oncol 2005;23:4079-4088.
    Bendamustine + rituximab                                                                                                                Wierda W, O'Brien S, Wen S, et al. Chemoimmunotherapy with fludarabine,
    Fischer K, Cramer P, Stilgenbauer S et al. Bendamustine combined with                                                                   cyclophosphamide, and rituximab for relapsed and refractory chronic
    rituximab (BR) in first-line therapy of advanced CLL: A multicenter phase II trial                                                      lymphocytic leukemia. J Clin Oncol 2005;23:4070-4078.
    of the German CLL Study Group (GCLLSG). Blood (ASH Annual Meeting                                                                       Tam CS, O'Brien S, Wierda W, et al. Long-term results of the fludarabine,
    Abstracts), 2009;114: Abstract 205.                                                                                                     cyclophosphamide, and rituximab regimen as initial therapy of chronic
    Chlorambucil                                                                                                                            lymphocytic leukemia. Blood 2008;112:975-980.
    Eichhorst BF, Busch R, Stilgenbauer S, et al. First-line therapy with fludarabine                                                       Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to
    compared with chlorambucil does not result in a major benefit for elderly                                                               fludarabine and cyclophosphamide in patients with chronic lymphocytic
    patients with advanced chronic lymphocytic leukemia. Blood 2009;114:3382-                                                               leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010;376:1164-
    3391.                                                                                                                                   1174.
    Rai KR, Peterson BL, Appelbaum FR, et al. Fludarabine compared with                                                                     Robak T, Dmoszynska A, Solal-Celigny P, et al. Rituximab plus fludarabine and
    chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J                                                              cyclophosphamide prolongs progression-free survival compared with
    Med 2000; 343:1750-1757.                                                                                                                fludarabine and cyclophosphamide alone in previously treated chronic
                                                                                                                                            lymphocytic leukemia. J Clin Oncol 2010;28:1756-1765.


                                                                                                                                                                                                                     Continued on next page
      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                            CSLL-D
   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.           4 of 5
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                                                            NCCN Guidelines™ Version 3.2011                                                                                                                                   NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                            CLL/SLL                                                                                                                                                                       Discussion

                                                                                             SUGGESTED TREATMENT REGIMENS
                                                                                                      REFERENCES
   Fludarabine + alemtuzumab
   Elter T, Borchmann P, Schulz H, et al. Fludarabine in combination with alemtuzumab is effective and feasible in patients with relapsed or refractory B-cell chronic
   lymphocytic leukemia: Results of a Phase II trial. J Clin Oncol 2005;23:7024-7031.
   Fludarabine + rituximab
   Byrd JC, Peterson BL, Morrison VA, et al. Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic,
   untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood 2003;101:6-14.
   HDMP (high-dose methylprenisolone) + rituximab
   Bowen DA, Call TG, Jenkins GD, et al. Methylprednisolone-rituximab is an effective salvage therapy for patients with relapsed chronic lymphocytic leukemia including
   those with unfavorable cytogenetic features. Leukemia and Lymphoma 2007;48:2412-2417.
   Castro JE, James DF, Sandoval-Sus JD, et al. Rituximab in combination with high-dose methylprednisolone for the treatment of chronic lymphocytic leukemia. Leukemia
   2009;23:1779-1789.
   Ofatumumab
   Wierda WG, Kipps TJ, Mayer J, et al. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol
   2010;28:1749-1755.
   Coiffier B, Lepretre S, Pedersen LM, et al. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell
   chronic lymphocytic leukemia: a phase 1-2 study. Blood 2008;111:1094-1100.
   OFAR (oxaliplatin, fludarabine, cytarabine, rituximab)
   Tsimberidou AM, Wierda WG, Plunkett W, et al. Phase I-II study of oxaliplatin, fludarabine, cytarabine, and rituximab combination therapy in patients with Richter's
   Syndrome or fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol 2008;26:196-203.
   Tsimberidou AM, Wierda WG, Badoux X, et al. Evaluation of oxaliplatin, fludarabine, cytarabine, and rituximab (OFAR) combination therapy in aggressive chronic
   lymphocytic leukemia (CLL) and Richter's syndrome (RS). J Clin Oncol 2010;28: Abstract 6521.
   PCR (pentostatin, cyclophosphamide, rituximab)
   Lamanna N, Kalaycio M, Maslak P, et al. Pentostatin, cyclophosphamide, and rituximab is an active, well-tolerated regimen for patients with previously treated chronic
   lymphocytic leukemia. J Clin Oncol 2006;24(10):1575-1581.
   Kay NE, Geyer SM, Call TG, et al. Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low
   accompanying toxicity in previously untreated B chronic lymphocytic leukemia. Blood 2007;109:405-411.




      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                            CSLL-D
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                                                            NCCN Guidelines™ Version 3.2011                                                                                                                                   NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                            CLL/SLL                                                                                                                                                                       Discussion

                                                                             RESPONSE DEFINITION AFTER TREATMENT FOR CLL a

      Parameter                                   Complete response                               Partial response                                        Progressive Disease                                     Stable Disease


                                                  None above                                                                                                                                                      Change from
      Lymphadenopathy b                                                                           Decrease ³ 50%                                          Increase ³ 50%
                                                  1.0 cm                                                                                                                                                          -49% to +49%

      Liver and/or                                                                                                                                                                                                Change from
                                                  Normal size                                     Decrease ³ 50%                                          Increase ³ 50%
      spleen size                                                                                                                                                                                                 -49% to +49%

      Constitutional
                                                  None                                            Any                                                     Any                                                     Any
      symptoms

                                                                                                  > 1500/mm 3 or
      Leukocytes                                  > 1500/mm 3                                                                                             Any                                                     Any
                                                                                                  > 50% improvement

      Circulating B                                                                               Decrease ³ 50%                                                                                                  Change from
                                                  Normal                                                                                                  Increase ³ 50%
      lymphocytes                                                                                 over baseline                                                                                                   -49% to +49%

                                                                                                  > 100,000/mm 3 or increase                              Decrease ³ 50%                                          Change from
      Platelet count                              > 100,000/mm 3
                                                                                                  ³ 50% over baseline                                     over baseline                                           -49% to +49%

                                                                                                                                                                                                                  Increase < 11.0 g/dL or
                                                  > 11.0 g/dL                                     > 2 g/dL from                                           Decrease of > 2 g/dL
      Hemoglobin                                                                                                                                                                                                  < 50% over baseline,
                                                  (untransfused)                                  baseline                                                from baseline
                                                                                                                                                                                                                  or decrease < 2 g/dL
                                                  Normocellular, < 30%                            Hypocellular, or ³ 30%
                                                                                                                                                          Increase of lymphcytes to                               No change of marrow
      Marrow                                      lymphocytes, no B-                              lymphocytes, or B-lymphoid
                                                                                                                                                          more than 30% from normal                               infiltrate
                                                  lymphoid nodules                                nodules, or not done
   a EichhorstB and Hallek M. Revision of the guidelines for diagnosis and therapy of chronic lymphocytic leukemia (CLL). Best Practice & Research Clinical Haematology.
     2007;20:469-477.
   b Sum of the products of multiple lymph nodes (as evaluated by CT scans in clinical trials, or by physical exam or ultrasound in general practice).

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

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                                                            NCCN Guidelines™ Version 3.2011                                                                                                                                   NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                            Follicular Lymphoma a (grade 1-2)                                                                                                                                             Discussion
   DIAGNOSIS b                                                                 WORKUP
   ESSENTIAL:                                                                   ESSENTIAL:
   · Hematopathology review of all slides with at least one                     · Physical exam: attention to node-bearing areas,
     paraffin block representative of the tumor. Rebiopsy if                      including Waldeyer’s ring, and to size of liver and spleen
     consult material is nondiagnostic.                                         · Performance status
   · An FNA or core needle biopsy alone is not generally                        · B symptoms
     suitable for the initial diagnosis of lymphoma. In certain                 · CBC, differential, platelets                               Stage                                                                                        See Initial
     circumstances, when a lymph node is not easily accessible                  · LDH                                                                                                                                                     Therapy
                                                                                                                                             I, II
     for excisional or incisional biopsy, a combination of core                 · Comprehensive metabolic panel                                                                                                                           (FOLL-2)
     biopsy and FNA biopsies in conjunction with appropriate                    · Chest/abdominal/pelvic CT with contrast of diagnostic
     ancillary techniques for the differential diagnosis                          quality
     (immunohistochemistry, flow cytometry, PCR for IgH and                     · Hepatitis B testing g
     TCR gene rearrangements, and FISH for major
                                                                                · Bone marrow biopsy + aspirate to document clinical
     translocations) may be sufficient for diagnosis. Histologic                  stage I-II disease h
     grading cannot be performed on an FNA.
                                                                                · Pregnancy testing in women of child-bearing age (if
   · Adequate immunophenotyping to establish diagnosis c,d                        chemotherapy planned)
     > Recommended panel for paraffin section                                   USEFUL IN SELECTED CASES:                                     Stage                                                                                        See Initial
       immunohistochemistry: CD20, CD3, CD5, CD10, BCL2, e                      · MUGA scan/echocardiogram if anthracycline or                IIX, III,                                                                                    Therapy
       BCL6, cyclin D1, CD21 or CD23, or                                          anthracenediones- based regimen is indicated                IV                                                                                           (FOLL-2)
     > Cell surface marker analysis by flow cytometry:                          · Neck CT
       kappa/lambda, CD19, CD20, CD5, CD23, CD10
                                                                                · Beta-2-microglobulin
   USEFUL UNDER CERTAIN CIRCUMSTANCES:
                                                                                · PET-CT scan
   · Molecular genetic analysis to detect: antigen gene receptor
     rearrangements; BCL2 rearrangement                                         · Uric acid
   · Cytogenetics or FISH: t(14;18); t(8;14) or variants                        · Discussion of fertility issues and sperm banking
   · Paraffin section immunohistochemistry: Ki67 f                              · SPEP and/or quantitative immunoglobulin levels
   a Follicular lymphoma, grade 1-2. Follicular lymphoma, grade 3 is an area of · Hepatitis C testing
     controversy. The distinction between follicular grade 3a and 3b has not been shown                                                   f There are reports showing Ki67 proliferation fraction of > 30 % may be
     to have clinical significance to date. Follicular lymphoma, grade 3 is commonly                                                        associated with a more aggressive clinical behavior but no evidence this
     treated according to the NCCN Diffuse Large B-Cell Lymphoma Guideline (BCEL-1).                                                        should guide treatment decisions.
     Any area of diffuse large B-cell lymphoma (DLBCL) in a follicular lymphoma of any                                                    g Hepatitis B testing is indicated because of the risk of reactivation with
     grade should be diagnosed and treated as a DLBCL.                                                                                      immunotherapy + chemotherapy. Tests include hepatitis B surface antigen and
   b Germinal center or follicular center cell phenotype type is not equivalent to follicular
                                                                                                                                            core antibody for a patient with no risk factors. For patients with risk factors or
     lymphoma and occurs in Burkitt lymphoma and some DLBCL.                                                                                previous history of hepatitis B, add e-antigen. If positive, check viral load and
   c Typical immunophenotype: CD10+, BCL2+, CD23+/-, CD43-, CD5-, CD20+,                                                                    consult with gastroenterologist.
     cyclin D1-, BCL6+. Rare cases of follicular lymphoma may be CD10- or BCL2-.                                                          h Bilateral or unilateral provided core biopsy is > 2 cm. If radioimmunotherapy is
   d See Use of Immunophenotyping and Genetic Testing in Differential Diagnosis of                                                          considered, bilateral cores are recommended and the pathologist should
     Mature B-cell and T/NK-cell Neoplasms (NHODG-A).                                                                                       provide the percent of overall cellular elements and the percent of cellular
   e In BCL2 negative young patients with localized disease, consider entity of pediatric                                                   elements involved in the marrow. If observation is initial therapy, bone marrow
     follicular lymphoma.                                                                                                                   biopsy may be deferred.
      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.           FOLL-1
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                                                            NCCN Guidelines™ Version 3.2011                                                                                                                                   NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                            Follicular Lymphoma (grade 1-2)                                                                                                                                               Discussion
   STAGE                                    INITIAL THERAPY i
                                                                                                                  Complete                            Clinical follow-up                                Progressive
                                            IFRT j (preferred for clinical
                                                                                                                  response o                          every 3-6 mo for 5 y                              disease o,r
                                            stage I or contiguous stage II)
                                            or                                                                    or partial                          and then yearly or as                             (For transformation
                                            Immunotherapy ±                                                       response o                          clinically indicated p,q                          See FOLL-4)
   Stage I, II                              chemotherapy (See FOLL-B) ±
                                            RT (category 2B for                                                   No response
                                            chemotherapy + RT) k
                                            or
                                            Observation (selected cases) l


                                            Indications for treatment: m                                                                                                     Clinical follow-up every                                Progressive
                                            · Candidate for clinical trial n                                      No                                                         3-6 mo for 5 y and then                                 disease o,r
                                                                                                                                               Observe
                                            · Symptoms                                                            indication                                                 yearly or as clinically                                 (For transformation
                                            · Threatened end-organ                                                                                                           indicated p,q                                           See FOLL-4)
   Stage IIX,                                 function                                                                                         See Suggested Regimens
   III, IV                                  · Cytopenia secondary to                                                                           (FOLL-B)
                                              lymphoma                                                                                         or
                                            · Bulky disease                                                       Indication                                                                                         See Initial
                                                                                                                                               Clinical trial n
                                            · Steady progression                                                  present
                                                                                                                                               or
                                                                                                                                                                                                                     Response (FOLL-3)
                                            · Patient preference                                                                               Local RT (palliation of locally
                                                                                                                                               symptomatic disease) j
   i When     determining initial treatment, consider excluding profoundly myelotoxic                                              o See  Response Criteria for Lymphoma (NHODG-C).
      regimens for patients who may be eligible for high dose therapy with                                                         p Follow-up  includes repeat diagnostic tests, including imaging (based on site of
      autologous stem cell rescue.                                                                                                   disease and clinical presentation) as clinically indicated.
   j See Principles of Radiation Therapy (NHODG-E).                                                                                q Consider clinical trials appropriate for patients on observation.
   k Initiation of chemotherapy or more extended RT can improve FFS (failure-free                                                  r Progressive disease should be histologically documented to rule out transformation
      survival), but has not been shown to improve overall survival. These are                                                       (preferentially, biopsy or marked increase in FDG uptake on PET), especially if LDH
      options for therapy.                                                                                                           levels are rising, single site is growing disproportionately, extranodal disease
   l Observation may be appropriate in circumstances where toxicity of involved-                                                     develops, new B symptoms develop, or there is marked heterogeneity or sites of
      field RT outweighs potential clinical benefit.                                                                                 intense FDG avidity on PET scan. A directed biopsy should be performed of a
   m See GELF criteria (FOLL-A).                                                                                                     suspicious area. If transformation is histologically confirmed, treat with
   n Given incurability with conventional therapy, consider investigational therapy as                                               anthracycline-based therapy. Positive functional imaging does not replace biopsy to
      first-line of treatment.                                                                                                       diagnose transformation. See Management of Transformation (FOLL-4).

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

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                                                            NCCN Guidelines™ Version 3.2011                                                                                                                                   NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                            Follicular Lymphoma (grade 1-2)                                                                                                                                               Discussion

   INITIAL RESPONSE                                                                                                                                                                                                                  ADDITIONAL
                                                                                                                                                                                                                                     THERAPY




                                                                             Clinical follow-
                                Consolidation or                                                                   Progressive
    Complete                                                                 up every 3-6 mo                                                          Indications for
                                extended therapy                                                                   disease o,r
    response o                                                               for 5 y and then                                                         treatment: m                                      No
                                (See FOLL-B)                                                                       (For                                                                                                              Observe
    or partial
                                or
                                                                             yearly or as
                                                                                                                   transformation                     · Candidate for clinical                          indication
    response o                                                               clinically                                                                 trial
                                Observe                                                                            see FOLL-4)
                                                                             indicated p                                                              · Symptoms
                                                                                                                                                      · Threatened end-organ
                                                                                                                                                        function                                                                     See Suggested
                                                                                                                                                      · Cytopenia secondary                                                          Regimens (FOLL-B)
                                                                                                                                                        to lymphoma                                                                  or
    No response or                                                                                                                                    · Bulky disease                                   Indication                   Clinical trial s
    progressive disease o,r                                                                                                                           · Steady progression                              present                      or
    (For transformation                                                                                                                               · Patient preference                                                           Local RT
    see FOLL-4)                                                                                                                                                                                                                      (palliation of locally
                                                                                                                                                                                                                                     symptomatic
                                                                                                                                                                                                                                     disease) j




   j See  Principles of Radiation Therapy (NHODG-E).
   m See   GELF criteria (FOLL-A).
   o See Response Criteria for Lymphoma (NHODG-C).
   p Follow-up includes repeat diagnostic tests, including imaging (based on site of disease and clinical presentation) as clinically indicated (about every 6 mo).
   r Progressive disease should be histologically documented to rule out transformation (preferentially, biopsy or marked increase in FDG uptake on PET), especially if LDH
     levels are rising, single site is growing disproportionately, extranodal disease develops, new B symptoms develop, or there is marked heterogeneity or sites of intense
     FDG avidity on PET scan. A directed biopsy should be performed of a suspicious area. If transformation is histologically confirmed, treat with anthracycline-based
     therapy. Positive functional imaging does not replace biopsy to diagnose transformation. See Management of Transformation (FOLL-4).
   s Clinical trials may involve novel agents, regimens, or transplantation.


      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.                FOLL-3
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                                                            NCCN Guidelines™ Version 3.2011                                                                                                                                   NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                            Follicular Lymphoma (grade 1-2)                                                                                                                                               Discussion
   HISTOLOGICAL TRANSFORMATION TO DIFFUSE LARGE B-CELL LYMPHOMA
                                             Clinical trial
                                             or
                                             Radioimmunotherapy
                                             or
                                             Chemotherapy (See BCEL-C)                                                                                                                                       Consider high-dose therapy
                   Multiple prior            ± rituximab                                                                                                              Responsive                             with autologous stem cell
                   therapies                 or                                                                                                                       disease                                rescue or allogeneic stem
                                             IFRT
                                                                                                                                                                                                             cell transplant v
                                             or
                                             Best Supportive Care
                                             (See NCCN Palliative Care                                                                                                                                       Observation
   Histological                              Guidelines)                                                                                                                                                     or
   transformation                                                                                                                                                                                            Clinical trial
   to diffuse                                                                                                                                                         Complete
                                                                                                                                                                                                             or
   large B-cell                                                                                                                                                       response o                             Consider high-dose therapy with
   lymphoma                                                                                                                                                                                                  autologous stem cell rescue or
                                                                                                                                                                                                             allogeneic stem cell transplant v

                                                                                                     Chemotherapy                                                                                            Consider high-dose therapy with
                                                                                                     (anthracycline-based                                                                                    autologous stem cell rescue or
                                         Minimal t or no prior                                       chemotherapy preferred                                           Partial                                allogeneic stem cell transplant v
                                         chemotherapy                                                unless contraindicated)                                          response o                             or
                                                                                                     (See BCEL-C) + rituximab                                                                                Clinical trial
                                                                                                                                                                                                             or
                                                                                                     ± RT u
                                                                                                                                                                                                             Consider radioimmunotherapy

                                                                                                                                                                                                             Clinical trial
                                                                                                                                                                                                             or
                                                                                                                                                                      No response
                                                                                                                                                                                                             Radioimmunotherapy
                                                                                                                                                                      or progressive
                                                                                                                                                                                                             or
                                                                                                                                                                      disease o                              Palliative or best supportive
   o See   Response Criteria for Lymphoma (NHODG-C).                                                                                                                                                         care
   t Involved-fieldRT alone or one course of single agent therapy including rituximab.
   u If locoregional transformation, consider adding RT.
   v Strongly recommend this treatment be given in the context of a clinical trial; nonmyeloblative approaches may also be considered.


      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          FOLL-4
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                                                            NCCN Guidelines™ Version 3.2011                                                                                                                                   NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                            Follicular Lymphoma (grade 1-2)                                                                                                                                               Discussion

                                                      GELF CRITERIA a,b                                                                                                               Nodal Areas

          · Involvement of ³ 3 nodal sites, each with a diameter of ³ 3 cm                                                                           Right Cervical                                                       Left Cervical
          · Any nodal or extranodal tumor mass with a diameter of ³ 7 cm                                                                                  Preauricular                                                     Preauricular
          · B symptoms                                                                                                                                 Upper Cervical
                                                                                                                                                      Median or Lower
                                                                                                                                                                                                                           Upper Cervical
                                                                                                                                                                                                                           Median or Lower
          · Splenomegaly                                                                                                                                  Postcervical                                                     Postcervical
                                                                                                                                                       Supraclavicular                                                     Supraclavicular
          · Pleural effusions or peritoneal ascites
                                                                                                                                                         Mediastinal
          · Cytopenias (leukocytes < 1.0 x 10 9/L and/or platelets < 100 x 10 9/L)                                                                        Paratracheal
          · Leukemia (> 5.0 x 10 9/L malignant cells)                                                                                                      Mediastinal
                                                                                                                                                                  Hilar
                                                                                                                                                       Right Axillary                                                     Left Axillary

                                                                                                                                                Right Epitrochlear                                                        Left Epitrochlear
                                                 FLIPI - 1 CRITERIA a,c
                                                                                                                                                         Para-Aortic                                                      Mesenteric
                   Age                                            ³ 60 y                                                                                   Para-Aortic                                                    Mesenteric
                                                                                                                                                         Common Iliac                                                     Splenic Hilar
                   Ann Arbor stage                                III-IV                                                                                  External Iliac                                                  Portal
                   Hemoglobin level                               < 12 g/dL                                                                                                                                               Celiac
                   Serum LDH level                                > ULN (upper limit of normal)                                                       Right Inguinal                                                      Left Inguinal
                   Number of nodal sites d                        ³5                                                                                            Inguinal                                                  Inguinal
                                                                                                                                                                Femoral                                                   Femoral


                                  Risk group according to FLIPI chart                                                                                Right Popliteal                                                      Left Popliteal

                                                                  Number of factors                                                                                                                                            Legend for labels
                                                                                                                                                                                                                               Blue = Bilateral
                                  Low                             0-1                                                                                                                                                          Black = Midline
                                  Intermediate                    2
                                  High                            ³3
                                                                                                                                                      Mannequin used for counting the number of involved areas. d
                                                                                                                                         © 2007 Dana-Farber Cancer Institute Inc.
                                                                                                                                         All rights reserved. Permission is hereby granted for copying this image by photocopy or similar
                                                                                                                                         process for use in the practice of medicine or for research purposes. No other use is permitted which
                                                                                                                                         will infringe the copyright without the express written consent of Dana-Farber Cancer Institute, Inc.
   a This provides useful prognostic information which may be used to guide therapeutic decisions.
   b Solal-Celigny P, Lepage E, Brousse N, et al. Doxorubicin containing regimen with or without interferon alfa 2b for advanced follicular lymphomas: final analysis of
     survival and toxicity in the Groupe d'Etude des Lymphomes Folliculaire 86 trial. J Clin Oncol 1998;16(7):2332-2338.
   c This research was originally published in Blood. Solal-Celigny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. Blood 2004;104:1258-
     1265. (c) the American Society of Hematology.
   d The map is used to determine number of nodal sites in FLIPI-1 criteria and is different than the conventional Ann Arbor site map.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.                 FOLL-A
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                                                            NCCN Guidelines™ Version 3.2011                                                                                                                                   NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                            Follicular Lymphoma (grade 1-2)                                                                                                                                               Discussion

                                                                                             SUGGESTED TREATMENT REGIMENS a,b
                                                                                                    (in alphabetical order)
       First-line Therapy c,d                                                                                                      First-line Consolidation or Extended Dosing
       · Bendamustine + rituximab (category 1)                                                                                     · Chemotherapy followed by radioimmunotherapy e,f,g (category 1)
       · RCHOP (rituximab, cyclophosphamide, doxorubicin,                                                                          · Rituximab maintenance h up to 2 y (category 1)
         vincristine, prednisone) (category 1)                                                                                     Second-line and Subsequent Therapy
       · RCVP (rituximab, cyclophosphamide, vincristine, prednisone)                                                               · Chemoimmunotherapy (as in first-line therapy)
         (category 1)                                                                                                              · FCMR (fludarabine, cyclophosphamide, mitoxantrone, rituximab)
       · Fludarabine + rituximab                                                                                                     (category 1)
       · RFND (rituximab, fludarabine, mitoxantrone, dexamethasone)                                                                · Radioimmunotherapy e,f (category 1)
       · Radioimmunotherapy e,f (category 2B)                                                                                      · See Second-line Therapy for DLBCL (BCEL-C 1 of 3) i
       · Rituximab
                                                                                                                                   Second-line Consolidation or Extended Dosing
       First-line Therapy for Elderly or Infirm (if none of the above are                                                          · High dose therapy with autologous stem cell rescue j
       tolerable)                                                                                                                  · Allogeneic stem cell transplant for highly selected
       · Radioimmunotherapy                                                                                                          patients k
       · Rituximab, preferred                                                                                                      · Rituximab maintenance h (category 1)
       · Single agent alkylators ± rituximab (eg, chlorambucil or
         cyclophosphamide)
       For patients with locally bulky or symptomatic disease, consider IFRT 4-30 Gy ± additional systemic therapy.
                                                                                                        See Monoclonal Antibody Directed at CD20 and Viral Reactivation (NHODG-D)
   a See   references for regimens FOLL-B 2 of 3 and FOLL-B 3 of 3.                                                                  f Ifradioimmunotherapy is considered, bilateral cores are recommended and the
   b The   choice of initial therapy requires consideration of many factors, including age,                                             pathologist should provide the percent of overall cellular elements and the percent
      comorbidities, and future treatment possibilities (eg, HDT with SCR). Therefore,                                                  of cellular elements involved in the marrow. Cytogenetics ± FISH for known MDS
      treatment selection is highly individualized.                                                                                     markers. Updates as of 2010 suggest a trend towards an increased risk of MDS
   c In combination chemotherapy, addition of rituximab has consistently increased                                                      with RIT treatment.
                                                                                                                                     g The full impact of an induction regimen containing rituximab on RIT consolidation is
      overall response rate, response duration, and progression-free survival. In
      addition some studies have demonstrated an overall survival benefit.                                                              unknown.
   d Initial management of patients with follicular lymphoma should include rituximab;                                               h In patients previously treated with chemotherapy, rituximab and anthracycline
      use caution in patients with hepatitis B.                                                                                         naive, maintenance rituximab extends disease-free, and event-free survival.
   e Selection of patients requires adequate marrow cellularity > 15% and < 25%                                                      i These agents can be administered without restriction for transplantability.
      involvement of lymphoma in bone marrow, and platelets > 100,000. In patients                                                   j High dose therapy with autologous stem cell rescue is an appropriate consolidative
      with prior autologous stem cell rescue, referral to a tertiary care center is highly                                              therapy to patients in second or third remission.
      recommended for radioimmunotherapy.                                                                                            k In highly selected patients, trials of fully ablative and nonmyeloablative allogeneic
                                                                                                                                        stem cell transplant have shown long term survival advantage, although there is a
                                                                                                                                        2-year treatment-related mortality rate of approximately 25% for non-myeloablative
                                                                                                                                        and 40% for fully ablative.
      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                            FOLL-B
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                                                            NCCN Guidelines™ Version 3.2011                                                                                                                                   NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                            Follicular Lymphoma (grade 1-2)                                                                                                                                               Discussion
                                                                                                SUGGESTED TREATMENT REGIMENS
                                                                                                          References
      First-line therapy                                                                                                                     Rituximab
      Bendamustine + rituximab:                                                                                                              Hainsworth JD, Litchy S, Burris HA, III, et al. Rituximab as first-line and
      Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab is                                                             maintenance therapy for patients with indolent Non-Hodgkin's lymphoma. J Clin
      superior in respect of progressionfree survival and CR rate when compared to                                                           Oncol 2002;20:4261-4267.
      CHOP plus rituximab as first-line treatment of patients with advanced follicular,                                                      Colombat P, Salles G, Brousse N, et al. Rituximab (anti-CD20 monoclonal
      indolent, and mantle cell lymphomas: Final results of a randomized phase III                                                           antibody) as single first-line therapy for patients with follicular lymphoma with a
      study of the StiL (Study Group Indolent Lymphomas, Germany). Blood (Blood)                                                             low tumor burden: clinical and molecular evaluation. Blood 2001;97:101-106.
      2009;114:405.                                                                                                                          Radioimmunotherapy
      Cyclophosphamide                                                                                                                       Kaminski MS, Tuck M, Estes J, et al. 131I-tositumomab therapy as initial
      Peterson BA, Petroni GR, Frizzera G, et al. Prolonged single-agent versus                                                              treatment for follicular lymphoma. N Engl J Med 2005;352:441-449.
      combination chemotherapy in indolent follicular lymphomas: a study of the                                                              Kaminski MS, Tuck M, Estes J, et al. Tositumomab and Iodine I-131
      cancer and leukemia group B. J Clin Oncol 2003;21:5-15.                                                                                Tositumomab for Previously Untreated, Advanced-Stage, Follicular Lymphoma:
      CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) +                                                                        Median 10 Year Follow-up Results. Blood 2009;114:3759.
      rituximab
      Czuczman MS, Weaver R, Alkuzweny B, et al. Prolonged clinical and molecular                                                            First-line Consolidation or Extended Dosing
      remission in patients with low-grade or follicular non-Hodgkin's lymphoma                                                              Chemotherapy followed by radioimmunotherapy
      treated with rituximab plus CHOP chemotherapy: 9-year follow-up. J Clin Oncol                                                          Press OW, Unger JM, Braziel RM, et al. Phase II trial of CHOP chemotherapy
      2004;22:4711-4716.                                                                                                                     followed by tositumomab/iodine I-131 tositumomab for previously untreated
      Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab                                                              follicular non-Hodgkin's lymphoma: five-year follow-up of Southwest Oncology
      added to the combination of cyclophosphamide, doxorubicin, vincristine, and                                                            Group Protocol S9911. J Clin Oncol 2006;24:4143-4149.
      prednisone (CHOP) significantly improves the outcome for patients with                                                                 Morschhauser F, Radford J, Van Hoof A, et al. Phase III trial of consolidation
      advanced-stage follicular lymphoma compared with therapy with CHOP alone:                                                              therapy with Yttrium-90–Ibritumomab Tiuxetan compared with no additional
      results of a prospective randomized study of the German Low-Grade                                                                      therapy after first remission in advanced follicular lymphoma. J Clin Oncol
      Lymphoma Study Group. Blood 2005;106:3725-3732.                                                                                        2008; 26:5156-5164.
      CVP (cyclophosphamide, vincristine, prednisone) + rituximab                                                                            Hagenbeek A, Radford J, Van Hoof A, et al. 90Y-Ibritumomab tiuxetan
      Marcus R, Imrie K, Solal-Celigny P, et al. Phase III study of R-CVP compared                                                           (Zevalin®) consolidation of first remission in advanced-stage follicular non-
      with cyclophosphamide, vincristine, and prednisone alone in patients with                                                              hodgkin's lymphoma: Updated results after a median follow-up of 66.2 months
      previously untreated advanced follicular lymphoma. J Clin Oncol 2008;26:4579-                                                          from the international, randomized, phase III First-Line Indolent Trial (FIT) in
      4586.                                                                                                                                  414 Patients. Blood (ASH Annual Meeting Abstracts). 2010;116:594-.
      Fludarabine + rituximab                                                                                                                Chemotherapy followed by rituximab
      Czuczman MS, Koryzna A, Mohr A, et al. Rituximab in combination with                                                                   Salles GA, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in
      fludarabine chemotherapy in low-grade of follicular lymphoma. J Clin Oncol                                                             patients with high tumour burden follicular lymphoma responding to rituximab
      2005;23:694-704.                                                                                                                       plus chemotherapy (PRIMA): A phase 3, randomised controlled trial. The
      FND (fludarabine, mitoxantrone, dexamethasone) + rituximab                                                                             Lancet 2011;377:42-51.
      McLaughlin P, Hagemeister FB, Rodriguez MA, et al. Safety of fludarabine,
      mitoxantrone, and dexamethasone combined with rituximab in the treatment of                                                                                                                                 Continued on next page
      stage IV indolent lymphoma. Semin Oncol 2000;27:37-41.
      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                            FOLL-B
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                                                            NCCN Guidelines™ Version 3.2011                                                                                                                                   NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                            Follicular Lymphoma (grade 1-2)                                                                                                                                               Discussion

                                                                                               SUGGESTED TREATMENT REGIMENS
                                                                                                         References
      Second-line therapy
      Bendamustine
      Robinson KS, Williams ME, van der Jagt RH, et al. Phase II multicenter study of bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle
      cell non-Hodgkin’s lymphoma. J Clin Oncol 2008; 26:4473-4479.
      Friedberg JW, Cohen P, Chen L, et al. Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin's lymphoma: results from a phase
      II multicenter, single-agent study. J Clin Oncol 2008;26(2):204-210.
      Kahl BS, Bartlett NL, Leonard JP, et al. Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma. Cancer
      2010;116:106-114.
      FCMR (fludarabine, cyclophosphamide, mitoxantrone, rituximab)
      Forstpointner R, Dreyling M, Repp R, et al. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly
      increases the response rate and prolongs survival as compared to FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas - results
      of a prospective randomized study of the German low grade lymphoma study group (GLSG). Blood 2004;104:3064-3071.
      Radioimmunotherapy
      Witzig TE, Flinn IW, Gordon LI, et al. Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin's
      lymphoma. J Clin Oncol 2002;20:3262-3269.
      Witzig TE, Gordon LI, Cabanillas F, et al. Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab
      immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol 2002;20:2453-2463.
      Kaminski MS, Zelenetz AD, Press OW, et al. Pivotal study of iodine I 131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non-
      Hodgkin's lymphomas. J Clin Oncol 2001;19:3918-3928.
      Fisher RI, Kaminski MS, Wahl RL, et al. Tositumomab and iodine-131 tositumomab produces durable complete remissions in a subset of heavily pretreated
      patients with low-grade and transformed non-Hodgkin's lymphomas. J Clin Oncol 2005;23:7565-7573.

      Second-line extended dosing
      Rituximab maintenance
      van Oers MHJ, Van Glabbeke M, Giurgea L, et al. Rituximab maintenance treatment of relapsed/resistant follicular non-hodgkin's lymphoma: Long-term outcome of
      the EORTC 20981 Phase III randomized Intergroup Study. J Clin Oncol 2010;28:2853-2858.
      Forstpointer R, Unterhalt M, Dreyling M, et al. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy
      with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell
      lymphomas: Results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood 2006;108:4003-4008.




                                                                                                                                                                                                                                            FOLL-B
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                                                            NCCN Guidelines™ Version 3.2011                                                                                                                                   NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                            Marginal Zone Lymphomas                                                                                                                                                       Discussion




                                                                       Gastric                               See Diagnosis and Workup (MALT-1)
    Extranodal marginal zone
    lymphoma of mucosa-
    associated lymphoid tissue
    (MALT lymphoma)
                                                                       Nongastric                            See Diagnosis and Workup (NGMLT-1)




    Nodal marginal zone lymphoma                                                                             See Diagnosis and Workup (NODE-1)




    Splenic marginal zone lymphoma                                                                           See Diagnosis and Workup (SPLN-1)




      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.           MZL-1
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                                                             NCCN Guidelines™ Version 3.2011
                                                             Extranodal Marginal Zone B-Cell Lymphoma                                                                                                                         NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                             Gastric MALT Lymphoma                                                                                                                                                        Discussion

   DIAGNOSIS                                                                                                                        WORKUP
                                                                                                                                     ESSENTIAL:
                                                                                                                                     · Physical exam with attention to nongastric sites
                                                                                                                                       (eyes, skin)
   ESSENTIAL:
                                                                                                                                     · Performance status
   · Hematopathology review of all slides with at least one paraffin                                                                 · CBC, differential, platelets
     block representative of the tumor. Rebiopsy if consult material                                                                 · Comprehensive metabolic panel
     is nondiagnostic. a,b                                                                                                           · LDH
   · Diagnosis of Gastric MALT lymphoma requires an endoscopic                                                                       · If H. pylori negative by histopathology, then use
     biopsy and an FNA is never adequate.                                                                                              noninvasive H. pylori testing (stool antigen test, urea
   · Adequate immunophenotyping to establish diagnosis c,d                                                                             breath test, blood antibody test)
     > Recommended panel for paraffin section
                                                                                                                                     · Hepatitis B testing f if rituximab contemplated
        immunohistochemistry: CD20, CD3, CD5, CD10, BCL2,
                                                                                                                                     · Chest/abdominal/pelvic CT with contrast of                                                        See Initial
        kappa/lambda, CD21 or CD23, cyclin D1, BCL6
                                                                                                                                       diagnostic quality                                                                                Therapy
        or
                                                                                                                                     · Endoscopy with ultrasound (if available) with multiple                                            (MALT-2)
     > Cell surface marker analysis by flow cytometry:
                                                                                                                                       biopsies of anatomical sites
        kappa/lambda, CD19, CD20, CD5, CD23, CD10
                                                                                                                                     · Pregnancy testing in women of child-bearing age (if
   · Helicobacter Pylori stain (gastric), if positive, then PCR or
                                                                                                                                       chemotherapy planned)
     FISH for t(11;18) e
                                                                                                                                     USEFUL IN SELECTED CASES
   USEFUL UNDER CERTAIN CIRCUMSTANCES:
                                                                                                                                     · Bone marrow biopsy ± aspirate
   · Molecular genetic analysis to detect: antigen receptor gene
                                                                                                                                     · MUGA scan/echocardiogram if anthracycline or
     rearrangements
                                                                                                                                       anthracenediones- based regimen is indicated
   · Cytogenetics or FISH: t(1;14), t(14;18), t(3;14)
                                                                                                                                     · Hepatitis C testing
                                                                                                                                     · Discussion of fertility issues and sperm banking
                                                                                                                                     · SPEP

   a Nondiagnostic    atypical lymphoid infiltrates that are H. Pylori positive, should be rebiopsied to confirm or exclude lymphoma prior to treatment of H. Pylori.
   b Any area of DLBCL should be treated according to the NCCN Diffuse Large B-Cell Lymphoma Guidelines (BCEL-1).
   c Typical immunophenotype: CD10-, CD5-, CD20+, cyclin D1-, BCL2 follicles-.
   d See Use of Immunophenotyping and Genetic Testing in Differential Diagnosis of Mature B-cell and T/NK-cell Neoplasms (NHODG-A).
   e Locally advanced disease is more likely in patients with gastric MALT lymphoma with t(11;18).
   f Hepatitis B testing is indicated because of the risk of reactivation with immunotherapy + chemotherapy. Tests include hepatitis B surface antigen and core antibody for a
     patient with no risk factors. For patients with risk factors or previous history of hepatitis B, add e-antigen. If positive, check viral load and consult with gastroenterologist.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          MALT-1
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                                                             NCCN Guidelines™ Version 3.2011
                                                             Extranodal Marginal Zone B-Cell Lymphoma                                                                                                                         NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                             Gastric MALT Lymphoma                                                                                                                                                        Discussion

   STAGE g                                            INITIAL THERAPY

   Stage I E1,                                        Currently accepted antibiotic                                    Evaluate for H. pylori eradication
   H. pylori positive                                 therapy for H. pylori i                                          with endoscopy (MALT-3)


   Stage I E2h
                                                      Currently accepted antibiotic                                    Evaluate for H. pylori eradication
   or Stage II Eh
                                                      therapy for H. pylori i                                          with endoscopy (MALT-3)
   H. pylori positive



                                                       RT j,k (preferred)
   Stage I E or II E                                                                                                                 Endoscopy for restaging,
                                                       or
   H. pylori negative                                                                                                                as per MALT-4
                                                       Rituximab (if RT is contraindicated)


                                            Indications for treatment:                                               No
                                            · Candidate for clinical trial l                                                                           Observe
                                                                                                                     indication
   Stage III E/IV                           · Symptoms
   (advanced-                               · GI bleeding
   stage disease                            · Threatened end-organ function                                                                            Induction chemo-
                                                                                                                                                                                                             Endoscopy for restaging, if
   uncommon)                                · Bulky disease                                                                                            immunotherapy n
                                                                                                                     Indication                                                                              evidence of recurrence,
                                            · Steady progression                                                                                       or
                                            · Patient preference                                                     present m                                                                               manage per follicular
                                                                                                                                                       Locoregional RT in
                                                                                                                                                                                                             lymphoma (see FOLL-3)
                                                                                                                                                       specific settings k
   g See   Lugano Staging System for gastrointestinal lymphoma (MALT-A).
   h Involvement    of submucosa or regional lymph nodes are much less likely to respond to antibiotic therapy. If there is
      persistent disease after evaluation, RT may be considered earlier in the course.
   i t(11;18) is a predictor for lack of response to antibiotics. These patients should be considered for alternative therapy.
   j If negative by both histology and serum antibodies, RT recommended.
   k See Principles of Radiation Therapy (NHODG-E).
   l Given incurability with conventional therapy, consider investigational therapy as first line of treatment.
   m Surgical resection is generally limited to specific clinical situations, ie, life-threatening hemorrhage.
   n See Suggested Treatment Regimens (FOLL-B).

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          MALT-2
Printed by Eric Kirkendall on 7/17/2011 6:41:14 PM. For personal use only. Not approved for distribution. Copyright © 2011 National Comprehensive Cancer Network, Inc., All Rights Reserved.

                                                             NCCN Guidelines™ Version 3.2011
                                                             Extranodal Marginal Zone B-Cell Lymphoma                                                                                                                         NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                             Gastric MALT Lymphoma                                                                                                                                                        Discussion

   3-MONTH RESTAGING AND FOLLOW-UP ENDOSCOPY

   AFTER ANTIBIOTICS                                                                                                                                                    ADDITIONAL THERAPY
                                                               H. pylori negative,
                                                                                                                                                                        Observe
                                                               Lymphoma negative

                                                                                                                                                                        Observe for
                                                                                                                                                                        another 3 mo p
                                                                                                                Asymptomatic
                                                                                                                                                                        or
                                                               H. pylori negative,                                                                                      RT k,p,q
                                                               Lymphoma positive
   Restage at 3 mo with
   endoscopy/biopsy o for                                                                                       Symptomatic                                             RT k
   H. pylori/lymphoma
   (restage earlier than 3
   mo if symptomatic)                                                                                                                                                                                                 See Follow-up
                                                                                                                                                                                                                      Endoscopy (MALT-5)
   after antibiotics
                                                               H. pylori positive,
                                                               Lymphoma negative                                                                                        Second-line
                                                                                                                                                                        antibiotic
                                                                                                                                                                        treatment
                                                                                                                Stable
                                                                                                                disease
                                                               H. pylori positive,
                                                               Lymphoma positive
                                                                                                                Progressive or                                          RT k and second-
                                                                                                                symptomatic                                             line antibiotic
                                                                                                                disease                                                 treatment


   k See   Principles of Radiation Therapy (NHODG-E).
   o Biopsy   to rule out large cell lymphoma. Any area of DLBCL should be treated according to the NCCN Diffuse Large B-Cell Lymphoma Guidelines (BCEL-1).
   p If re-evaluation suggests slowly responding disease or asymptomatic nonprogression, continued observation may be warranted. RT can be considered as
     early as 3 mo after observation but can be prolonged to 18 mo (category 2B).
   q If patient originally had clinical Stage I
                                                E2 or Stage II E, early RT should be considered if there is no response to antibiotics.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          MALT-3
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                                                             NCCN Guidelines™ Version 3.2011
                                                             Extranodal Marginal Zone B-Cell Lymphoma                                                                                                                         NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                             Gastric MALT Lymphoma                                                                                                                                                        Discussion

   3-6 MONTH RESTAGING AND FOLLOW-UP ENDOSCOPY
   AFTER RT                                                                                                            ADDITIONAL THERAPY


                                                               H. pylori negative                                                                                       See Follow-up
                                                                                                                         Observe
                                                               Lymphoma negative                                                                                        Endoscopy (MALT-5)




                                                               H. pylori negative
                                                                                                                         See FOLL-2
                                                               Lymphoma positive

   Restage at 3-6 mo
   with endoscopy and
   biopsy o after RT


                                                               H. pylori positive                                        Consider antibiotic                             See Follow-up
                                                               Lymphoma negative                                         treatment                                       Endoscopy (MALT-5)




                                                               H. pylori positive
                                                                                                                         See FOLL-2
                                                               Lymphoma positive




   o Biopsy    to rule out large cell lymphoma. Any area of DLBCL should be treated according to the Diffuse Large B-Cell Lymphoma Guidelines (BCEL-1).

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          MALT-4
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                                                             NCCN Guidelines™ Version 3.2011
                                                             Extranodal Marginal Zone B-Cell Lymphoma                                                                                                                         NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                             Gastric MALT Lymphoma                                                                                                                                                        Discussion

   FOLLOW-UP ENDOSCOPY

                                                                                                                                                                               See follicular lymphoma
                                                                                                                                               Recurrence
                                                                                                                                                                               indications for treatment
                                                                                                                                               post RT
                                                                                                                                                                               (FOLL-3)
                                                                                       Clinical follow-up
                                                    Complete                           every 3-6 mo for 5 y
                                                    response                           and then yearly or as
                                                                                       clinically indicated r                                                                         Systemic
                                                                                                                                               Recurrence
                                                                                                                                               post antibiotics
                                                                                                                                                                                      Locoregional RT k
    Repeat endoscopy
    after 3 mo o

                                                                                                                                           See follicular lymphoma
                                                                                       Previous RT                                         indications for treatment
                                                                                                                                           (FOLL-3)

                                                    No response


                                                                                       Previous antibiotic
                                                                                                                                           Locoregional RT k
                                                                                       treatment




   k See Principles of Radiation Therapy (NHODG-E).
   o Biopsy to rule out large cell lymphoma. Any area of DLBCL should be treated according to the Diffuse Large B-Cell Lymphoma Guidelines (BCEL-1).
   r Optimal interval for follow-up endoscopy and imaging is not known. Follow-up endoscopy and imaging at NCCN institutions is driven by symptoms.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          MALT-5
Printed by Eric Kirkendall on 7/17/2011 6:41:14 PM. For personal use only. Not approved for distribution. Copyright © 2011 National Comprehensive Cancer Network, Inc., All Rights Reserved.

                                                             NCCN Guidelines™ Version 3.2011
                                                             Extranodal Marginal Zone B-Cell Lymphoma                                                                                                                         NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                             Gastric MALT Lymphoma                                                                                                                                                        Discussion

                                                      STAGING OF GASTRIC MALT LYMPHOMA: COMPARISON OF DIFFERENT SYSTEMS

                                               Lugano Staging System for                                             Ann Arbor                 TNM Staging System                             Tumor extension
                                               gastrointestinal lymphomas                                              Stage                    adapted for gastric
                                                                                                                                                   lymphoma
                                        Stage I E                 Confined to GI tract a
                                                                  I E1 = mucosa, submucosa                              IE                         T1 N0 M0                               Mucosa, submucosa

                                                                  I E2 = muscularis                                     IE                         T2 N0 M0                               Muscularis propria
                                                                  propria, serosa
                                                                                                                        IE                         T3 N0 M0                               Serosa
                                        Stage II E               Extending into abdomen
                                                                 II E1 = local nodal                                    II E                       T1-3 N1 M0                             Perigastric lymph
                                                                 involvement                                                                                                              nodes
                                                                 II E2 = distant nodal                                  II E                       T1-3 N2 M0                             More distant regional
                                                                 involvement                                                                                                              lymph nodes

                                        Stage II E               Penetration of serosa to                               II E                       T4 N0 M0                               Invasion of adjacent
                                                                 involve adjacent organs                                                                                                  structures
                                                                 or tissues
                                        Stage III-IV b Disseminated                                                     III E                      T1-4 N3 M0                             Lymph nodes on both
                                                       extranodal involvement                                                                                                             sides of the
                                                       or concomitant                                                   IV                         T1-4 N0-3 M1                           diaphragm/distant
                                                       supradiaphragmatic                                                                                                                 metastases (eg, bone
                                                       nodal involvement                                                                                                                  marrow or additional
                                                                                                                                                                                          extranodal sites)
                                                   Yahalom et al. Extranodal Marginal Zone B-cell Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT
                                                   lymphoma) in Mauch et al eds. Non-Hodgkin's Lymphomas. Philadelphia: Lippincott, 2004:352.
   a Single primary or multiple, noncontiguous.
   b Involvement of multiple extranodal sites in MALT
                                                    lymphoma appears to be biologically distinct from multiple extranodal involvement in other lymphomas, and these
     patients may be managed by treating each site separately with excision or RT. In contrast, cases with disseminated nodal involvement appear to behave more like
     nodal MZL or like disseminated FL.
      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          MALT-A
Printed by Eric Kirkendall on 7/17/2011 6:41:14 PM. For personal use only. Not approved for distribution. Copyright © 2011 National Comprehensive Cancer Network, Inc., All Rights Reserved.

                                                             NCCN Guidelines™ Version 3.2011
                                                             Extranodal Marginal Zone B-Cell Lymphoma a                                                                                                                       NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                             Nongastric MALT Lymphoma b                                                                                                                                                   Discussion

   DIAGNOSIS                                                                                                         WORKUP

                                                                                                                     ESSENTIAL:
   ESSENTIAL:                                                                                                        · Physical exam with performance status
   · Hematopathology review of all slides with at                                                                    · CBC, differential, platelets
     least one paraffin block representative of the                                                                  · Comprehensive metabolic panel
     tumor. Rebiopsy if consult material is                                                                          · LDH
     nondiagnostic.                                                                                                  · Hepatitis B testing e if rituximab contemplated
   · Adequate immunophenotyping to establish                                                                         · Chest/abdominal/pelvic CT with contrast of
     diagnosis c,d                                                                                                     diagnostic quality
     > Recommended panel for paraffin section                                                                        · Pregnancy testing in women of child-bearing
       immunohistochemistry: CD20, CD3, CD5,                                                                           age (if chemotherapy planned)
       CD10, BCL2, kappa lambda, CD21 or CD23,
                                                                                                                     USEFUL IN SELECTED CASES                                                                                        See Initial Therapy
       cyclin D1                                                                                                                                                                                                                     (NGMLT-2)
       or                                                                                                            · MUGA scan/echocardiogram if anthracycline or
     > Cell surface marker analysis by flow                                                                            anthracenediones- based regimen is indicated
       cytometry: kappa/lambda, CD19, CD20, CD5,                                                                     · Bone marrow biopsy ± aspirate (for patients
       CD23, CD10                                                                                                      with multifocal disease)
                                                                                                                     · Endoscopy with multiple biopsies of anatomical
   USEFUL UNDER CERTAIN CIRCUMSTANCES:                                                                                 sites
   · Molecular genetic analysis to detect: antigen                                                                   · PET-CT scan
     receptor gene rearrangements; PCR for t(11;18)                                                                  · MRI
   · Cytogenetics or FISH: t(11;18); t(11;14); t(3;14);                                                              · Hepatitis C testing
     t(14;18)                                                                                                        · Discussion of fertility issues and sperm banking
                                                                                                                     · SPEP


   a Typical sites of extranodal marginal zone lymphoma other than the stomach include the following: bowel (small and large), breast, head and neck, lung, ocular adenxa,
     ovary, parotid, prostate, and salivary gland. Infectious agents have been reported to be associated with many nongastric sites but testing for these agents is not
     required for management.
   b Non-cutaneous, for cutaneous marginal zone B-cell lymphoma, see CUTB.
   c Typical immunophenotype: CD10-, CD5-, CD20+, CD23-/+, CD43-/+, cyclin D1-, BCL2 follicles-.
   d See Use of Immunophenotyping and Genetic Testing in Differential Diagnosis of Mature B-cell and T/NK-cell Neoplasms (NHODG-A).
   e Hepatitis B testing is indicated because of the risk of reactivation with immunotherapy + chemotherapy. Tests include hepatitis B surface antigen and core antibody for a
     patient with no risk factors. For patients with risk factors or previous history of hepatitis B, add e-antigen. If positive, check viral load and consult with gastroenterologist.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.             NGMLT-1
Printed by Eric Kirkendall on 7/17/2011 6:41:14 PM. For personal use only. Not approved for distribution. Copyright © 2011 National Comprehensive Cancer Network, Inc., All Rights Reserved.

                                                             NCCN Guidelines™ Version 3.2011
                                                             Extranodal Marginal Zone B-Cell Lymphoma                                                                                                                         NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                             Nongastric MALT Lymphoma                                                                                                                                                     Discussion

   STAGE                             TREATMENT h
                                                                                                                                                                                                                               RT
                                                                                                                                                                                                                               or
                                                                                                                                                                                                                               Manage per NCCN
                                                                                                                                                                                                   Local
                                                                                                                                                                                                                               Follicular Lymphoma
                                                                                                                                                                                                   recurrence
                                                                                                                                                                                                                               Guidelines for
                                     RT i,j                                                                                                     Clinical follow-up                                                             advanced stage
                                     or
                                                                                                        Positive                Consider        every 3-6 mo for 5 y                                                           (FOLL-2)
                                     Surgery may be considered for
                                     certain sites k (lung, breast                                      margins                 locoregional RT and then yearly or
   Stage I-II                                                                                                                                   as clinically
                                     [lumpectomy], thyroid,
                                                                                                        Negative                                indicated m                                                                    Manage per NCCN
                                     colon/small bowel                                                                          Observe
                                     or                                                                 margins                                                     Systemic                                                   Follicular Lymphoma
                                     Observation in selected cases l                                                                                                                                                           Guidelines for
                                                                                                                                                                    recurrence
                                                                                                                                                                                                                               advanced stage
                                                                                                                                                                                                                               (FOLL-2)
   Extranodal                                    RT
                                                 or
   (multiple sites) f
                                                 Observation in selected cases l
   Stage III, IV:
   extranodal disease                            Manage per Follicular
                                                 Lymphoma Guidelines for
   and multiple nodal
                                                 advanced stage (FOLL-2)
   sites

   Stage I-IV, MALT
   lymphomas                                     Treat per NCCN Diffuse
   coexistent with                               Large B-Cell Lymphoma
   large cell                                    Guidelines (BCEL-1)
   lymphoma h

    f Treatment   of each site may be indicated (eg, bilateral conjunctiva) both at                                                  i Dose   is site dependent with lower dose reserved for eye involvement.
      diagnosis and at relapse.                                                                                                      j See  Principles of Radiation Therapy (NHODG-E).
    g DLBCL coexistent with MALT cell lymphoma is managed as DLBCL.                                                                  k Surgical excision for adequate diagnosis may be appropriate treatment for disease.
    h Based on anecdotal responses to antibiotics in ocular and cutaneous marginal                                                   l Observation may be considered for patients whose diagnostic biopsy was excisional
      zone lymphomas, some physicians will give an empiric course of doxycycline                                                        or involved-field RT or systemic treatment could result in significant comorbidity.
      prior to initiating other therapy.                                                                                             m Follow-up includes diagnostic tests and imaging as clinically indicated.


      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.         NGMLT-2
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Nodal Marginal Zone Lymphoma                                                                                                                                                   Discussion

   DIAGNOSIS a                                                                                                                         WORKUP
   ESSENTIAL:                                                                                                                          ESSENTIAL:
   · Hematopathology review of all slides with at least one paraffin                                                                   · Physical exam with performance status
     block representative of the tumor. Rebiopsy if consult material is                                                                · CBC, differential, platelets
     nondiagnostic.                                                                                                                    · Comprehensive metabolic panel
   · An FNA or core needle biopsy alone is not generally suitable for                                                                  · LDH
     the initial diagnosis of lymphoma. In certain circumstances,                                                                      · Hepatitis B testing d if rituximab contemplated
     when a lymph node is not easily accessible for excisional or                                                                      · Chest/abdominal/pelvic CT with contrast of
     incisional biopsy, a combination of core biopsy and FNA                                                                             diagnostic quality
     biopsies in conjunction with appropriate ancillary techniques for                                                                 · Bone marrow biopsy + aspirate to document
     the differential diagnosis (immunohistochemistry, flow                                                                              clinical stage I-II disease e
     cytometry, PCR for IgH and TCR gene rearrangements, and FISH                                                                      · Evaluation to rule out extranodal primary sites
     for major translocations) may be sufficient for diagnosis.                                                                          > Neck nodes: ocular, parotid, thyroid, and
                                                                                                                                                                                                                                      See
                                                                                                                                            salivary gland
     Histologic grading cannot be performed on an FNA.                                                                                                                                                                                Management
                                                                                                                                         > Axillary nodes: lung, breast, and skin
   · Adequate immunophenotyping to establish diagnosis b,c                                                                               > Mediastinal/hilar nodes: lung
                                                                                                                                                                                                                                      as per
     > Paraffin panel: CD20, CD3, CD5, CD10, BCL2, kappa/lambda,                                                                         > Abdominal nodes: splenic and GI
                                                                                                                                                                                                                                      Follicular
       CD21 or CD23, cyclin D1                                                                                                                                                                                                        Lymphoma
                                                                                                                                         > Inguinal/iliac nodes: GI and skin                                                          (FOLL-2)
       or                                                                                                                              · Pregnancy testing in women of child-bearing age
     > Cell surface marker analysis by flow cytometry:                                                                                   (if chemotherapy planned)
       kappa/lambda, CD19, CD20, CD5, CD23, CD10                                                                                       USEFUL IN SELECTED CASES
   · Pediatric nodal marginal zone lymphoma should be considered                                                                       · MUGA scan/echocardiogram if anthracycline or
     with localized disease in a young patient.                                                                                          anthracenediones-based regimen is indicated
   USEFUL UNDER CERTAIN CIRCUMSTANCES FOR                                                                                              · Additional imaging as appropriate
   CLARIFICATION OF DIAGNOSIS:                                                                                                         · PET-CT scan
   · Molecular genetic analysis to detect: antigen receptor gene                                                                       · Hepatitis C testing
     rearrangements; PCR for t(11;18)                                                                                                  · Discussion of fertility issues and sperm banking
   · Cytogenetics or FISH: t(11;18); t(1;14); t(14;18); del(13q); del(7q)                                                              · SPEP
   a Nodal MZL is rare and occurs most commonly as spread from extranodal MALT;                                                     immunotherapy + chemotherapy. Tests include hepatitis B surface antigen and core
     must also be distinguished from nodal FL, MCL, lymphoplasmacytic lymphoma,                                                       antibody for a patient with no risk factors. For patients with risk factors or previous
     and CLL, all of which are more common.                                                                                           history of hepatitis B, add e-antigen. If positive, check viral load and consult with
   b Typical immunophenotype: CD10-, CD5-, CD20+, CD23-/+, CD43-/+ and cyclin                                                         gastroenterologist.
     D1-, BCL2 follicles-.                                                                                                          e Bilateral or unilateral provided core biopsy is > 2 cm. If radioimmunotherapy is
   c See Use of Immunophenotyping and Genetic Testing in Differential Diagnosis of                                                    considered, bilateral cores are recommended and the pathologist should provide the
     Mature B-cell and T/NK-cell Neoplasms (NHODG-A).                                                                                 percent of overall cellular elements and the percent of cellular elements involved in
   d Hepatitis B testing is indicated because of the risk of reactivation with                                                        the marrow. If observation is initial therapy, bone marrow biopsy may be deferred.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          NODE-1
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Splenic Marginal Zone Lymphoma                                                                                                                                                 Discussion

   DIAGNOSIS                                                                                                                                WORKUP
   ESSENTIAL:
   · Hematopathology review of all slides with at least one paraffin                                                                        ESSENTIAL:
     block representative of the tumor. Rebiopsy if consult material is                                                                     · Physical exam with performance status
     nondiagnostic. a                                                                                                                       · CBC, differential, platelets
   · An FNA or core needle biopsy alone is not generally suitable for                                                                       · Comprehensive metabolic panel
     the initial diagnosis of lymphoma. In certain circumstances, when a                                                                    · LDH
     lymph node is not easily accessible for excisional or incisional                                                                       · Hepatitis B testing d if rituximab contemplated
     biopsy, a combination of core biopsy and FNA biopsies in                                                                               · Hepatitis C testing
     conjunction with appropriate ancillary techniques for the                                                                              · Chest/abdominal/pelvic CT with contrast of
     differential diagnosis (immunohistochemistry, flow cytometry, PCR                                                                        diagnostic quality
     for IgH and TCR gene rearrangements, and FISH for major                                                                                · Bone marrow biopsy ± aspirate
                                                                                                                                                                                                                                         See Initial
     translocations) may be sufficient for diagnosis.                                                                                       · SPEP and/or quantitative immunoglobulin levels
                                                                                                                                                                                                                                         Therapy
   · Adequate immunophenotyping to establish diagnosis b,c                                                                                  · Pregnancy testing in women of child-bearing                                                (SPLN-2)
     > Recommended panel for paraffin section immunohistochemistry:                                                                           age (if chemotherapy planned)
       CD20, CD3, CD5, CD10, BCL2, kappa/lambda, CD21 or CD23,
       cyclin D1, IgD, CD43, annexin-1                                                                                                      USEFUL IN SELECTED CASES
       or                                                                                                                                   · Additional imaging as appropriate
     > Cell surface marker analysis by flow cytometry (peripheral blood,                                                                    · PET-CT scan
       bone marrow, or tissue):                                                                                                             · Discussion of fertility issues and sperm banking
       kappa/lambda, CD19, CD20, CD5, CD23, CD10, CD43, CD103                                                                               · Immunofixation of blood (for elevated
   USEFUL UNDER CERTAIN CIRCUMSTANCES:                                                                                                        immunoglobulins or positive SPEP)
   · Molecular genetic analysis to detect: antigen receptor gene                                                                            · Cryoglobulins
     rearrangements; PCR for t(11;18)                                                                                                       · Directs Coombs testing
   · Cytogenetics or FISH: CLL panel; t(11;18); t(11;14); t(14;18); del(7q)
   a SMZL  is most definitively diagnosed at splenectomy, since the immunophenotype is                                                    b Typical immunophenotype: CD10-, CD5-, CD20+, CD23-/+, CD43-/+ and cyclin
     nonspecific and morphologic features on the bone marrow may not be diagnostic.                                                         D1-, BCL2 follicles-, annexin-1, CD103- (distinction from hairy cell leukemia)
     However, the diagnosis of SMZL may be made on the basis of bone marrow +/-                                                             with expression of both IgM and IgD.
     peripheral blood involvement by small lymphoid cells with immunoglobulin (Ig) light                                                  c See Use of Immunophenotyping and Genetic Testing in Differential Diagnosis of
     chain restriction that lack characteristic features of other small B-cell neoplasms                                                    Mature B-cell and T/NK-cell Neoplasms (NHODG-A).
     (CD5, CD10, cyclin D1). Plasmacytoid differentiation with cytoplasmic Ig detectable                                                  d Hepatitis B testing is indicated because of the risk of reactivation with
     on paraffin sections may occur. In such cases, the differential diagnosis may                                                          immunotherapy + chemotherapy. Tests include hepatitis B surface antigen and
     include lymphoplasmacytic lymphoma. With a characteristic intrasinusoidal                                                              core antibody for a patient with no risk factors. For patients with risk factors or
     lymphocytic infiltration of the bone marrow, the diagnosis can strongly be                                                             previous history of hepatitis B, add e-antigen. If positive, check viral load and
     suggested on bone marrow biopsy alone, if the immunophenotype is consistent.                                                           consult with gastroenterologist.
      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          SPLN-1
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Splenic Marginal Zone Lymphoma                                                                                                                                                 Discussion

   CLINICAL PRESENTATION                                                         MANAGEMENT

   Asymptomatic,
   without progressive
                                                                                Observe
   cytopenia, no
   splenomegaly
                                                                                                                    No
                                                                                                                    contraindications                       Appropriate
                                                                                                                    for treatment of                        treatment
                                                                                                                    hepatitis
                                                 Hepatitis C                    Hepatology                                                                                                                                           If progression of
                                                 positive                       consult                                                                                                     Clinical follow-
                                                                                                                                                                                                                                     disease, manage
                                                                                                                                                                                            up every 3-6 mo
                                                                                                                                                                                                                                     per NCCN Follicular
                                                                                                                    Contraindications                                                       for 5 y and then
                                                                                                                                                                                                                                     Lymphoma
                                                                                                                    for treatment of                                                        yearly or as
                                                                                                                                                                                                                                     Guidelines for
                                                                                                                    hepatitis                                                               clinically
                                                                                                                                                                                                                                     advanced stage
                                                                                                                                                                                            indicated g
                                                                                                                                                                                                                                     (FOLL-2)
   Splenomegaly


                                                                                                                                                         Splenectomy e
                                                                                                                    · Cytopenias
                                                                                                                                                         or
                                                                                                                    · Symptoms
                                                                                                                                                         Rituximab f
                                                 Hepatitis C
                                                                                 Assess
                                                 negative
                                                                                                                     No symptoms                         Observe




   e Pneumococcal   and meningococcal vaccination should be performed at least 2 weeks before splenectomy.
   f Tsimberidou AM, Catovsky D, Schlette E, et al. Outcomes in patients with splenic marginal zone lymphoma and marginal zone lymphoma treated with rituximab with or
     without chemotherapy or chemotherapy alone. Cancer 2006;107:125-135.
   g Follow-up includes diagnostic tests and imaging as clinically indicated.


      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.               SPLN-2
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Mantle Cell Lymphoma                                                                                                                                                           Discussion

   DIAGNOSIS                                                                                                             WORKUP
   ESSENTIAL:                                                                                                            ESSENTIAL:
   · Hematopathology review of all slides with at least one                                                              · Physical exam: Attention to node-bearing areas,
     paraffin block representative of the tumor. Rebiopsy if                                                               including Waldeyer’s ring, and to size of liver and
     consult material is nondiagnostic.                                                                                    spleen
   · An FNA or core needle biopsy alone is not generally                                                                 · Performance status
     suitable for the initial diagnosis of lymphoma. In certain                                                          · B symptoms
     circumstances, when a lymph node is not easily                                                                      · CBC, differential, platelets
     accessible for excisional or incisional biopsy, a                                                                   · Comprehensive metabolic panel
     combination of core biopsy and FNA biopsies in                                                                      · LDH
     conjunction with appropriate ancillary techniques for the                                                           · Bone marrow biopsy ± aspirate
     differential diagnosis(immunohistochemistry, flow                                                                   · Chest/abdominal/pelvic CT with contrast of
     cytometry, PCR for IgH and TCR gene rearrangements,                                                                   diagnostic quality
     and FISH for major translocations) may be sufficient for                                                            · Hepatitis B testing d if rituximab contemplated                                                           See Induction
                                                                                                                                                                                                                                     Therapy
     diagnosis.                                                                                                          · MUGA scan/echocardiogram if anthracycline or
                                                                                                                                                                                                                                     (MANT-2)
   · Adequate immunophenotyping to establish diagnosis a,b                                                                 anthracenediones- based regimen is indicated
     > Recommended panel for paraffin section                                                                            · Pregnancy testing in women of child-bearing age
       immunohistochemistry: CD20, CD3, CD5, cyclin D1,                                                                    (if chemotherapy planned)
       CD10, CD21, CD23, BCL2, BCL6, Ki67 c                                                                              USEFUL UNDER CERTAIN CIRCUMSTANCES
       or                                                                                                                · Endoscopy/colonoscopy e
     > Cell surface marker analysis by flow cytometry:                                                                   · Neck CT
       kappa/lambda, CD19, CD20, CD5, CD23, CD10                                                                         · Uric acid
                                                                                                                         · Discussion of fertility issues and sperm banking
   USEFUL UNDER CERTAIN CIRCUMSTANCES:                                                                                   · Lumbar puncture (for blastic variant or
   · Molecular genetic analysis to detect: antigen receptor                                                                CNS symptoms)
     gene rearrangements; BCL1 rearrangements                                                                            · Beta-2-microglobulin
   · Cytogenetics or FISH: t(11;14); t(14;18); CLL panel                                                                 · PET-CT scan
   a Typicalimmunophenotype: CD5+, CD20+, CD43+, CD23-/+, cyclin D1+,                                                                   d Hepatitis B testing is indicated because of the risk of reactivation with
     CD10-/+ Note: Some cases of MCL may be CD5- or CD 23+. If the diagnosis                                                              immunotherapy + chemotherapy. Tests include hepatitis B surface antigen
     is suspected, cyclin D1 staining or FISH for t(11;14) should be done.                                                                and core antibody for a patient with no risk factors. For patients with risk
   b See Use of Immunophenotyping and Genetic Testing in Differential Diagnosis                                                           factors or previous history of hepatitis B, add e-antigen. If positive, check viral
     of Mature B-cell and T/NK-cell Neoplasms (NHODG-A).                                                                                  load and consult with gastroenterologist.
   c Ki67 proliferation fraction of < 30% is associated with a more favorable                                                           e Essential for confirmation of stage I- II disease. See discussion for details.
     prognosis. However, it is not used to guide treatment.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.           MANT-1
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Mantle Cell Lymphoma                                                                                                                                                           Discussion

                                                       INDUCTION THERAPY f                                                          INITIAL                             RELAPSE
                                                                                                                                    RESPONSE



   Stage I, II                                         See Suggested Regimens
   (localized                                          (MANT-A) ± RT h                                                              Complete
                                                                                                                                                                        Relapse
   presentation,                                       or                                                                           response j
   extremely rare)                                     RT g,h
                                                                                                                                                                                                                Clinical trial k
                                                                                                                                                                                                                or
                                                                                                                                    Partial                                                                     Second-line treatment
                                                                                                                                    response j                                                                  · RT
                                                                                                                                                                                                                · See Suggested Regimens
                                                                                                                                                                                                                  (MANT-A)
                                                       Clinical trial
                                                       or
                                                       See Suggested Regimens                                                       Progression j
   Stage
                                                       (MANT-A)
   IIX, III, IV
                                                       or
                                                       Observation in highly
                                                       selected cases i




   f Early referral for high dose therapy with stem cell rescue is advisable for planning purposes.
   g Leitch  HA, Gascoyne RD, Chhanabhai M, et al. Limited-stage mantle-cell lymphoma. Ann Oncol 2003;14:1555-1561.
   h See Principles of Radiation Therapy (NHODG-E).
   i Martin P, Chadburn A, Christos P, et al. Outcome of deferred initial therapy in mantle-cell lymphoma. J Clin Oncol 2009;27:1209-1213.
   j See Response Criteria for Lymphoma (NHODG-C).
   k Option for clinical trials of adjuvant therapy or for relapsed disease involving high dose therapy with autologous or allogeneic stem cell rescue, immunotherapy with
      nonmyeloablative stem cell rescue, or evaluation of treatment with new agents are appropriate.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          MANT-2
Printed by Eric Kirkendall on 7/17/2011 6:41:14 PM. For personal use only. Not approved for distribution. Copyright © 2011 National Comprehensive Cancer Network, Inc., All Rights Reserved.




                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Mantle Cell Lymphoma                                                                                                                                                           Discussion

                                                       SUGGESTED TREATMENT REGIMENS a
                                                                (in alphabetical order)
   Induction Therapy                                                        First-line Consolidation d
   · Aggressive therapy                                                     · Clinical trial
     > HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and           · High dose therapy with autologous stem cell rescue e
       dexamethasone alternating with high-dose methotrexate and
       cytarabine) + rituximab                                              Second-line Therapy
     > NORDIC regimen b (dose-intensified induction                         · Bendamustine ± rituximab
       immunochemotherapy with rituximab + cyclophosphamide,                · Bortezomib ± rituximab
       vincristine, doxorubicin, prednisone [maxi-CHOP]) alternating with · Cladribine + rituximab
       rituximab + high-dose cytarabine)                                    · FC (fludarabine, cyclophosphamide) ± rituximab
     > CALGB regimen b (rituximab + methotrexate with augmented CHOP · FCMR (fludarabine, cyclophosphamide, mitoxantrone, rituximab)
       [cyclophosphamide, doxorubicin, vincristine, prednisone])            · FMR (fludarabine, mitoxantrone, rituximab)
       (rituximab + methotrexate with augmented CHOP                        · Lenalidomide ± rituximab
       [cyclophosphamide, doxorubicin, vincristine, prednisone])            · PCR (pentostatin, cyclophosphamide, rituximab)
     > Sequential RCHOP/RICE b (rituximab, cyclophosphamide,
                                                                            · PEPC (prednisone, etoposide, procarbazine, cyclophosphamide) ±
       doxorubicin, vincristine, prednisone) (rituximab, ifosfamide,
                                                                              rituximab
       carboplatin, etoposide)
     > Alternating RCHOP/RDHAP b (rituximab, cyclophosphamide,
                                                                            · See Second-line Therapy for DLBCL (BCEL-C 1 of 3) f
       doxorubicin, vincristine, prednisone)/(rituximab, dexamethasone,
                                                                                                                                      Second-line Consolidation
       cisplatin, cytarabine)
                                                                                                                                      · Allogeneic stem cell transplant (nonmyeloablative or
   · Less aggressive therapy
     > Bendamustine + rituximab
                                                                                                                                        myeloablative)
     > CHOP + rituximab c
                                                                                                                                      See Monoclonal Antibody Directed at CD20 and Viral
     > Cladribine + rituximab
     > CVP (cyclophosphamide, vincristine, prednisone) + rituximab
                                                                                                                                      Reactivation (NHODG-D)
     > Dose-adjusted EPOCH (etoposide, prednisone, vincristine,
       cyclophosphamide, doxorubicin) + rituximab
     > Modified rituximab-HyperCVAD with rituximab maintenance in
       patients older than 65 y
   a See references for regimens MANT-A 2 of 3 and MANT-A 3 of 3.                                                                       consolidation; however, less aggressive regimens followed by consolidation with
   b These  regimens include first-line consolidation with high dose therapy and                                                        high dose therapy may also result in a good long-term outcome.
     autologous stem cell rescue (HDT/ASCR).                                                                                         e Randomized data with anthracycline-containing regimens suggest an improvement
   c There is a randomized trial that demonstrated that RCHOP was not superior to                                                       in progression free survival with the addition of first-line high dose therapy with
     CHOP.                                                                                                                              autologous stem cell consolidation.
   d Typically patients will receive an aggressive induction regimen prior to                                                        f These agents can be administered without restriction for transplantability.


      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                            MANT-A
   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.            1 of 3
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Mantle Cell Lymphoma                                                                                                                                                           Discussion

                                                                                                SUGGESTED TREATMENT REGIMENS
                                                                                                          References
    InductionTherapy                                                                                                                  previously untreated mantle cell lymphoma: results of a prospective randomized trial of the
    Aggressive therapy                                                                                                                German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol 2005;23:1984-1992.
    HyperCVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone                                                              Cladribine + rituximab
    alternating with methotrexate and cytarabine) + rituximab                                                                         Inwards DJ, Fishkin PA, Hillman DW, et al. Long-term results of the treatment of patients
    Romaguera JE, Fayad L, Rodriguez MA, et al. High rate of durable remissions after                                                 with mantle cell lymphoma with cladribine (2-CDA) alone (95-80-53) or 2-CDA and rituximab
    treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus                                                  (N0189) in the North Central Cancer Treatment Group. Cancer 2008;113:108-116.
    hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J                                               CVP + rituximab
    Clin Oncol 2005;23:7013-7023.                                                                                                     Teodorovic I, Pittaluga S, Kluin-Nelemans J, et al. Efficacy of four different regimens in 64
    Nordic trial regimen (Dose-intensified induction immunochemotherapy with                                                          mantle-cell lymphoma cases: clinicopathologic comparison with 498 other non-Hodgkin's
    rituximab + cyclophosphamide, vincristine, doxorubicin, prednisone [maxi-CHOP])                                                   lymphoma subtypes. European Organization for the Research and Treatment of Cancer
    alternating with rituximab + high-dose cytarabine)                                                                                Lymphoma Cooperative Group. J Clin Oncol 1995;13:2819-2826.
    Geisler CH, Kolstad A, Laurell A, et al. Long-term progression-free survival of mantle cell                                       Martin P, Chadburn A, Christos P, et al. Intensive treatment strategies may not provide
    lymphoma following intensive front-line immunochemotherapy with in vivo-purged stem                                               superior outcomes in mantle cell lymphoma: Overall survival exceeding 7 years with
    cell rescue: A non-randomized phase-II multicenter study by the Nordic Lymphoma                                                   standard therapies. Ann Oncol 2008;19:1327-1330.
    Group. Blood 2008;112:2687-2693.                                                                                                  Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and
    CALGB regimen (rituximab + methotrexate with augmented CHOP):                                                                     doxorubicin) + rituximab
    Damon LE, Johnson JL, Niedzwiecki D, et al. Immunochemotherapy and autologous                                                     Wilson WH, Gutierrez M, O'Connor P, et al. The role of rituximab and chemotherapy in
    stem-cell transplantation for untreated patients with mantle-cell lymphoma: CALGB                                                 aggressive B-cell lymphoma: a preliminary report of dose-adjusted EPOCH-R. Semin Oncol
    59909. J Clin Oncol 2009;27:6101-6108.                                                                                            2002;29:41-47.
    RCHOP/RICE                                                                                                                        Modified HyperCVAD with rituximab maintenance
    Schaffel R, Hedvat CV, Teruya-Feldstein J, et al. Prognostic impact of proliferative index                                        Kahl BS, Long WL, Eickhoff JC, et al. Maintenance rituximab following induction
    determined by quantitative image analysis and the International Prognostic Index in                                               chemoimmunotherapy may prolong progression-free survival in mantle cell lymphoma: A
    patients with mantle cell lymphoma. Ann Oncol 2010;21:133-9.                                                                      pilot study from the Wisconsin Oncology Network. Ann Oncology 2006;17:1418-1423.
    RCHOP/RDHAP
    Pott C, Hoster E, Beldjord K, et al. R-CHOP/R-DHAP compared to R-CHOP induction                                                   First-line consolidation
    followed by high dose therapy with autologous stem cell transplantation induces higher                                            High dose therapy with autologous stem sell rescue
    rates of molecular remission in MCL: Results of the MCL Younger Intergroup Trial of the                                           Dreyling M, Lenz G, Hoster E, et al. Early consolidation by myeloablative radiochemotherapy
    European MCL Network. Blood (ASH Annual Meeting Abstracts). 2010;116:965-.                                                        followed by autologous stem cell transplantation in first remission significantly prolongs
                                                                                                                                      progression-free survival in mantle cell lymphoma: results of a prospective randomized trial
    Less aggressive therapy                                                                                                           of the European MCL Network. Blood 2005;105:2677-2684.
    Bendamustine + rituximab                                                                                                          Thieblemont C, Antal D, Lacotte-Thierry L, et al. Chemotherapy with rituximab followed by
    Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab Is superior                                               high-dose therapy and autologous stem cell transplantation in patients with mantle cell
    in respect of progression free survival and CR rate when compared to CHOP plus                                                    lymphoma. Cancer 2005;104:1434-1441.
    rituximab as first-line treatment of patients with advanced follicular, indolent, and mantle                                      Ritchie D, Seymour J, Grigg A, et al. The hyper-CVAD–rituximab chemotherapy programme
    cell lymphomas: Final results of a randomized phase III study of the StiL (Study Group                                            followed by high-dose busulfan, melphalan and autologous stem cell transplantation
    Indolent Lymphomas, Germany). Blood (ASH Annual Meeting Abstracts). 2009;114:405.                                                 produces excellent event-free survival in patients with previously untreated mantle cell
    CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) + rituximab                                                         lymphoma. Annals of Hematology 2007;86:101-105.
    Lenz G, Dreyling M, Hoster E, et al. Immunochemotherapy with rituximab and
    cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves
    response and time to treatment failure, but not long-term outcome in patients with


      Note: All recommendations are category 2A unless otherwise indicated.
                                                                                                                                                                                                                     Continued on next page
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                            MANT-A
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Mantle Cell Lymphoma                                                                                                                                                           Discussion

                                                                                                SUGGESTED TREATMENT REGIMENS
                                                                                                          References
      Second-line Therapy
      Bendamustine
      Robinson KS, Williams ME, van der Jagt RH, et al. Phase II multicenter study of bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell Non-
      Hodgkin’s Lymphoma. J Clin Oncol 2008; 26:4473-4479.
      Rummel MJ, Al-Batran SE, Kim S-Z, et al. Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-
      hodgkin's lymphoma. J Clin Oncol 2005;23:3383-3389.
      Bortezomib
      Goy A, Bernstein SH, Kahl BS, et al. Bortezomib in patients with relapsed or refractory mantle cell lymphoma: updated time-to-event analyses of the multicenter phase 2
      PINNACLE study. Ann Oncol 2009;20:520-525.
      Cladribine
      Rummel MJ, Chow KU, Jager E, et al. Treatment of mantle-cell lymphomas with intermittent two-hour infusion of cladribine as first-line therapy or in first relapse. Ann Oncol
      1999;10:115-117.
      Inwards DJ, Fishkin PA, Hillman DW, et al. Long-term results of the treatment of patients with mantle cell lymphoma with cladribine (2-CDA) alone (95-80-53) or 2-CDA and
      rituximab (N0189) in the North Central Cancer Treatment Group. Cancer. 2008;113:108-116.
      FC (fludarabine and cyclophosphamid) ± rituximab
      Cohen BJ, Moskowitz C, Straus D et al. Cyclophosphamide/fludarabine (CF) is active in the treatment of mantle cell lymphoma. Leuk Lymphoma 2001;42:1015-1022.
      FCMR (fludarabine, cyclophosphamide, mitoxantrone, rituximab)
      Forstpointner R, Dreyling M, Repp R, et al. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the
      response rate and prolongs survival as compared to FCM alone in patients with relapsed and refractory follicular and mantle cell lymphoma - results of a prospective randomized
      study of the German low grade lymphoma study group (GLSG). Blood 2004;104:3064-3071.
      FMR (fludarabine, mitoxantrone, rituximab)
      Levine AM, Tulpule A, Smith L, Espina BM, Mohrbacher AF, Feinstein DI. Results of a pilot trial of fludarabine, mitoxantrone and rituxan in mantle cell lymphoma. ASH Annual
      Meeting Abstracts. 2005;106:945.
      Lenalidomide
      Habermann TM, Lossos IS, Justice G, et al. Lenalidomide oral monotherapy produces a high response rate in patients with relapsed or refractory mantle cell lymphoma. Br J
      Haematol 2009;145:344-349.
      Reeder CB, Witzig TE, Zinzani PL, et al. Efficacy and safety of lenalidomide oral monotherapy in patients with relapsed or refractory mantle-cell lymphoma: Results from an
      international study (NHL-003). ASCO Meeting Abstracts. 2009;27:8569.
      Lenalidomide + rituximab
      Wang L, Fayad L, Hagemeister FB, et al. A phase I/II study of lenalidomide in combination with rituximab in relapsed/refractory mantle cell lymphoma. ASH Annual Meeting
      Abstracts. 2009;114:2719.
      PEP-C (prednisone, etoposide, procarbazine, cyclophosphamide) ± rituximab
      Coleman M, Martin P, Ruan J, et al. Prednisone, etoposide, procarbazine, and cyclophosphamide (PEP-C) oral combination chemotherapy regimen for recurring/refractory
      lymphoma: low-dose metronomic, multidrug therapy. Cancer 2008;112(10):2228-2232.




      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                           MANT-A
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Diffuse Large B-Cell Lymphoma                                                                                                                                                  Discussion

   DIAGNOSIS a,b                                                                                                           SUBTYPES
   ESSENTIAL:
   · Hematopathology review of all slides with at least one
     paraffin block representative of the tumor. Rebiopsy if
     consult material is nondiagnostic.
   · An FNA or core needle biopsy alone is not generally
     suitable for the initial diagnosis of lymphoma. In certain
     circumstances, when a lymph node is not easily accessible
     for excisional or incisional biopsy, a combination of core
     biopsy and FNA biopsies in conjunction with appropriate                                                               · Subtypes included:
     ancillary techniques for the differential diagnosis                                                                     > Diffuse large B-cell lymphoma (DLBCL), NOS f
     (immunohistochemistry, flow cytometry, PCR for IgH and                                                                  > DLBCL coexistent with follicular lymphoma of any grade
     TCR gene rearrangements, and FISH for major                                                                             > DLBCL coexistent with gastric MALT lymphoma
     translocations) may be sufficient for diagnosis.                                                                        > DLBCL coexistent with nongastric MALT lymphoma                                                             See
   · Adequate immunophenotyping to establish diagnosisc,d                                                                    > Follicular Lymphoma grade 3                                                                                Workup
     > Recommended panel for paraffin section                                                                                > Intravascular large B-cell lymphoma                                                                        (BCEL-2)
       immunohistochemistry: CD20, CD3, CD5, CD10, CD45,                                                                     > DLBCL associated with chronic inflammation
       BCL2, BCL6, Ki-67, IRF4/MUM1                                                                                          > ALK positive DLBCL
       or                                                                                                                    > EBV positive DLBCL of the elderly
     > Cell surface marker analysis by flow cytometry:                                                                       > T-cell/histiocyte rich large B-cell lymphoma
       kappa/lambda, CD45, CD3, CD5, CD19, CD10, CD20

   USEFUL UNDER CERTAIN CIRCUMSTANCES:                                                                                     · Subtypes not included:
   · Additional immunohistochemical studies to establish                                                                     > Cutaneous B-cell lymphoma (See CUTB-1)
     lymphoma subtype                                                                                                        > Primary DLBCL of the CNS
     > Paraffin panel: cyclin D1, kappa/lambda, CD138, EBV,
       ALK, HTLV                                                                                                          Primary Mediastinal Large B-Cell Lymphoma (PMBL), see BCEL-B.
   · Molecular genetic analysis to detect: antigen receptor gene
     rearrangements; BCL1, BCL2, MYC rearrangements e
   · Cytogenetics or FISH: t(14;18); e t(3;v); t(8;14)                                                                          d See  Use of Immunophenotyping and Genetic Testing in Differential Diagnosis of
   a Burkittlymphoma intermediate histology or DLBCL CD10 + tumors with very                                                      Mature B-cell and T/NK-cell Neoplasms (NHODG-A).
     high proliferation > 90% with or without Burkitt lymphoma-like features might                                              e Standard of care is not established for DLBCL with t(14;18) with concurrent MYC
     be considered for more aggressive treatment as per BURK-A.                                                                   rearrangements.
   b See International Prognostic Index (BCEL-A).                                                                               f Germinal center (or follicular center) cell phenotype is not equivalent to follicular
   c Typical immunophenotype: CD20+, CD45+, CD3-; other markers used for                                                          lymphoma and can occur in DLBCL and Burkitt lymphoma. Morphology is required
     subclassification.                                                                                                           to establish diagnosis.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          BCEL-1
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Diffuse Large B-Cell Lymphoma                                                                                                                                                  Discussion

   WORKUP

    ESSENTIAL:
    · Physical exam: attention to node-bearing areas, including
      Waldeyer’s ring, and to size of liver and spleen
    · Performance status
    · B symptoms
    · CBC, differential, platelets
    · LDH
    · Comprehensive metabolic panel
    · Uric acid
    · Chest/abdominal/pelvic CT with contrast of diagnostic quality
    · Unilateral or bilateral bone marrow biopsy (1-2 cm) ± aspirate
    · Calculation of International Prognostic Index (IPI) b
    · Hepatitis B testing g                                                                                                                 See Induction
    · MUGA scan/echocardiogram if anthracycline or                                                                                          Therapy (BCEL-3)
      anthracenediones- based regimen is indicated
    · PET-CT scan
    · Pregnancy testing in women of child-bearing age
    · Beta-2-microglobulin (category 2B)

    USEFUL IN SELECTED CASES:
    · Neck CT, Head CT, or MRI
    · Discussion of fertility issues and sperm banking
    · HIV
    · Lumbar puncture, if paranasal sinus, testicular, epidural,
      bone marrow with large cell lymphoma, HIV lymphoma, or
      ³ 2 extranodal sites



   b See International Prognostic Index (BCEL-A).
   g HepatitisB testing is indicated because of the risk of reactivation with immunotherapy + chemotherapy. Tests include hepatitis B surface antigen and
     core antibody for a patient with no risk factors. For patients with risk factors or previous history of hepatitis B, add e-antigen. If positive, check viral
     load and consult with gastroenterologist.
      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          BCEL-2
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Diffuse Large B-Cell Lymphoma                                                                                                                                                  Discussion

   STAGE                                                                                                                           INDUCTION THERAPY k                                            Consider prophylaxis for tumor
                                                                                                                                                                                                  lysis syndrome (See NHODG-B)
                                                                          Adverse risk factors
                                                                          present:
                                                                                                                                    RCHOP x 3 cycles + RT l
                                                                          · Elevated LDH
                                                                                                                                    or
                                                                          · Stage II
                                                                                                                                    RCHOP x 6 cycles ± RT l
                                                                          · Age > 60 y
                                        Nonbulky                          · Performance status ³ 2                                                                                                                                   See Pre RT
                                        (< 10 cm)                                                                                                                                                                                    evaluation
                                                                                                                                    RCHOP x 3 cycles + RT l                                                                          (BCEL-4)
                                                                          Adverse risk                                              or
                                                                          factors not present                                       RCHOP x 6 cycles ± RT l
   Stage I, II h,i                                                                                                                  (category 2B for RT)


                                                                                                                                                                                                                                     See Pre RT
                                        Bulky
                                                                                                                                    RCHOP x 6 cycles ± RT l (category 1)                                                             evaluation
                                        (³ 10 cm)
                                                                                                                                                                                                                                     (BCEL-4)


                                                                                                                                    Clinical trial m
   Stage III,      IV h,j                                                                                                           or                                                                                               See Interim
                                                                                                                                    RCHOP x 6 cycles n,o (category 1) p                                                              restaging
                                                                                                                                                                                                                                     (BCEL-5)


   h In  testicular lymphoma, after completion of chemotherapy, RT should be given                                              k Recommendations     are for HIV-negative lymphoma only.
      to contralateral testis (30-36 Gy).                                                                                          See AIDS-2 for HIV-positive DLBCL.
   i In patients who are not candidates for chemotherapy involved field radiation                                               l See Principles of Radiation Therapy (NHODG-E).
      therapy (IFRT) is recommended.                                                                                            m May include high-dose therapy.
   j In selected settings (paranasal sinus, testicular, epidural, bone marrow with                                              n Based on current clinical trials, CHOP is preferable due to reduced toxicities, but other
      large cell lymphoma, HIV lymphoma, or ³ 2 extranodal sites), CNS prophylaxis                                                 comparable anthracycline-based regimens are acceptable.
      should be given (4-8 doses of intrathecal methotrexate and/or cytarabine                                                  o For other regimens, see BCEL-C.
      during the course of treatment). Recent data regarding Stage IE DLBCL of                                                  p In selected cases, RT to initially bulky sites of disease may be beneficial (category 2B).
      breast has been suggested as a potential risk for CNS disease.
      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.             BCEL-3
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Diffuse Large B-Cell Lymphoma                                                                                                                                                  Discussion

   PRE RT EVALUATION                                                                  FOLLOW-UP THERAPY                                        END OF TREATMENT                            INITIAL RESPONSE
                                                                                                                                               RESTAGING t                                 (after completion of induction
                                                                                                                                                                                           chemotherapy)

                                                                                                                                                                                                                        Clinical
                                                  Complete
                                                                                      Complete planned                                                                                                                  follow-up
                                                  response q
                                                                                      course of treatment s                                                                                                             every 3-6 mo
                                                  (PET negative)                                                                                                                          Complete                      for 5 y and
                                                                                                                                                                                          response q,u                  then yearly or   Relapse,
                                                                                      Complete course of                                       At completion of                                                                          See
                                                                                                                                                                                                                        as clinically
                                                                                      therapy with higher RT                                   treatment, repeat                                                                         Relapse or
                                                                                                                                                                                                                        indicated
                                                                                      dose l,s                                                 all positive
                                                                                                                                                                                                                                         Refractory
                                                                                      or                                                                                                                                                 Disease
   Stage I, II:                                                                                                                                studies. s If PET-CT                       Partial                                        (BCEL-6)
                                                                                      High dose therapy with
   Pre RT evaluation,                                                                                                                          scan positive,                             response q
                                                                                      autologous stem cell
   repeat all positive                                                                                                                         rebiopsy before
                                                  Partial                             rescue ± RT pre- or post-
   studies. If PET-CT                                                                                                                          changing course
                                                  response q,r                        transplant                                                                                           No response
   scan positive,                                                                     or                                                       of treatment.
                                                  (PET positive)                                                                                                                           or
   rebiopsy before                                                                    Clinical trial (may include
                                                                                                                                                                                           progressive
   changing course                                                                    allogeneic stem cell
                                                                                                                                                                                           disease q
   of treatment.                                                                      transplant ± RT pre- or
                                                                                      post- transplant)


                                                  No response                         See Additional Therapy for
                                                  or                                  Relapse (BCEL-6)
                                                  progressive                         or
                                                                                      RT in select patients who are not
                                                  disease q
                                                                                      candidates for chemotherapy
   l See Principles of Radiation Therapy (NHODG-E).
   q See  Response Criteria for Lymphoma (NHODG-C).
   r Documented PR includes a biological measure of disease: positive PET-CT scan, or ideally positive biopsy.
   s Wait a minimum of 8 weeks after RT to repeat PET-CT scan. The optimum timing of repeat PET-CT is unknown. False positives may occur due to posttreatment changes.
   t There is evidence that addition of maintenance rituximab does not improve survival.
   u Patients in first remission may be candidates for consolidation trials including high dose therapy with autologous stem cell rescue.


      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          BCEL-4
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Diffuse Large B-Cell Lymphoma                                                                                                                                                  Discussion

   INTERIM RESTAGING                                                   FOLLOW-UP THERAPY END OF                                                       INITIAL RESPONSE
                                                                                         TREATMENT                                                    (after completion of
                                                                                         RESTAGING t                                                  induction
                                                                                                                                                      chemotherapy) Observation
                                                                                                                                                                       (preferred)
                                                                                                                                                                       or                                                 Clinical
                                                                                                                                                                       Consider RT to
                                                                                                                                                                                                                          follow-up
                                      Complete                                                                                                                         initially bulky
                                                                       Continue RCHOP o                                                                                                                                   every 3-6 mo
                                                                                                                   At completion of                     Complete       disease
                                      response q                                                                                                                                                                          for 5 y and
                                                                       to a total of 6 cycles                      treatment, repeat                    response  q,u  (category 2B)
                                      (PET negative)                                                                                                                   or                                                 then yearly
                                                                                                                   all positive                         (PET
                                                                                                                                                                       Consider high                                      or as
                                                                                                                   studies. If PET-                     negative)                                                                      Relapse,
                                                                                                                                                                       dose therapy                                       clinically
                                                                                                                   CT scan                                                                                                indicated    See
                                                                                                                                                                       with autologous                                                 Relapse or
                                                                                                                   positive,
   Stage III, IV:                                                                                                                                                      stem cell rescue                                                Refractory
   After 2-4                                                           Continue RCHOP o                            rebiopsy before
                                      Partial                                                                                                                          in high risk                                                    Disease
                                                                       to a total of 6 cycles                      changing course
   cycles, repeat                     response q,r                                                                                                      Partial        patients                                                        (BCEL-6)
                                                                       or                                          of treatment.                        response q
   all positive                       (PET positive)                                                                                                                   (category 2B)
   studies v                                                           Clinical trial                                                                   (PET
                                                                                                                                                        positive)

                                                                       See Additional Therapy                                                            No response
                                       No response                     for Relapse (BCEL-6)                                                              or
                                       or                              or                                                                                progressive
                                       progressive                     RT in select patients who                                                         disease q
                                       disease q                       are not candidates for
                                                                       chemotherapy

   o For  other regimens, see BCEL-C.
   q See   Response Criteria for Lymphoma (NHODG-C).
   r Documented PR includes a biological measure of disease: positive PET-CT scan, or ideally positive biopsy.
   t There is evidence that the addition of maintenance rituximab does not improve survival.
   u Patients in first remission may be candidates for consolidation trials including high dose therapy with autologous stem cell rescue.
   v PET-CT scan at interim restaging can lead to increased false positives and should be carefully considered in select cases. If PET-CT scan performed and positive,
      rebiopsy before changing course of treatment.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          BCEL-5
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Diffuse Large B-Cell Lymphoma                                                                                                                                                  Discussion

   RELAPSE/                                                             ADDITIONAL                                      RESPONSE #2                                             CONSOLIDATION/                                        RELAPSE #2
   REFRACTORY DISEASE                                                   THERAPY                                                                                                 ADDITIONAL THERAPY                                    OR GREATER

                                                                                                                                                                                High dose therapy with
                                                                                                                                                                                autologous stem cell
                                                                                                                                                                                rescue (category 1 for CR,                           Clinical trial y
                                                                                                                                                                                category 2A for all others)
                                                                                                                        Complete response q                                     ± involved field RT w
                                                                                                                        or                                                      or
                                                                                                                        partial response q                                      Clinical trial
                                                                                                                                                                                or
                                                                                                                                                                                Allogeneic stem cell
                                  For patients                                                                                                                                  transplant in selected
                                  with intention                       Second-line therapy                                                                                      cases x
                                  to proceed to                        See Suggested
                                  high- dose                           Regimens (BCEL-C)
                                  therapy                                                                                                                                                                                             Clinical trial
   Relapse/                                                                                                                                                                                                                           or
   refractory                                                                                                                                                                                                                         Palliative RT
   disease                                                                                                              No response                                                                                                   or
                                                                       Clinical trial                                                                                                                                                 Best
                                                                       or                                                                                                                                                             supportive
                                  Non
                                                                       Second-line therapy                                                                                                                                            care
                                  candidates
                                  for high-dose                        See Suggested
                                  therapy                              Regimens (BCEL-C)
                                                                       or
                                                                       Palliative RT


   q See  Response Criteria for Lymphoma (NHODG-C).
   w Additional   RT can be given before or after high dose therapy with stem cell rescue to sites of previous positive disease.
   x Selected cases include mobilization failures and persistent bone marrow involvement.
   y Clinical trials or individual regimens: Patients who progress after three successive regimens are unlikely to derive additional benefit from currently utilized
     combination chemotherapy regimens, except for patients with a long disease-free interval.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.           BCEL-6
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Diffuse Large B-Cell Lymphoma                                                                                                                                                  Discussion



                                                                                             INTERNATIONAL PROGNOSTIC INDEX a



                                    ALL PATIENTS:                                                                                           INTERNATIONAL INDEX, ALL PATIENTS:
                                    · Age > 60 years                                                                                        · Low                0 or 1
                                    · Serum LDH > 1 x normal                                                                                · Low intermediate     2
                                    · Performance status 2-4                                                                                · High intermediate    3
                                    · Stage III or IV                                                                                       · High               4 or 5
                                    · Extranodal involvement > 1 site




                                                                               AGE-ADJUSTED INTERNATIONAL PROGNOSTIC INDEX a



                                    PATIENTS £ 60 YEARS:                                                                           INTERNATIONAL INDEX, PATIENTS £ 60 YEARS:
                                    · Stage III or IV                                                                              · Low                0
                                    · Serum LDH > 1 x normal                                                                       · Low/intermediate   1
                                    · Performance status 2-4                                                                       · High/intermediate  2
                                                                                                                                   · High               3




   a Adaptedwith permission, The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. A predictive model for aggressive
     non-hodgkin’s lymphoma. N Engl J Med1993; 329:987-994. Copyright © 1993 Massachusetts Medical Society. All rights reserved.                                                                                                     Back to Workup
                                                                                                                                                                                                                                     (BCEL-1)
      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          BCEL-A
Printed by Eric Kirkendall on 7/17/2011 6:41:14 PM. For personal use only. Not approved for distribution. Copyright © 2011 National Comprehensive Cancer Network, Inc., All Rights Reserved.




                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Diffuse Large B-Cell Lymphoma                                                                                                                                                  Discussion

                                                                                    Primary Mediastinal Large B-Cell Lymphoma (PMBL)
                                            PMBL can be defined as a clinical entity presenting with primary site of disease in mediastinum
                                            with or without other sites and has histology of DLBCL.



                                          · Clinical pathologic correlation is required to establish diagnosis.

                                          · Optimal first-line therapy is more controversial than other subtypes of NHL.

                                          · Because of relative rarity of PMBL, the role of R-CHOP-21 is not established as the definitive
                                            treatment option for this disease. However, R-CHOP-21 is widely used in NCCN institutions
                                            based on data in DLBCL and other regimens have been used (see BCEL-C). There are data
                                            suggesting that more intense therapy may be better based on non-randomized comparisons.

                                          · Role of RT is controversial; if PET-CT scan negative at the end of treatment, may be observed.

                                          · Residual mediastinal masses are common. PET-CT scan is essential post-treatment. Biopsy
                                            of PET- CT scan positive mass is recommended if additional treatment is contemplated.




      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          BCEL-B
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Diffuse Large B-Cell Lymphoma                                                                                                                                                  Discussion

                                                                                              SUGGESTED TREATMENT REGIMENS a
                                                                                                    (in alphabetical order)

       First-line Therapy                                                                                                             Second-line Therapy b,e,f (For patients with intention to proceed to
       · RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine,                                                                high dose therapy with autologous stem cell rescue)
         prednisone) (category 1)                                                                                                     · DHAP (dexamethasone, cisplatin, cytarabine) ± rituximab
       · Dose-dense RCHOP 14 (category 2B)                                                                                            · ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin) ±
       · Dose-adjusted EPOCH (etoposide, prednisone, vincristine,                                                                       rituximab
         cyclophosphamide, doxorubicin) + rituximab (category 2B)                                                                     · GDP (gemcitabine, dexamethasone, cisplatin) ± rituximab
                                                                                                                                      · GemOx (gemcitabine, oxaliplatin) ± rituximab
       First-line Therapy for patients with poor left ventricular function b,c                                                        · ICE (ifosfamide, carboplatin, etoposide) ± rituximab
       · RCEPP (rituximab, cyclophosphamide, etoposide, prednisone,                                                                   · MINE (mesna, ifosfamide, mitoxantrone, etoposide) ± rituximab
         procarbazine)
       · RCDOP (rituximab, cyclophosphamide, liposomal doxorubicin,                                                                   Second-line Therapy b,e,f (non candidates for high dose therapy)
         vincristine, prednisone)                                                                                                     · Clinical trial
       · RCNOP (rituximab, cyclophosphamide, mitoxantrone, vincristine,                                                               · CEPP (cyclophosphamide, etoposide, prednisone, procarbazine) ±
         prednisone)                                                                                                                    rituximab - PO and IV
       · DA-EPOCH d (etoposide, prednisone, vincristine,                                                                              · DA-EPOCH ± rituximab
         cyclophosphamide, doxorubicin) + rituximab                                                                                   · CEOP (cyclophosphamide, etoposide, vincristine, prednisone) ±
       · RCEOP (rituximab, cyclophosphamide, etoposide, vincristine,                                                                    rituximab
         prednisone)                                                                                                                  · GDP ± rituximab
                                                                                                                                      · GemOx ± rituximab
       First-line Consolidation                                                                                                       · Lenalidomide ± rituximab
       · High dose therapy with autologous stem cell rescue in high risk                                                              · Rituximab
         patients (category 2B)

        See Monoclonal Antibody Directed at CD20 and Viral
        Reactivation (NHODG-D)
   a See  references for regimens BCEL-C 2 of 3 and BCEL-C 3 of 3.                                                                   base dose and not increased.
   b Inclusion  of any anthracycline or anthracenedione in patients with impaired                                                  e Ifadditional anthracycline is administered after a full course of therapy, careful
     cardiac functioning should have more frequent cardiac monitoring.                                                               cardiac monitoring is essential. Dexrazoxane may be added as a
   c There is limited published data regarding the use of these regimens, however,                                                   cardioprotectant.
     they are used at NCCN institutions for the first-line treatment of DLBCL for                                                  f Rituixmab would be included in second line therapy if there is relapse after a
     patients with poor ventricular left function.                                                                                   reasonable remission (> 6 mo); however, rituximab would often be omitted in
   d If upward dose adjustment is necessary, doxorubicin should be maintained at                                                     patients with primary refractory disease.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                            BCEL-C
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Diffuse Large B-Cell Lymphoma                                                                                                                                                  Discussion

                                                                                                SUGGESTED TREATMENT REGIMENS
                                                                                                          References
      First-line Therapy                                                                                                              Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide,
      CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) + rituximab                                                       doxorubicin) + rituximab
      with RT                                                                                                                         Purroy N, Lopez A, Vallespi T, Gironella M, Bergua J, Sancho JM. Dose-adjusted
      Miller TP, Dahlberg S, Cassady JR, et al. Chemotherapy alone compared with                                                      EPOCH plus rituximab (DA-EPOCH-R) in untreated patients with poor risk large B-cell
      chemotherapy plus radiotherapy for localized intermediate- and high-grade non-                                                  lymphoma. A phase 2 study conducted by the Spanish PETHEMA Group. ASH Annual
      hodgkin's lymphoma. N Engl J Med 1998;339:21-26.                                                                                Meeting Abstracts. 2009;114:2701-.
      Horning SJ, Weller E, Kim K, et al. Chemotherapy with or without radiotherapy in                                                Wilson WH, Dunleavy K, Pittaluga S, et al. Phase II study of dose-adjusted EPOCH
      limited-stage diffuse aggressive non-hodgkin's lymphoma: Eastern Cooperative                                                    and rituximab in untreated diffuse large B-cell lymphoma with analysis of germinal
      Oncology Group Study 1484. J Clin Oncol 2004;22:3032-3038.                                                                      center and post-germinal center biomarkers. J Clin Oncol 2008;26:2717-2724.
      Persky DO, Unger JM, Spier CM, et al. Phase II study of rituximab plus three
      cycles of CHOP and involved-field radiotherapy for patients with limited-stage                                                  First-line Therapy for patients with poor ventricular left function
      aggressive B-cell lymphoma: Southwest Oncology Group Study 0014. J Clin Oncol                                                   CDOP (cyclophosphamide, liposomal doxorubicin, vincristine and prednisone) +
      2008;26:2258-226.                                                                                                               rituximab
      CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) + rituximab                                                       Martino R, Perea G, Caballero MD, et al. Cyclophosphamide, pegylated liposomal
      Coiffier B, Thieblemont C, Van Den Neste E, et al. Long-term outcome of patients                                                doxorubicin (Caelyx), vincristine and prednisone (CCOP) in elderly patients with diffuse
      in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to                                                   large B-cell lymphoma: results from a prospective phase II study. Haematologica
      standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes                                                    2002;87:822-827.
      des Lymphomes de l'Adulte. Blood 2010;116:2040-2045.                                                                            Zaja F, Tomadini V, Zaccaria A, et al. CHOP-rituximab with pegylated liposomal
      Feugier P, Van Hoof A, Sebban C, et al. Long-term results of the R-CHOP study in                                                doxorubicin for the treatment of elderly patients with diffuse large B-cell lymphoma.
      the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the                                            Leuk Lymphoma 2006;47:2174-2180.
      Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 2005;23:4117-4126.                                                       CNOP (cyclophosphamide, mitoxantrone, vincristine, prednisone) + rituximab
      Pfreundschuh M, Trumper L, Osterborg A, et al. CHOP-like chemotherapy plus                                                      Bessell EM, Burton A, Haynes AP, et al. A randomised multicentre trial of modified
      rituximab versus CHOP-like chemotherapy alone in young patients with good-                                                      CHOP versus MCOP in patients aged 65 years and over with aggressive non-
      prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the                                                   Hodgkin's lymphoma. Ann Oncol 2003;14:258-267.
      MabThera International Trial (MInT) Group. Lancet Oncol 2006;7:379-391.                                                         Bezwoda W, Rastogi RB, Erazo Valla A, et al. Long-term results of a multicentre
      Pfreundschuh M, Schubert J, Ziepert M, et al. Six versus eight cycles of bi-weekly                                              randomised, comparative phase III trial of CHOP versus CNOP regimens in patients
      CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-                                                  with intermediate- and high-grade non-Hodgkin's lymphomas. Novantrone International
      cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol                                                        Study Group. Eur J Cancer 1995;31A:903-911.
      2008;9:105-116.                                                                                                                 Sonneveld P, de Ridder M, van der Lelie H, et al. Comparison of doxorubicin and
      Dose-dense CHOP 14 + rituximab                                                                                                  mitoxantrone in the treatment of elderly patients with advanced diffuse non-Hodgkin's
      Blayney DW, LeBlanc ML, Grogan T, et al. Dose-intense chemotherapy every 2                                                      lymphoma using CHOP versus CNOP chemotherapy. J Clin Oncol 1995;13:2530-
      weeks with dose-intense cyclophosphamide, doxorubicin, vincristine, and                                                         2539.
      prednisone may improve survival in intermediate- and high-grade lymphoma: a                                                     RCEOP (ritximab, cyclophosphamide, etoposide, vincristine, prednisone)
      phase II study of the Southwest Oncology Group (SWOG 9349). J Clin Oncol                                                        Moccia et al. R-CHOP with etoposide substituted for doxorubicin (R-CEOP): Excellent
      2003;21:2466-2473                                                                                                               outcome in diffuse large B cell lymphoma for patients with a contraindication to
                                                                                                                                      anthracyclines. 2009 ASH Annual Meeting. Abstract 408.

                                                                                                                                                                                                                     Continued on next page
      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                            BCEL-C
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Diffuse Large B-Cell Lymphoma                                                                                                                                                  Discussion

                                                                                               SUGGESTED TREATMENT REGIMENS
                                                                                                         References
   Second-line Therapy                                                                                                               etoposide (R-ICE) for relapsed non-Hodgkin's lymphoma. Ann Oncol 2003;14
   DHAP (dexamethasone, cisplatin, cytarabine) ± rituximab                                                                           Suppl 1:i17-20.
   Velasquez WS, Cabanillas F, Salvador P, et al. Effective salvage therapy for                                                      Gisselbrecht C, Glass B, Mounier N, et al. R-ICE versus R-DHAP in relapsed
   lymphoma with cisplatin in combination with high-dose Ara-C and dexamethasone                                                     patients with CD20 diffuse large B-cell lymphoma (DLBCL) followed by
   (DHAP). Blood 1988;71:117-122.                                                                                                    autologous stem cell transplantation: CORAL study. J Clin Oncol 2009;27:8509-.
   Mey UJ, Orlopp KS, Flieger D, et al. Dexamethasone, high-dose cytarabine, and                                                     Lenalidomide
   cisplatin in combination with rituximab as salvage treatment for patients with                                                    Czuczman MS, Vose J, Zinzani P, et al. Efficacy and safety of lenalidomide oral
   relapsed or refractory aggressive non-Hodgkin's lymphoma. Cancer Invest                                                           monotherapy in patients with relapsed or refractory diffuse large B-cell
   2006;24:593-600.                                                                                                                  lymphoma: Results from an international study (NHL-003). J Clin Oncol (Meeting
   Gisselbrecht C, Glass B, Mounier N, et al. R-ICE versus R-DHAP in relapsed                                                        Abstracts). 2009;27:e19504.
   patients with CD20 diffuse large B-cell lymphoma (DLBCL) followed by autologous                                                   Wiernik PH, Lossos IS, Tuscano JM, et al. Lenalidomide monotherapy in
   stem cell transplantation: CORAL study. J Clin Oncol 2009;27:8509-.                                                               relapsed or refractory aggressive Non-Hodgkin's lymphoma. J Clin Oncol
   ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin) ± rituximab                                                          2008;26:4952-4957.
   Velasquez WS, McLaughlin P, Tucker S, et al. ESHAP - an effective chemotherapy                                                    CEPP (cyclophosphamide, etoposide, prednisone, procarbazine) ±
   regimen in refractory and relapsing lymphoma: a 4-year follow-up study. J Clin                                                    rituximab
   Oncol 1994;12:1169-1176.                                                                                                          Chao NJ, Rosenberg SA, and Horning SJ. CEPP(B): An effective and well-
   Martin A, Conde E, Arnan M, et al. R-ESHAP as salvage therapy for patients with                                                   tolerated regimen in poor-risk, aggressive non-Hodgkin's lymphoma. Blood
   relapsed or refractory diffuse large B-cell lymphoma: the influence of prior                                                      1990;76:1293-1298.
   exposure to rituximab on outcome. A GEL/TAMO study. Haematologica                                                                 EPOCH + rituximab
   2008;93:1829-1836                                                                                                                 Gutierrez M, Chabner BA, Pearson D, et al. Role of a doxorubicin-containing
   GDP (gemcitabine, dexamethasone, cisplatin) ± rituximab                                                                           regimen in relapsed and resistant lymphomas: An 8-year follow-up study of
   Crump M, Baetz T, Couban S, et al. Gemcitabine, dexamethasone, and cisplatin in                                                   EPOCH. J Clin Oncol 2000;18:3633-3642.
   patients with recurrent or refractory aggressive histology B-cell non-Hodgkin                                                     Jermann M, Jost LM, Taverna C, et al. Rituximab-EPOCH, an effective salvage
   lymphoma: a Phase II study by the National Cancer Institute of Canada Clinical                                                    therapy for relapsed, refractory or transformed B-cell lymphomas: Results of a
   Trials Group (NCIC-CTG). Cancer 2004;101:1835-1842.                                                                               phase II study. Ann Oncol 2004;15:511-516.
   GemOX (gemcitabine, oxaliplatin) + rituximab                                                                                      RGemOx (rituximab, gemcitabine, oxaliplatin)
   Lopez A, Gutierrez A, Palacios A, et al. GEMOX-R regimen is a highly effective                                                    Corazzelli G, Capobianco G, Arcamone M, et al. Long-term results of
   salvage regimen in patients with refractory/relapsing diffuse large-cell lymphoma: a                                              gemcitabine plus oxaliplatin with and without rituximab as salvage treatment for
   phase II study. Eur J Haematol 2008;80(2):127-132.                                                                                transplant-ineligible patients with refractory/relapsing B-cell lymphoma. Cancer
   ICE (ifosfamide, carboplatin, etoposide) ± rituximab                                                                              Chemother Pharmacol 2009;64:907-916.
   Zelenetz AD, Hamlin P, Kewalramani T, et al. Ifosfamide, carboplatin, etoposide                                                   El Gnaoui T, Dupuis J, Belhadj K, et al. Rituximab, gemcitabine and oxaliplatin:
   (ICE)-based second-line chemotherapy for the management of relapsed and                                                           an effective salvage regimen for patients with relapsed or refractory B-cell
   refractory aggressive non-Hodgkin's lymphoma. Ann Oncol 2003;14[suppl 1]:i5-10.                                                   lymphoma not candidates for high-dose therapy. Ann Oncol 2007;18:1363-1368.
   Kewalramani T, Zelenetz AD, Nimer SD, et al. Rituximab and ICE (RICE) as
   second-line therapy prior to autologous stem cell transplantation for relapsed or
   primary refractory diffuse large B-cell lymphoma. Blood 2004;103:3684-8.
   Vose J, Sneller V. Outpatient regimen rituximab plus ifosfamide, carboplatin and


      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                            BCEL-C
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Burkitt Lymphoma                                                                                                                                                               Discussion

   DIAGNOSIS a,b                                                                                                                   WORKUP
   ESSENTIAL:                                                                                                                      ESSENTIAL:
   · Hematopathology review of all slides with at least one paraffin                                                               · Physical exam: attention to node-bearing areas,
     block representative of the tumor. Rebiopsy if consult material                                                                 including Waldeyer’s ring, and to size of liver and
     is nondiagnostic.                                                                                                               spleen
   · An FNA or core needle biopsy alone is not generally suitable                                                                  · Performance status
     for the initial diagnosis of lymphoma. In certain circumstances,                                                              · B symptoms
     when a lymph node is not easily accessible for excisional or                                                                  · CBC, differential, platelets
     incisional biopsy, a combination of core biopsy and FNA                                                                       · LDH
     biopsies in conjunction with appropriate ancillary techniques                                                                 · Comprehensive metabolic panel
     for the differential diagnosis (immunohistochemistry, flow                                                                    · Uric acid
                                                                                                                                                                                                                                       See Risk
     cytometry, PCR for IgH and TCR gene rearrangements, and                                                                       · Chest/abdominal/pelvic CT with contrast of
                                                                                                                                                                                                                                       Assessment
     FISH for major translocations) may be sufficient for diagnosis.                                                                 diagnostic quality                                                                                and
   · Adequate immunophenotyping to establish diagnosis c,d                                                                         · Lumbar puncture                                                                                   Induction
     > Paraffin panel: CD45 (LCA), CD20, CD3, CD10, Ki-67, BLC2,                                                                   · Flow cytometry of cerebrospinal fluid                                                             Therapy
        BCL6, TdT                                                                                                                  · Unilateral or bilateral bone marrow biopsy ± aspirate                                             (BURK-2)
        or                                                                                                                         · HIV testing
     > Cell surface marker analysis by flow cytometry:                                                                             · Hepatitis B testing e
        kappa/lambda, CD45, CD20, CD3, CD5, CD19, CD10, TdT                                                                        · MUGA scan/echocardiogram if anthracycline or
   · Cytogenetics or FISH: t(8;14) or variants; MYC; IgH; BCL2;                                                                      anthracenediones- based regimen is indicated
     BCL6 rearrangements                                                                                                           · Pregnancy testing in women of child-bearing age (if
                                                                                                                                     chemotherapy planned)
   USEFUL UNDER CERTAIN CIRCUMSTANCES:                                                                                             USEFUL IN SELECTED CASES:
   · ISH for EBV EBER                                                                                                              · Neck CT
   · Molecular genetic analysis to detect: antigen receptor gene                                                                   · Discussion of fertility issues and sperm banking
     rearrangements; MYC rearrangement                                                                                             · Beta-2-microglobulin
   a WHO   2008 classification recognizes that it may not always be possible to                                                    · PET-CT scan f
     distinguish between DLBLC and Burkitt lymphoma. In the setting where it is not
     possible to distinguish, aggressive therapy per this guideline is appropriate in
     selected cases.                                                                                                               e Hepatitis
   b This disease is complex and curable; it is preferred that treatment occur at                                                                B testing is indicated because of the risk of reactivation with
     centers with expertise in the management of the disease.                                                                         immunotherapy + chemotherapy. Tests include hepatitis B surface antigen and core
   c Typical immunophenotype: sIg+, CD10+, CD20+, TdT-, Ki67+ (100%), BCL2-,                                                          antibody for a patient with no risk factors. For patients with risk factors or previous
     BCL6+, MYC rearrangement only by cytogenetics or FISH.                                                                           history of hepatitis B, add e-antigen. If positive, check viral load and consult with
   d See Use of Immunophenotyping and Genetic Testing in Differential Diagnosis                                                       gastroenterologist.
                                                                                                                                   f Initiation of therapy should not be delayed in order to obtain a PET-CT scan.
     of Mature B-cell and T/NK-cell Neoplasms (NHODG-A).
      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          BURK-1
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Burkitt Lymphoma                                                                                                                                                               Discussion

   RISK ASSESSMENT                                       INDUCTION THERAPY                                 INITIAL RESPONSE                                                                          RELAPSE

                                                                                                                                                                                                      Clinical trial
                                                                                                                                              Follow-up after complete                                or
                                                                                                                                              response:                                               Second-line chemotherapy (BURK-A)
   Low risk                                                                                                Complete                                                                                   followed by high dose chemotherapy
                                                                                                                                              every 2-3 mo for 1 y,
                                                                                                           response h                                                                                 with HSCT in selected patients
   · Normal LDH                                                                                                                               then every 3 mo for 1 y,
                                                         Clinical trial g                                                                                                                             or
   · Completely resected                                                                                                                      then every 6 mo i
                                                         or                                                                                                                                           Best supportive care
     abdominal lesion or
                                                         See Suggested
     single extra-
                                                         Regimens (BURK-A)                                                                                                                           Clinical trial g
     abdominal mass
     < 10 cm                                                                                                                                                                                         or
                                                                                                           < Complete
                                                                                                                                                                                                     Individual approach
                                                                                                           response h
                                                                                                                                                                                                     or
                                                                                                                                                                                                     Palliative RT

     Prophylaxis for tumor lysis                                                                                                                                           Follow-up after complete response:
     syndrome is mandatory                                                                                                                                                 every 2-3 mo for 1 y,
                                                                                                                                              Observe
     (See NHODG-B)                                                                                                                                                         then every 3 mo for 1 y,
                                                                                                                                                                           then every 6 mo i
                                                                                                           Complete                           or                                                     Clinical trial
                                                                                                           response h
                                                                                                                                                                                                     or
                                                         Clinical trial g                                                                                                                            Second-line chemotherapy (BURK-A)
                                                                                                                                              Consolidation                                          followed by high dose chemotherapy
                                                         or
    High risk                                                                                                                                 in clinical trial                                      with HSCT in selected patients
                                                         See Suggested
                                                         Regimens (BURK-A)                                                                                                                           or
                                                                                                                                                                                                     Best supportive care
                                                                                                                                                                                                     Clinical trial g
                                                                                                                                                                                                     or
                                                                                                           < Complete
                                                                                                                                                                                                     Individual approach
                                                                                                           response h
                                                                                                                                                                                                     or
   g Clinical
            trials may include high dose therapy with allogeneic or autologous stem cell rescue.
   h See
                                                                                                                                                                                                     Palliative RT
         Response Criteria for Lymphoma (NHODG-C).
   i Relapse after 2 y is rare, therefore, follow-up should be individualized according to patient characteristics.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          BURK-2
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Burkitt Lymphoma                                                                                                                                                               Discussion

                                                                                              SUGGESTED TREATMENT REGIMENS a
                                                                                                    (in alphabetical order)
    CHOP is not adequate therapy.
    Induction therapy
    Low Risk- Combination Regimens
    · CALGB 9251 regimen (cyclophosphamide and prednisone followed by cycles containing either ifosfamide or cyclophosphamide;
      high-dose methotrexate, leucovorin, vincristine, dexamethasone, and either doxorubicin or etoposide or cytarabine; or
      intrathecal triple therapy [methotrexate, cytarabine and hydrocortisone]).
    · CODOX-M (original or modified) (cyclophosphamide, doxorubicin, vincristine with intrathecal methotrexate and cytarabine
      followed by high-dose systemic methotrexate) ± rituximab (3 cycles)
    · Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) + rituximab (minimum 3 cycles with
      one additional cycle beyond CR) (regimen includes intrathecal methotrexate) (Data is for patients without CNS disease.)
    · HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose methotrexate and
      cytarabine + rituximab (regimen includes intrathecal therapy)

    High Risk- Combination Regimens
    · CALGB 9251 regimen (cyclophosphamide and prednisone followed by cycles containing either ifosfamide or cyclophosphamide;
      high-dose methotrexate, leucovorin, vincristine, dexamethasone, and either doxorubicin or etoposide or cytarabine; or
      intrathecal triple therapy [methotrexate, cytarabine and hydrocortisone] with prophylactic CNS irradiation in select patients)
    · CODOX-M (original or modified) (cyclophosphamide, doxorubicin, vincristine with intrathecal methotrexate and cytarabine
      followed by high-dose systemic methotrexate) alternating with IVAC (ifosfamide, cytarabine, etoposide and intrathecal
      methotrexate) ± rituximab
    · Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) + rituximab (For high risk patients
      not able to tolerate aggressive treatments) (regimen includes intrathecal methotrexate) (Data is for patients without CNS disease.)
    · HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with high-dose methotrexate and
      cytarabine + rituximab (regimen includes intrathecal therapy)
    Second-line therapy (select patients with reasonable remission)
    · Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) + rituximab (minimum 3 cycles with one
      additional cycle beyond CR) (regimen includes intrathecal methotrexate) (Data is for patients without CNS disease.)
    · RIVAC (rituximab, ifosfamide, cytarabine, etoposide and intrathecal methotrexate) if have not received previously
    · RGDP (rituximab, gemcitabine, dexamethasone, cisplatin)
    · HDAC (high-dose cytarabine)
                                                                                                                                                                                  See Monoclonal Antibody Directed at CD20
    a See   references for regimens BURK-A 2 of 2.                                                                                                                                and Viral Reactivation (NHODG-D)

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                           BURK-A
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Burkitt Lymphoma                                                                                                                                                               Discussion

                                                                                                SUGGESTED TREATMENT REGIMENS
                                                                                                          References
        Low Risk- Combination Regimens                                                                                                    High Risk- Combination Regimens
        CALGB 9251 regimen                                                                                                                CALGB 9251 regimen
        Lee EJ, Petroni GR, Schiffer CA, et al. Brief-duration high-intensity                                                             Lee EJ, Petroni GR, Schiffer CA, et al. Brief-duration high-intensity
        chemotherapy for patients with small noncleaved-cell lymphoma or FAB L3                                                           chemotherapy for patients with small noncleaved-cell lymphoma or FAB L3
        Acute Lymphocytic Leukemia: Results of Cancer and Leukemia Group B                                                                Acute Lymphocytic Leukemia: Results of Cancer and Leukemia Group B
        Study 9251. J Clin Oncol 2001;19:4014-4022.                                                                                       Study 9251. J Clin Oncol 2001;19:4014-4022.
        Rizzieri DA, Johnson JL, Niedzwiecki D, et al. Intensive chemotherapy with                                                        Rizzieri DA, Johnson JL, Niedzwiecki D, et al. Intensive chemotherapy with
        and without cranial radiation for Burkitt leukemia and lymphoma: Final                                                            and without cranial radiation for Burkitt leukemia and lymphoma: Final results
        results of Cancer and Leukemia Group B Study 9251. Cancer                                                                         of Cancer and Leukemia Group B Study 9251. Cancer 2004;100:1438-1448.
        2004;100:1438-1448.                                                                                                               CODOX-M (original or modified) (cyclophosphamide, doxorubicin,
        CODOX-M (original or modified) (cyclophosphamide, doxorubicin,                                                                    vincristine with intrathecal methotrexate and cytarabine followed by
        vincristine with intrathecal methotrexate and cytarabine followed by                                                              high-dose systemic methotrexate) alternating with IVAC (ifosfamide,
        high-dose systemic methotrexate) ± rituximab                                                                                      cytarabine, etoposide and intrathecal methotrexate) ± rituximab
        LaCasce A, Howard O, Lib S, et al. Modified magrath regimens for adults                                                           LaCasce A, Howard O, Lib S, et al. Modified magrath regimens for adults with
        with Burkitt and Burkitt-like lymphoma: preserved efficacy with decreased                                                         Burkitt and Burkitt-like lymphoma: preserved efficacy with decreased toxicity.
        toxicity. Leuk Lymphoma 2004;45:761-767.                                                                                          Leuk Lymphoma 2004;45:761-767.
        Mead GM, Sydes MR, Walewski J, et al. An international evaluation of                                                              Mead GM, Sydes MR, Walewski J, et al. An international evaluation of
        CODOX-M and CODOX-M alternating with IVAC in adult Burkitt's lymphoma:                                                            CODOX-M and CODOX-M alternating with IVAC in adult Burkitt's lymphoma:
        results of United Kingdom Lymphoma Group LY06 study. Ann Oncol                                                                    results of United Kingdom Lymphoma Group LY06 study. Ann Oncol
        2002;13:1264-1274.                                                                                                                2002;13:1264-1274.
        Dose-adjusted EPOCH plus rituximab (regimen includes IT                                                                           Dose-adjusted EPOCH plus rituximab (regimen includes IT
        methotrexate)                                                                                                                     methotrexate)
        Dunleavy K, Little, RF, Pittaluga S, et al. A prospective study of Dose-                                                          Dunleavy K, Little, RF, Pittaluga S, et al. A prospective study of Dose-Adjusted
        Adjusted (DA) EPOCH with rituximab in adult patients with newly diagnosed                                                         (DA) EPOCH with Rituximab in adult patients with newly diagnosed Burkitt
        Burkitt lymphoma: A regimen with high efficacy and low toxicity. 10th                                                             lymphoma: A regimen with high efficacy and low toxicity. 10th International
        International Conference on Malignant Lymphomas Abstracts. Annals of                                                              Conference on Malignant Lymphomas Abstracts. Annals of Oncology
        Oncology. 2008;19(suppl_4): iv83-iv84 (Abstract 009)                                                                              2008;19(suppl_4): iv83-iv84 (Abstract 009).
        HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and                                                                        HyperCVAD (cyclophospuhamide, vincristine, doxorubicin, and
        dexamethasone) alternating with high-dose methotrexate and                                                                        dexamethasone) alternating with high-dose methotrexate and cytarabine
        cytarabine + rituximab                                                                                                            ± rituximab
        Thomas DA, Faderl S, O'Brien S, Bueso-Ramos C, et al.                                                                             Thomas DA, Faderl S, O'Brien S, et al. Chemoimmunotherapy with hyper-
        Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of                                                            CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type
        adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia.                                                          lymphoma or acute lymphoblastic leukemia. Cancer 2006;106:1569-1580.
        Cancer 2006;106:1569-1580.



      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                           BURK-A
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Lymphoblastic Lymphoma                                                                                                                                                         Discussion

   DIAGNOSIS a                                                                                                                          WORKUP
   ESSENTIAL:                                                                                                                           ESSENTIAL:
   · Hematopathology review of all slides with at least one paraffin                                                                    · Physical exam: attention to node-bearing areas,
     block representative of the tumor. Rebiopsy if consult material                                                                      including Waldeyer’s ring, and to size of liver and
     is nondiagnostic.                                                                                                                    spleen
   · An FNA or core needle biopsy alone is not generally suitable for                                                                   · Performance status
     the initial diagnosis of lymphoma. In certain circumstances,                                                                       · B symptoms
     when a lymph node is not easily accessible for excisional or                                                                       · CBC, differential, platelets
     incisional biopsy, a combination of core biopsy and FNA
                                                                                                                                        · LDH
     biopsies in conjunction with appropriate ancillary techniques for
                                                                                                                                        · Comprehensive metabolic panel
     the differential diagnosis (immunohistochemistry, flow
     cytometry, PCR for IgH and TCR gene rearrangements, and FISH                                                                       · Uric acid, phosphate
     for major translocations) may be sufficient for diagnosis.                                                                         · Chest/abdominal/pelvic CT with contrast of
   · Adequate immunophenotyping to establish diagnosis b,c                                                                                diagnostic quality                                                                          See Clinical
     > Paraffin panel: CD45 (LCA), CD20, CD79a, CD3, CD2, CD5,                                                                          · Lumbar puncture                                                                             Assessment
        TdT, CD1a, CD10, cyclin D1                                                                                                      · Flow cytometry of cerebrospinal fluid                                                       and Induction
        or                                                                                                                              · Bilateral or unilateral bone marrow biopsy ±                                                Therapy
     > Cell surface marker analysis by flow cytometry:                                                                                    aspirate with flow and cytogenetics                                                         (BLAST-2)
        kappa/lambda, CD45, CD3, CD5, CD4, CD7, CD8, CD19, CD20,                                                                        · Hepatitis B testing d
        CD10, TdT, CD13, CD33, CD1a, cytoplasmic CD3, CD22,                                                                             · MUGA scan/echocardiogram if anthracycline or
        myeloperoxidase                                                                                                                   anthracenediones- based regimen is indicated
                                                                                                                                        · Pregnancy testing in women of child-bearing age
   USEFUL UNDER CERTAIN CIRCUMSTANCES:                                                                                                    (if chemotherapy planned)
   · Additional immunohistochemical studies to establish lymphoma
     subtype                                                                                                                            USEFUL IN SELECTED CASES:
     > Frozen: kappa/lambda                                                                                                             · Head MRI
     > Paraffin panel: CD22, CD4, CD8, cyclin D1                                                                                        · Discussion of fertility issues and sperm banking
   · Molecular genetic analysis to detect: antigen receptor gene                                                                        · Beta-2-microglobulin
     rearrangements                                                                                                                     · PET-CT scan e
   · Cytogenetics or FISH: MYC; t(9;22); t(8;14) and variants
   a This disease is complex and curable; it is preferred that treatment occur at centers                                              d Hepatitis  B testing is indicated because of the risk of reactivation with
     with expertise in the management of the disease.                                                                                    immunotherapy + chemotherapy. Tests include hepatitis B surface antigen and
   b Typical immunophenotype: LBL-B: sIg-, CD10+/-, CD19+, CD20-/+, TdT+. LBL-T:                                                         core antibody for a patient with no risk factors. For patients with risk factors or
     sIg-, CD10-, CD19/20-, CD3-/+, CD4/8+/+, CD1a+/-, TdT+, CD2+, CD7+.                                                                 previous history of hepatitis B, add e-antigen. If positive, check viral load and
   c See Use of Immunophenotyping and Genetic Testing in Differential Diagnosis of                                                       consult with gastroenterologist.
                                                                                                                                       e Initiation of therapy should not be delayed in order to obtain a PET-CT scan.
     Mature B-cell and T/NK-cell Neoplasms (NHODG-A).

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.         BLAST-1
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Lymphoblastic Lymphoma                                                                                                                                                         Discussion

   CLINICAL                                  INDUCTION THERAPY                                           INITIAL RESPONSE                                                                        RELAPSE
   ASSESSMENT

                                             Prophylaxis for tumor lysis
                                             syndrome is mandatory
                                             (See NHODG-B)
                                                                                                                                                                                                                                     Attempt reinduction
                                                                                                                                                                                                                                     with combination
                                                                                                          Complete                                           Observe                                                                 chemotherapy
                                                                                                          response g                                         or                                  Relapse                             or
                                                                                                          (PET negative)                                     Clinical trial f                                                        Allogeneic HSCT
                                                                                                                                                                                                                                     or
                                                                                                                                                                                                                                     Clinical trial
   Stage I–IV                              Clinical trial f
   (disease is                             or
   considered to                           See Suggested Regimens
                                                                                                                                                                               Biopsy
   be systemic)                            (BLAST-A)
                                                                                                                                                                               negative

                                                                                                          Partial                                 Rebiopsy
                                                                                                          response g                              to confirm
                                                                                                          (PET positive)                          disease

                                                                                                                                                                                                           Clinical trial f
                                                                                                                                                                               Biopsy
                                                                                                                                                                                                           or                              Allogeneic
                                                                                                                                                                               positive
                                                                                                                                                                                                           Consider RT                     HSCT




   f For   poor risk patients, consideration of high dose therapy with autologous or allogeneic stem cell rescue is appropriate.
   g See    Response Criteria for Lymphoma (NHODG-C).

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.             BLAST-2
Printed by Eric Kirkendall on 7/17/2011 6:41:14 PM. For personal use only. Not approved for distribution. Copyright © 2011 National Comprehensive Cancer Network, Inc., All Rights Reserved.




                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Lymphoblastic Lymphoma                                                                                                                                                         Discussion

                                                                                              SUGGESTED TREATMENT REGIMENS a
                                                                                                    (in alphabetical order)

     BFM (Berlin–Frankfurt–Munster)
     · Standard BFM regimen:
       > Induction phase:
         7 Vincristine, daunomycin, prednisone, L-asparaginase, cytarabine (IT), and methotrexate (IT).
       > Consolidation phase (5 weeks):
         7 Prednisone, cyclophosphamide, mercaptopurine, vincristine, cytarabine, IT methotrexate, and RT.
       > Interim Maintenance phase (8 weeks):
         7 Mercaptopurine and methotrexate (PO)
       > Delayed intensification (7 weeks):
         7 Reinduction phase (4 weeks):
            - Dexamethasone, vincristine, and doxorubicin.
         7 Reconsolidation phase (3 weeks):
            - L-asparaginase, vincristine, cyclophosphamide, thioguanine, cytarabine, and intrathecal methotrexate.
       > Long-term maintenance (12 weeks):
         7 Vincristine, prednisone, mercaptopurine, methotrexate (PO and IT).
     · Augmented BFM regimen:
       > Induction I:
         7 Prednisone, vincristine, daunorubicin, L-asparaginase, methotrexate (IT).
       > Induction II:
         7 Cyclophosphamide, cytarabine, 6-mercaptopurine, methotrexate (IT)
       > Consolidation I:
         7 Cytarabine, mitoxantrone, methotrexate, asparaginase, 6-mercaptopurine
       > Reinduction I
         7 Prednisolone, vincristine, doxorubicin
         7 Triple prophylaxis: methotrexate, cytarabine, dexamethasone
       > Reinduction II
         7 Cyclophosphamide, cytarabine, 6-thioguanine
         7 Triple prophylaxis: methotrexate, cytarabine, dexamethasone
       > Consolidation II                                                                                                                                                                                               Suggested Treatment
         7 Etoposide, cytarabine                                                                                                                                                                                        Regimens continued
         7 Cyclophosphamide, cytarabine
                                                                                                                                                                                                                        on BLAST-A 2 of 3
   a See   references for regimens BLAST-A 3 of 3.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                           BLAST-A
   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.            1 of 3
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Lymphoblastic Lymphoma                                                                                                                                                         Discussion

                                                                                              SUGGESTED TREATMENT REGIMENS a
                                                                                                    (in alphabetical order)
    · CALGB ALL regimen
      > Induction therapy (4 weeks):
        7 Cyclophosphamide, daunorubicin, vincristine, prednisone, and L-asparaginase.
        7 For patients 60 years and older: the doses of cyclophsphamide, daunorubicin, and prednisone are modified (see reference for
          details).
      > Early intensification (4 weeks):
        7 Intrathecal methotrexate, cyclophosphamide, 6-mercaptopurine, cytarabine, vincristine, and L-asparaginase.
      > CNS prophylaxis and interim maintenance:
        7 Cranial irradiation in select cases, intrathecal methotrexate, 6-mercaptopurine, and methotrexate (PO).
      > Late intensification (8 weeks):
        7 Doxorubicin, vincristine, dexamethasone, cyclophosphamide, 6-thioguanine, and cytarabine.
      > Prolonged maintenance (until 24 months from diagnosis):
        7 Vincristine, prednisone, methotrexate (PO), and 6-mercaptopurine.

    · HyperCVAD b (cyclophosphamide, vincristine, doxorubicin, dexamethasone) alternating with methotrexate + cytarabine, including
      intrathecal methotrexate
      > Maintenance therapy
        7 6-mercaptopurine, methotrexate, vincristine, and prednisone (POMP)
      > In the cases of CD20 positive (³ 20%) acute lymphoblastic lymphoma (ALL), the addition of rituximab should be considered.
      > In cases of Philadelphia chromosome positive ALL, imatinib should be incorporated into regimen.

    · LMB-86 regimen
      > Cytoreductive therapy
        7 COP (cyclophosphamide, vincristine, and prednisone)
      > Induction therapy
        7 COPADM (cyclophosphamide, vincristine, prednisone, doxorubicin, and high-dose methotrexate)
      > Consolidation therapy
        7 CYVE (cytarabine and etoposide; regimen includes high-dose cytarabine)
    · Maintenance chemotherapy
      > Up to 2 y of maintenance based on the treatment protocol is recommended.
                                                                                                                                                            See Suggested Treatment Regimens on BLAST-A 1 of 3
   a See  references for regimens BLAST-A 3 of 3.
   b For T-cell lymphoblastic lymphomas with primary mediastinal presentation, residual masses are irradiated.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                           BLAST-A
   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.            2 of 3
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Lymphoblastic Lymphoma                                                                                                                                                         Discussion

                                                                                                SUGGESTED TREATMENT REGIMENS
                                                                                                          References
                         BFM (Berlin–Frankfurt–Munster)
                         Standard BFM
                         Stock W, La M, Sanford B, et al. What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on
                         cooperative group protocols? A comparison of Children's Cancer Group and Cancer and Leukemia Group B studies. Blood 2008;112:1646-1654.
                         Augmented BFM
                         Hoelzer D, Gokbuget N, Digel W, et al. Outcome of adult patients with T-lymphoblastic lymphoma treated according to protocols for acute
                         lymphoblastic leukemia. Blood 2002;99:4379-4385.

                         CALGB ALL regimen
                         Larson R, Dodge R, Burns C, et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic
                         leukemia: cancer and leukemia group B study 8811. Blood 1995;85:2025-2037.

                         HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate-cytarabine)
                         followed by POMP (mercaptopurine, methotrexate, vincristine, and prednisone) maintenance
                         Kantarjian HM, O'Brien S, Smith TL, et al. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J
                         Clin Oncol 2000;18:547-561.
                         Thomas DA, O'Brien S, Cortes J, et al. Outcome with the hyper-CVAD regimens in lymphoblastic lymphoma. Blood 2004;104:1624-1630.

                         LMB-86 regimen
                         Soussain C, Patte C, Ostronoff M, et al. Small noncleaved cell lymphoma and leukemia in adults. A retrospective study of 65 adults treated with the
                         LMB pediatric protocols. Blood 1995;85:664-674.




      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                           BLAST-A
   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.            3 of 3
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           AIDS-Related B-Cell Lymphomas                                                                                                                                                  Discussion

   DIAGNOSIS                                                                                                                        WORKUP
   ESSENTIAL:                                                                                                                       ESSENTIAL
   · Hematopathology review of all slides with at least one paraffin                                                                · Physical exam: attention to node-bearing areas,
     block representative of the tumor. Rebiopsy if consult material                                                                  including Waldeyer’s ring, and to size of liver and
     is nondiagnostic.                                                                                                                spleen
   · An FNA or core needle biopsy alone is not generally suitable                                                                   · Performance status
     for the initial diagnosis of lymphoma. In certain circumstances,                                                               · B symptoms
     when a lymph node is not easily accessible for excisional or                                                                   · CBC, differential, platelets
     incisional biopsy, a combination of core biopsy and FNA                                                                        · LDH
     biopsies in conjunction with appropriate ancillary techniques                                                                  · Comprehensive metabolic panel
     for the differential diagnosis (immunohistochemistry, flow                                                                     · Uric acid, phosphate
     cytometry, PCR for IgH and TCR gene rearrangements, and                                                                        · Chest/abdominal/pelvic CT with contrast of
     FISH for major translocations) may be sufficient for diagnosis.                                                                  diagnostic quality
   · Adequate immunophenotyping to establish diagnosis a                                                                            · PET-CT scan
     > Recommended panel for paraffin section                                                                                       · Bone marrow biopsy ± aspirate                                                                  See Treatment
        immunohistochemistry: CD45 (LCA), CD20, CD3, CD10,                                                                                                                                                                           and Follow-up
                                                                                                                                    · CD4 count
        BCL2, BCL6, Ki-67, CD138, kappa/lambda, HHV8                                                                                                                                                                                 (AIDS-2) and
                                                                                                                                    · LP                                                                                             (AIDS-3)
        or
                                                                                                                                    · Viral load
     > Cell surface marker analysis by flow cytometry:
        kappa/lambda, CD45, CD3, CD5, CD19, CD10, TdT, CD14,                                                                        · Hepatitis B testing b
        CD20                                                                                                                        · MUGA scan/echocardiogram if anthracycline or
   · Epstein-Barr virus (EBER-ISH)                                                                                                    anthracenediones- based regimen is indicated
                                                                                                                                    · Pregnancy testing in women of child-bearing age
   USEFUL UNDER CERTAIN CIRCUMSTANCES:                                                                                                (if chemotherapy planned)
   · Additional immunohistochemical studies to establish                                                                            USEFUL IN SELECTED CASES
     lymphoma subtype                                                                                                               · UGI/barium enema/endoscopy
     > DLBCL, Burkitt, Plasmablastic, Primary effusion:                                                                             · Neck CT
       CD10, BCL2, Ki-67, BCL6, CD138                                                                                               · Plain bone radiographs and bone scan
   · Molecular genetic analysis to detect: antigen receptor gene                                                                    · Discussion of fertility issues and sperm banking
     rearrangements; BCL2, BCL6, MYC rearrangements                                                                                 · Beta-2-microglobulin
   · Cytogenetics or FISH: BCL2; BCL6; MYC                                                                                          · Brain MRI with gadolinium, or head CT
   a See  Use of Immunophenotyping and Genetic Tesitng in Differential Diagnosis of Mature B-cell and T/NK-cell Neoplasms (NHODG-A).
   b HepatitisB testing is indicated because of the risk of reactivation with immunotherapy + chemotherapy. Tests include hepatitis B surface antigen and core antibody for a
     patient with no risk factors. For patients with risk factors or previous history of hepatitis B, add e-antigen. If positive, check viral load and consult with gastroenterologist.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.           AIDS-1
Printed by Eric Kirkendall on 7/17/2011 6:41:14 PM. For personal use only. Not approved for distribution. Copyright © 2011 National Comprehensive Cancer Network, Inc., All Rights Reserved.




                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           AIDS-Related B-Cell Lymphomas                                                                                                                                                  Discussion

                                                                                                TREATMENT AND FOLLOW-UP
                  Antiretrovirals can be administered safely with chemotherapy, however some regimens have recommended discontinuation.
                  Any change in antiviral therapy should be done in consultation with an infectious disease specialist.

                                                                                                · Suggested regimens: d
                                                                                                  > CODOX-M/IVAC: cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate
                                                                                                    alternating with ifosfamide, etoposide, high-dose cytarabine ± rituximab e
                                                                                                  > Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide,
                                                                                                    doxorubicin) ± rituximab e (+ rituximab is for favorable presentation)
   Burkitt lymphoma
                                                                                                  > CDE (cyclophosphamide, doxorubicin, etoposide) ± rituximab e (+ rituximab is for
                                                                                                    favorable presentation)
                                                                                                  > Consider CHOP with high-dose methotrexate ± rituximab e (+ rituximab is for favorable
                                                                                                    presentation) Avoid methotrexate dose > 3 g/m 2
                                                                                                · GCSF for all patients

                                                                                                · Suggested regimens: d
                                                                                                  > Dose-adjusted EPOCH
                                                                                                  > CDE
   · Lymphoma associated with
                                                                                                  > CHOP
     Castleman’s disease                                                                                                                                                                                           For DLBCL relapse,
                                                                                                  > CDOP (cyclophosphamide, liposomal doxorubicin,
   · Diffuse large B-cell lymphoma                                                                   vincristine, prednisone)
                                                                                                                                                                                                                   see BCEL-6
   · Primary effusion lymphoma c                                                                · GCSF for all patients
                                                                                                · Intrathecal therapy (IT) f
   See Monoclonal Antibody Directed at CD20                                                     · If CD20+, add rituximab with chemotherapy e
   and Viral Reactivation (NHODG-D)
   c Most   cases are CD20 negative and addition of rituximab is not indicated.
   d See   references for regimens AIDS-A.
   e Patients on active antiretrovirals with persistently low CD4 count of <100 tend to have poor prognosis and higher risk of infection associated with the addition of
      rituximab. Spina M, Jaeger U, Sparano JA, et al. Rituximab plus infusional cyclophosphamide, doxorubicin, and etoposide in HIV-associated non-Hodgkin lymphoma:
      pooled results from 3 phase 2 trials. Blood 2005;105:1891-1897. Sparano JA, Lee JY, Kaplan LD et al. Rituximab plus concurrent infusional EPOCH chemotherapy is
      highly effective in HIV-associated B-cell non-Hodgkin lymphoma. Blood 2010;115:3008-3016. Kaplan LD, Lee JY, Ambinder RF, et al. Rituximab does not improve
      clinical outcome in a randomized phase 3 trial of CHOP with or without rituximab in patients with HIV-associated non-Hodgkin lymphoma: AIDS-Malignancies
      Consortium Trial 010. Blood 2005;106:1538-1543.
   f Prophylactic IT methotrexate is used at some NCCN institutions for all patients. At other NCCN institutions, patients with HIV-associated DLBCL receive IT methotrexate
      in selective settings (paranasal sinus, testicular, epidural, bone marrow with large cell lymphoma, HIV-lymphoma, or ³ 2 extranodal sites).

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.           AIDS-2
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           AIDS-Related B-Cell Lymphomas                                                                                                                                                  Discussion

                                                                                                    TREATMENT AND FOLLOW-UP

                Antiretrovirals can be administered safely with chemotherapy however some regimens have recommended discontinuation.
                Any change in antiviral therapy should be done in consultation with an infectious disease specialist.

                                                                                                · Suggested regimens: d
                                                                                                  > CODOX-M/IVAC
                                                                                                  > Dose-adjusted EPOCH
    Plasmablastic lymphoma g
                                                                                                  > HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and
                                                                                                    dexamethasone alternating with high-dose methotrexate and cytarabine)
                                                                                                · Standard CHOP is not adequate therapy


                                                                                                · Consider high-dose methotrexate
                                                                                                · Consider RT alone
    Primary CNS lymphoma                                                                        · For select patients with good performance status on HAART,
                                                                                                  see NCCN CNS Guidelines- Primary CNS Lymphoma
                                                                                                · Best Supportive Care (See NCCN Palliative Care Guidelines)




   See Monoclonal Antibody Directed at CD20 and
   Viral Reactivation (NHODG-D)
   d See   references for regimens AIDS-A.
   g Management     can also apply to HIV negative plasmablastic lymphoma.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.           AIDS-3
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           AIDS-Related B-Cell Lymphomas                                                                                                                                                  Discussion

                                                                                                SUGGESTED TREATMENT REGIMENS
                                                                                                          References

                                     CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate alternating with ifosfamide,
                                     etoposide, high-dose cytarabine)
                                     Wang ES, Straus DJ, Teruya-Feldstein J, et al. Intensive chemotherapy with cyclophosphamide, doxorubicin, high-dose
                                     methotrexate/ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) for human immunodeficiency virus-associated
                                     Burkitt lymphoma. Cancer 2003;98:1196-1205

                                     Dose- adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin)
                                     Little RF, Pittaluga S, Grant N, et al. Highly effective treatment of acquired immunodeficiency syndrome-related lymphoma with
                                     dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology. Blood 2003;101:4653-4659.

                                     CDE (cyclophosphamide, doxorubicin, and etoposide)
                                     Sparano JA, Lee S, Chen MG, et al. Phase II trial of infusional cyclophosphamide, doxorubicin, and etoposide in patients with HIV-
                                     associated non-Hodgkin's Lymphoma: An Eastern Cooperative Oncology Group Trial (E1494). J Clin Oncol 2004;22:1491-1500.

                                     CDE + rituximab
                                     Spina M, Jaeger U, Sparano JA, et al. Rituximab plus infusional cyclophosphamide, doxorubicin, and etoposide in HIV-associated
                                     non-Hodgkin lymphoma: pooled results from 3 phase 2 trials. Blood 2005;105:1891-1897.
                                     Spina M, Simonelli C, Vaccher E, et al. Long-term follow-up of rituximab and infusional cyclophosphamide, doxorubicin, and
                                     etoposide (CDE) in combination with HAART in HIV related Non-Hodgkin's Lymphomas (NHL). ASH Annual Meeting Abstracts.
                                     2008;112:1467.

                                     CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)
                                     Ratner L, Lee J, Tang S, et al. Chemotherapy for human immunodeficiency virus-associated non-Hodgkin's Lymphoma in
                                     combination with highly active antiretroviral therapy. J Clin Oncol 2001;19:2171-2178.




      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          AIDS-A
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Primary Cutaneous B-Cell Lymphoma a                                                                                                                                            Discussion

  DIAGNOSIS                                                          WORKUP
  ESSENTIAL:
  · Review of all slides with at least one paraffin block
    representative of the tumor should be done by a                  ESSENTIAL: d
    pathologist with expertise in the diagnosis of primary           · Complete history and physical examination-           See Initial Therapy for
    cutaneous B-cell lymphoma. Rebiopsy if consult                     including complete skin exam                         Primary Cutaneous
    material is nondiagnostic.                                       · CBC, differential, comprehensive metabolic           Marginal Zone
  · Histopathology review of adequate biopsy (punch,                   panel                                                Lymphoma (CUTB-2)
    incisional, excisional).                                         · LDH
  · Adequate immunophenotyping to establish                          · Hepatitis B testing e if rituximab considered
                 b,c
    diagnosis                                                        · Chest/abdominal/pelvic CT                            See Initial Therapy
    > Recommended panel for paraffin section                         · Bone marrow biopsy, if PC-DLBCL, Leg type
       immunohistochemistry: CD20, CD79a, CD3, CD5,                                                                         for Primary
                                                                     · Pregnancy testing in women of child-bearing          Cutaneous Follicle
       CD10, BCL2, BCL6, Ki-67, kappa/lambda, IRF4/MUM1                age (if chemotherapy planned)
  USEFUL IN CERTAIN CIRCUMSTANCES:                                                                                          Center B-Cell
  · Additional immunohistochemical studies to establish                                                                     Lymphoma (CUTB-2)
                                                                     USEFUL IN SELECTED CASES:
    lymphoma subtype                                                 · PET-CT scan
    > Paraffin panel: cyclin D1                                      · Bone marrow biopsy
    > Assessment of surface IgM and IgD expression (to                                                                      See Initial Therapy for
                                                                       > Consider if PCFCL
       further help in distinguishing DLBCL, leg type from             > Optional if PCMZL                                  Primary Cutaneous
       follicle center lymphoma)                                     · Peripheral blood flow cytometry, if CBC              B-Cell Lymphoma,
  · Molecular genetic analysis to detect: antigen receptor             demonstrates lymphocytosis                           Leg Type (CUTB-4)
    gene rearrangements; IgH gene rearrangement by                   · SPEP/quantitative immunoglobulins for PCMZL
    PCR
  · Cytogenetics or FISH: t(14;18)                                PC-DLBCL, Leg type: Primary Cutaneous Diffuse Large B-cell Lymphoma, Leg type
  NOTE: A germinal (or follicle) center phenotype and large cells PCMZL: Primary Cutaneous Marginal Zone B-cell Lymphoma
   in a skin lesion is not equivalent to DLBCL but is consistent  PCFCL: Primary Cutaneous Follicle Center B-cell Lymphoma
   with primary cutaneous germinal/follicle center lymphoma.
   a For non-cutaneous, see Nongastric MALT Lymphoma (NGMLT-1).                                                                    d Rule  out drug-induced cutaneous lymphoid hyperplasia.
   b See  Use of Immunophenotyping and Genetic Testing in Differential Diagnosis                                                   e Hepatitis B testing is indicated because of the risk of reactivation with
     of Mature B-cell and T/NK-cell Neoplasms (NHODG-A).                                                                              immunotherapy + chemotherapy. Tests include hepatitis B surface antigen and
   c Typical immunophenotype: PC-DLBCL: CD20+ Bcl2+ CD10- Bcl6+/-                                                                     core antibody for a patient with no risk factors. For patients with risk factors or
     IRF4/MUM1+/- ; PCFCL: CD20+ Bcl2- CD10-/+ Bcl6+ IRF4/MUM1-; PCMZL:                                                               previous history of hepatitis B, add e-antigen. If positive, check viral load and
     CD20+ Bcl2+/- CD10- Bcl6- IRF4/MUM1+/- cytoplasmic kappa+ or lambda+ in                                                          consult with gastroenterologist.
     about 40%
      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.         CUTB-1
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Primary Cutaneous B-Cell Lymphoma                                                                                                                                              Discussion
   PRIMARY CUTANEOUS MARGINAL ZONE OR FOLLICLE CENTER B-CELL LYMPHOMA f
   STAGE g             INITIAL THERAPY h                                                                                                                                                                SECONDARY THERAPY
                                                                                                                                                                                                        Observation
                                                                                                                                                                                                        or
                                                                                                                                                                                                        Excision          Relapsed
                                                                                                                                                                                                        or
                                                                                                                                                                                                                          disease,
                                                                                                                                                          Regional                                      Topicals j
                                                                                                                                                                                                        or                See
                                                     Local RT                                                                                                                                                             CUTB-3
                                                                                                                                                                                                        Injected steroids
                                                     (preferred)                                                                                                                                        or
   Solitary/regional,
                                                     or                                                                 Persistent or                                                                   Local RT
   T1-2                                              Excision                                                                                             Generalized disease
                                                                                               CR/PR                    progressive
   (Ann Arbor                                        or                                                                 disease                           (extracutaneous                               Manage as per FOLL-2
   Stage IE)                                         Observation in                                                                                       disease)
                                                     selected cases i
                                                                                                                                                         Generalized disease
                                                                                                                                                         (skin only)


                                                    Observation
                                                    or
                                                    Rituximab
                                                    or
                                                    Topicals j                                                                                                Persistent or
   Generalized disease                              or                                                                                                                                            Relapsed disease,
                                                                                                                                   CR/PR                      progressive
   (skin only), T3                                  Local RT for palliation of symptoms                                                                                                           See CUTB-3
                                                    or                                                                                                        disease
                                                    Intralesional steroids
                                                    or
                                                    Palliative chemotherapy k such as                                                                                                                           See Monoclonal Antibody
                                                    chlorambucil ± rituximab or CVP ±                                                                                                                           Directed at CD20 and Viral
                                                    rituximab                                                                                                                                                   Reactivation (NHODG-D)
   Extracutaneous
   disease                                          Manage as per FOLL-2                                                           i When   RT or surgical treatment is neither not feasible nor desired.
   f Unlessclinically indicated, additional imaging studies during the course of                                                   j There  are case reports showing efficacy of topicals which include steroids,
     treatment are not needed.                                                                                                        imiquimod, nitrogen mustard, bexarotene.
   g See TNM Classification of Cutaneous Lymphoma other than MF/SS (CUTB-A).                                                       k In rare circumstances for very extensive disease, other combination chemotherapy
   h See Treatment References (CUTB-B).                                                                                               regimens listed in FOLL-B are used.
      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.         CUTB-2
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Primary Cutaneous B-Cell Lymphoma                                                                                                                                              Discussion

   PRIMARY CUTANEOUS MARGINAL ZONE OR FOLLICLE CENTER B-CELL LYMPHOMA f
   RELAPSED    STAGE g             ADDITIONAL THERAPY h
   DISEASE
                                                                                                                                                                                             Regional
                                                                                Observation
                                                                                or                                                                       Persistent or                       Generalized disease
                                                                                Excision                                                                                                                                             Manage as
                                                                                                                                 CR/PR                   progressive                         (extracutaneous
                                                                                or                                                                                                                                                   per FOLL-2
                               Solitary/regional, T1-2                                                                                                   disease                             disease)
                                                                                Topicals j
                               (Ann Arbor Stage IE)                             or
                                                                                Intralesional steroids                                                                                       Generalized disease
                                                                                                                                 Refractory l                                                (skin only)
                                                                                or
                                                                                Local RT




                                                                                Observation
   Relapsed                                                                     or
                                                                                Rituximab                                                                                                                 Persistent or
   disease
                                                                                or                                                                               CR/PR                                    progressive
                                                                                Topicals j                                                                                                                disease
                               Generalized disease                              or
                               (skin only), T3                                  Local RT for palliation of symptoms
                                                                                or
                                                                                                                                                                  Refractory l
                                                                                Intralesional steroids
                                                                                or                                                                                                                                   See Monoclonal Antibody
                                                                                Palliative chemotherapy k such as                                                                                                    Directed at CD20 and Viral
                                                                                chlorambucil ± rituximab or CVP ±                                                                                                    Reactivation (NHODG-D)
                                                                                rituximab
                               Extracutaneous
                                                                                                                                                           Manage as per FOLL-2
   f Unless
                               disease                                                                                                j There
           clinically indicated, additional imaging studies during the course of                                                               are case reports showing efficacy of topicals which include steroids,
     treatment is not needed.                                                                                                            imiquimod, nitrogen mustard, bexarotene.
   g See TNM Classification of Cutaneous Lymphoma other than MF/SS (CUTB-A).                                                          k In rare circumstances for very extensive disease, other combination
   h See Treatment References (CUTB-B).                                                                                                  chemotherapy regimens listed in FOLL-B are used.
                                                                                                                                      l Refractory to all previous treatments.


      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.         CUTB-3
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Primary Cutaneous B-Cell Lymphoma                                                                                                                                              Discussion

   PRIMARY CUTANEOUS DIFFUSE LARGE B-CELL LYMPHOMA, LEG TYPE

   STAGE g                                            INITIAL THERAPY                                                                                                                                SECONDARY THERAPY



                                                                                                                                                                                                       R-CHOP (if not
                                                                                                     CR                 Observe                    Relapse
                                                      R-CHOP m +            local RT                                                                                                                   previously received)
                                                      or                                                                                                                                               or
   Solitary regional, T1-2                                                                                                                                                                             Manage as per BCEL-6
   (Ann Arbor Stage IE)                               Local RT n
                                                      or                                                                                                                                               or
                                                      Clinical trial                                                                                                                                   Local RT to previously
                                                                                                     PR                                                                                                unirradiated tumor




                                                                                                      CR                 Observe                    Relapse
                                                                                                                                                                                                       Manage as per BCEL-6
                                                      R-CHOP ± local RT                                                                                                                                or
   Generalized disease
                                                      or                                                                                                                                               Local RT for palliation
   (skin only), T3                                                                                                                                                                                     or
                                                      Clinical trial
                                                                                                                                                                                                       Radioimmunotherapy
                                                                                                      PR



   Extracutaneous
                                                     Manage as per BCEL-3
   disease
                                                                                                                                                                                                            See Monoclonal Antibody
                                                                                                                                                                                                            Directed at CD20 and Viral
                                                                                                                                                                                                            Reactivation (NHODG-D)

   g See TNM Classification of Cutaneous Lymphoma other than MF/SS (CUTB-A).
   m For alternate regimens, see BCEL-C.
   n For patients not able to tolerate chemotherapy.


      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.         CUTB-4
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Primary Cutaneous B-Cell Lymphoma                                                                                                                                              Discussion

                                                             TNM CLASSIFICATION OF CUTANEOUS LYMPHOMA OTHER THAN MF/SS a,b

                         T
                             T1                  Solitary skin involvement
                                                        T1a: a solitary lesion < 5 cm diameter
                                                        T1b: a solitary > 5 cm diameter
                             T2                  Regional skin involvement: multiple lesions limited to 1 body region or 2 contiguous body regions b
                                                        T2a: all-disease-encompassing in a < 15-cm-diameter circular area
                                                        T2b: all-disease-encompassing in a > 15- and < 30-cm-diameter circular area
                                                        T2c: all-disease-encompassing in a > 30-cm-diameter circular area
                             T3                  Generalized skin involvement
                                                        T3a: multiple lesions involving 2 noncontiguous body regions b
                                                        T3b: multiple lesions involving ³ 3 body regions b
                         N
                             N0                  No clinical or pathologic lymph node involvement
                             N1                  Involvement of 1 peripheral lymph node region c that drains an area of current or prior skin involvement
                             N2                  Involvement of 2 or more peripheral lymph node regions c or involvement of any lymph node region
                                                 that does not drain an area of current or prior skin involvement
                             N3                  Involvement of central lymph nodes

                         M
                          M0                     No evidence of extracutaneous non–lymph node disease
                             M1                  Extracutaneous non-lymph node disease present




   a This work was originally published in Blood. Kim YH, Willemze R, Pimpinell Ni, et al, for the ISCL and the EORTC. TNM classification system for primary
     cutaneous lymphomas other than mycosis fungoides and Sézary syndrome: A proposal of the International Society for Cutaneous Lymphomas (ISCL) and the
     Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC) Blood 2007;110:479-484. © the American
     Society of Hematology.
   b For definition of body regions, see Body Regions for the Designation of T (skin involvement) Category (CUTB-A 2 of 2).
   c Definition of lymph node regions is consistent with the Ann Arbor system: Peripheral sites: antecubital, cervical, supraclavicular, axillary, inguinal-femoral, and
     popliteal. Central sites: mediastinal, pulmonary hilar, paraortic, iliac.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                            CUTB-A
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Primary Cutaneous B-Cell Lymphoma                                                                                                                                              Discussion

                                                         BODY REGIONS FOR THE DESIGNATION OF T (SKIN INVOLVEMENT) CATEGORY a,b,c




   a Kim  YH, Willemze R, Pimpinell Ni, et al, for the ISCL and the EORTC. TNM classification system for primary cutaneous lymphomas other than mycosis
     fungoides and Sézary syndrome: A proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the
     European Organization of Research and Treatment of Cancer (EORTC) Blood 2007;110:479-484.
   b Left and right extremities are assessed as separate body regions. The designation of these body regions are based on regional lymph node drainage patterns.
   c Definition of body regions: Head and neck: inferior border—superior border of clavicles, T1 spinous process. Chest: superior border—superior border of
     clavicles; inferior border—inferior margin of rib cage; lateral borders—midaxillary lines, glenohumeral joints (inclusive of axillae). Abdomen/genital: superior
     border—inferior margin of rib cage; inferior border—inguinal folds, anterior perineum; lateral borders—mid-axillary lines. Upper back: superior border—T1
     spinous process; inferior border—inferior margin of rib cage; lateral borders—mid-axillary lines. Lower back/buttocks: superior border—inferior margin of rib
     cage; inferior border—inferior gluteal fold, anterior perineum (inclusive of perineum); lateral borders—midaxillary lines. Each upper arm: superior
     borders—glenohumeral joints (exclusive of axillae); inferior borders—ulnar/radial-humeral (elbow) joint. Each lower arm/hand: superior borders—ulnar/radial-
     humeral (elbow) joint. Each upper leg (thigh): superior borders—inguinal folds, inferior gluteal folds; inferior borders—mid-patellae, midpopliteal fossae. Each
     lower leg/foot: superior borders—mid-patellae, mid-popliteal fossae.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                            CUTB-A
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Primary Cutaneous B-Cell Lymphoma                                                                                                                                              Discussion

                                                                                                        TREATMENT REFERENCES
   Rituximab                                                                                                                           Chemotherapy
   Morales AV, Advani R, Horwitz SM, et al. Indolent primary cutaneous B-cell lymphoma:                                                Hoefnagel JJ, Vermeer MH, Jansen PM, et al. Primary cutaneous marginal zone B-
   experience using systemic rituximab. J Am Acad Dermatol 2008;59:953-957.                                                            cell lymphoma: Clinical and therapeutic features in 50 cases. Arch Dermatol
   Heinzerling LM, Urbanek M, Funk JO, et al. Reduction of tumor burden and                                                            2005;141:1139-1145.
   stabilization of disease by systemic therapy with anti-CD20 antibody (rituximab) in                                                 Bekkenk MW, Vermeer MH, Geerts ML, et al. Treatment of multifocal primary
   patients with primary cutaneous B-cell lymphoma. Cancer 2000;89:1835-1844.                                                          cutaneous B-cell lymphoma: a clinical follow-up study of 29 patients. J Clin Oncol
   Valencak J, Weihsengruber F, Rappersberger K, et al. Rituximab monotherapy for                                                      1999;17:2471-2478.
   primary cutaneous B-cell lymphoma: Response and follow-up in 16 patients. Ann                                                       Senff NJ, Noordijk EM, Kim YH, et al. European Organization for Research and
   Oncol 2009;20:326-330.                                                                                                              Treatment of Cancer and International Society for Cutaneous Lymphoma consensus
   Senff NJ, Noordijk EM, Kim YH, et al. European Organization for Research and                                                        recommendations for the management of cutaneous B-cell lymphomas. Blood
   Treatment of Cancer and International Society for Cutaneous Lymphoma consensus                                                      2008;112:1600-1609.
   recommendations for the management of cutaneous B-cell lymphomas. Blood                                                             Grange F, Beylot-Barry M, Courville P, et al. Primary cutaneous diffuse large B-cell
   2008;112:1600-1609.                                                                                                                 lymphoma, leg type: clinicopathologic features and prognostic analysis in 60 cases.
   Heinzerling L, Dummer R, Kempf W, Schmid MH, Burg G. Intralesional therapy with                                                     Arch Dermatol 2007;143:1144-1150.
   anti-CD20 monoclonal antibody rituximab in primary cutaneous B-cell lymphoma. Arch                                                  Brice P, Cazals D, Mounier N, et al. Primary cutaneous large-cell lymphoma: analysis
   Dermatol 2000;136:374-378.                                                                                                          of 49 patients included in the LNH87 prospective trial of polychemotherapy for high-
   Topicals                                                                                                                            grade lymphomas. Groupe d'Etude des Lymphomes de l'Adulte. Leukemia
   Topical/intralesional corticosteroids                                                                                               1998;12:213-219.
   Bekkenk MW, Vermeer MH, Geerts ML, et al. Treatment of multifocal primary cutaneous                                                 Rijlaarsdam JU, Toonstra J, Meijer OW, Noordijk EM, Willemze R. Treatment of
   B-cell lymphoma: a clinical follow-up study of 29 patients. J Clin Oncol 1999;17:2471-                                              primary cutaneous B-cell lymphomas of follicle center cell origin: A clinical follow-up
   2478.                                                                                                                               study of 55 patients treated with radiotherapy or polychemotherapy. J Clin Oncol
                                                                                                                                       1996;14:549-555.
   Topical nitrogen mustard                                                                                                            Vermeer MH, Geelen FA, van Haselen CW, et al. Primary cutaneous large B-cell
   Bachmeyer C, Orlandini V, Aractingi S. Topical mechlorethamine and clobetasol in                                                    lymphomas of the legs. A distinct type of cutaneous B-cell lymphoma with an
   multifocal primary cutaneous marginal zone-B cell lymphoma. British Journal of                                                      intermediate prognosis. Dutch Cutaneous Lymphoma Working Group. Arch Dermatol
   Dermatology 2006;154:1207-1209.                                                                                                     1996;132:1304-1308.

   Topical bexarotene
   Trent JT, Romanelli P, Kerdel FA. Topical Targretin and Intralesional Interferon Alfa for
   Cutaneous Lymphoma of the Scalp. Arch Dermatol 2002;138:1421-1423.

   Topical imiquimod
   Coors EA, Schuler G, Von Den Driesch P. Topical imiquimod as treatment for different
   kinds of cutaneous lymphoma. Eur J Dermatol 2006;16:391-393.
   Stavrakoglou A, Brown VL, Coutts I. Successful treatment of primary cutaneous follicle
   centre lymphoma with topical 5% imiquimod. Br J Dermatol 2007;157:620-622.



      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Peripheral T-Cell Lymphoma                                                                                                                                                     Discussion

   DIAGNOSIS                                                                                                                SUBTYPES
   ESSENTIAL:
   · Review of all slides with at least one paraffin block
     representative of the tumor should be done by a
     hematopathologist with expertise in the diagnosis of
     PTCL. Rebiopsy if consult material is nondiagnostic.
   · An FNA alone is not sufficient for the initial diagnosis of
     peripheral T-cell lymphoma.
                                                                                                                            Subtypes included:
   · Adequate immunophenotyping to establish diagnosis a,b
                                                                                                                            · Peripheral T-cell lymphoma (PTCL), NOS
     > Recommended panel for paraffin section
                                                                                                                            · Angioimmunoblastic T-cell lymphoma (AITL) c                                                              See Workup
       immunohistochemistry: CD20, CD3, CD10, BCL6,
                                                                                                                            · Anaplastic large cell lymphoma (ALCL), ALK positive                                                      (TCEL-2)
       Ki-67, CD5, CD30, CD2, CD4, CD8, CD7, CD56, CD57
                                                                                                                            · Anaplastic large cell lymphoma (ALCL), ALK negative
       CD21, CD23, EBER, ALK
                                                                                                                            · Enteropathy associated T-cell lymphoma (EATL)
       or
     > Cell surface marker analysis by flow cytometry:
                                                                                                                            Subtypes not included:
       kappa/lambda, CD45, CD3, CD5, CD19, CD10, CD20,
                                                                                                                            · Primary cutaneous ALCL
       CD30, CD4, CD8, CD7, CD2
                                                                                                                            · All other T-cell lymphomas
   USEFUL UNDER CERTAIN CIRCUMSTANCES:
   · Molecular genetic analysis to detect: antigen receptor
     gene rearrangements; t(2;5) and variants
   · Additional immunohistochemical studies to establish                                                                   Extranodal NK/T-cell lymphoma, nasal type (See NKTL-1)
     lymphoma subtype: βF1, CD279
   · Cytogenetics or FISH
   · CXCL-13, PD-1




   a Molecular   diagnosis for T-cell receptor rearrangements should be done in most circumstances to confirm clonality. T-cell receptors rearrangements alone are not
     sufficient for diagnosis.
   b See Use of Immunophenotyping and Genetic Testing in Differential Diagnosis of Mature B-cell and T/NK-cell Neoplasms (NHODG-A).
   c AITL may occasionally present with concurrent DLBCL. EBV and appropriate immunohistochemistry should be performed.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Peripheral T-Cell Lymphoma                                                                                                                                                     Discussion

    WORKUP

     ESSENTIAL: d
     · Physical exam: attention to node-bearing areas,
       including Waldeyer's ring, size of liver and spleen,
       skin rash and nasopharynx
     · Performance status
     · B symptoms
     · CBC, differential, platelets
     · Bone marrow biopsy
     · LDH
     · Comprehensive metabolic panel
     · Uric acid
     · Chest/abdominal/pelvic CT with contrast of                                                            See Induction
       diagnostic quality                                                                                    Therapy (TCEL-3)
     · Calculation of International Prognostic Index (IPI) e
     · MUGA scan/echocardiogram if anthracycline or
       anthracenediones- based regimen is indicated
     · Pregnancy testing in women of child-bearing age
       (if chemotherapy planned)

     USEFUL IN SELECTED CASES:
     · PET-CT scan
     · Neck CT
     · Head CT or MRI
     · Skin biopsy
     · Discussion of fertility issues and sperm banking
     · HIV, HTLV-1




   d The   role of intrathecal prophylaxis in PTCL is largely unknown.
   e See   International Prognostic Index (TCEL-A).

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          TCEL-2
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Peripheral T-Cell Lymphoma                                                                                                                                                     Discussion

                                   STAGE                                        INDUCTION THERAPY                                    Consider prophylaxis for tumor
                                                                                                                                     lysis syndrome (See NHODG-B)

                                                                                CHOP + RT for limited                                                          Relapse,
   ALCL, ALK +                                                                                                                                                 See Additional
                                                                                stage disease
                                                                                                                                                               Therapy (TCEL-5)
                                                                                Clinical trial (preferred)
                                                                                or                                                                                      Interim restaging:
                                                 aaIPI e
                                                                                Multiagent chemotherapy g                                                               repeat all positive                                              See
                                                 low/low-
                                                                                4 - 6 cycles + locoregional                                                             studies. If PET-CT scan                                          Follow-up
                                                 intermediate
                                                                                RT (30-40 Gy to involved                                                                positive, rebiopsy                                               Therapy
                                                                                region)                                                                                 before changing course                                           (TCEL-4)
                                  Stage                                                                                                                                 of treatment.
                                  I, II
                                                                                                                                                                                 Clinical trial
   · PTCL, NOS                                                                                                                                                                   or
   · ALCL, ALK -                                 aaIPI e                        Clinical trial                                                        Complete                   Consider high dose therapy
   · AITL f                                      high/high-                     (preferred)                       At completion of                    response i                 with stem cell rescue j
   · EATL                                        intermediate                   or                                treatment, repeat                                              or
                                                                                                                                                                                                                                         Relapse,
                                                                                Multiagent                        all positive                                                   Observe
                                                                                                                                                                                                                                         See
                                                                                chemotherapy g                    studies. If PET-                                                                                                       Additional
                                  Stage
                                                                                6 - 8 cycles                      CT scan positive,                                                                                                      Therapy
                                  III, IV
                                                                                ± RT h                            rebiopsy before                                                                                                        (TCEL-5)
                                                                                                                  changing course
                                                                                                                  of treatment.                        Partial response
                                                                                                                                                       or no response
                                                                                                                                                       or progressive
   e See  International Prognostic Index (TCEL-A).                                                                                                     disease i
   f Forselected patients (elderly, comorbid conditions), a trial of single agent corticosteroid may be considered for symptom management.
   g See Suggested Treatment Regimens (TCEL-B).
   h Patients with locoregional disease receive RT.
   i See Response Criteria for Lymphoma (NHODG-C).
   j Localized areas can be irradiated before or after high dose therapy.


      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          TCEL-3
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Peripheral T-Cell Lymphoma                                                                                                                                                     Discussion

   STAGE I/II, LOW/LOW- INTERMEDIATE
   INTERIM                                       FOLLOW-UP THERAPY                                             END OF TREATMENT
   RESPONSE                                                                                                    RESTAGING
                                                                                                                                                                                              Clinical follow-
                                                                                                                                                                                              up every 3-6 mo
                                                                                                                                                                 Complete                                                            Relapse,
                                                                                                                                                                                              for 5 y and then                       See Additional
                                                                                                                                                                 response i                   yearly or as
                                                 Complete                                                                                                                                                                            Therapy (TCEL-5)
   Complete                                                                                                    At completion of                                                               clinically
                                                 planned course                                                                                                                               indicated
   response i                                                                                                  treatment, repeat
                                                 of treatment (RT)
                                                                                                               all positive
                                                                                                               studies. If PET -                                 Partial                                                             See Additional
                                                                                                               CT scan positive,                                 response i                                                          Therapy (TCEL-5)
                                                                                                               rebiopsy before
                                                 RT (30-40 Gy)
                                                                                                               changing course
                                                 or
                                                 High dose therapy with                                        of treatment.
   Partial                                       stem cell rescue ± RT                                                                                            Progressive                                                        See Additional
   response i                                    or                                                                                                               disease i                                                          Therapy (TCEL-5)
                                                 Clinical trial (may include
                                                 allogeneic stem cell
                                                 transplant ± RT)




   No response                                   RT
   or progressive                                or
                                                 See Additional Therapy
   disease i
                                                 for Relapse (TCEL-5)




   i See   Response Criteria for Lymphoma (NHODG-C).

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.            TCEL-4
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Peripheral T-Cell Lymphoma                                                                                                                                                     Discussion

   RELAPSE/                                                            ADDITIONAL                                                                                                CONSOLIDATION/                                       RELAPSE #2
   REFRACTORY                                                          THERAPY                                                                                                   ADDITIONAL THERAPY                                   OR GREATER
   DISEASE
                                                                                                                                                                                 Clinical trial
                                                                                                                                                                                 or
                                                                                                                                                                                 Allogeneic stem cell
                                                                                                                               Complete response i                               transplant j (non
                                                                                                                               or                                                myeloablative or ablative)
                                                                                                                               partial response i                                or                                                  Clinical trial
                                                                                                                                                                                 High dose therapy with
                                                                                                                                                                                 autologous stem cell
                                                                       Clinical trial preferred                                                                                  rescue j
                                 Candidate for                         or
                                 transplant                            Second-line therapy
                                                                       See Suggested
                                                                       Regimens (TCEL-B)

                                                                                                                                                                                                                                     Clinical trial
                                                                                                                                                                                                                                     or
   Relapse/                                                                                                                                                                                                                          Best
   refractory                                                                                                                  No response                                                                                           supportive
   disease                                                                                                                                                                                                                           care
                                                                                                                                                                                                                                     or
                                                                                                                                                                                                                                     Palliative RT

                                                                       Clinical trial
                                  Non-                                 or
                                  candidate for                        Second-line therapy
                                  transplant                           See Suggested Regimens (TCEL-B)
                                                                       or
                                                                       Palliative RT
   i See   Response Criteria for Lymphoma (NHODG-C).
   j Localized areas can be irradiated before or after high dose therapy.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.           TCEL-5
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Peripheral T-Cell Lymphoma                                                                                                                                                     Discussion




                                     INTERNATIONAL PROGNOSTIC INDEX a                                                                                                  Prognostic Index for PTCL-U (PIT) b
                                                                                                                                                                RISK FACTORS:                                           PROGNOSTIC RISK:
      ALL PATIENTS:                                            INTERNATIONAL INDEX, ALL PATIENTS:
                                                                                                                                                                · Age > 60 years                                        · Group 1   0
      · Age > 60 years                                         · Low                    0 or 1
                                                                                                                                                                · Serum LDH > 1 x normal                                · Group 2   1
      · Serum LDH > 1 x normal                                 · Low intermediate         2
                                                                                                                                                                · Performance status 2-4                                · Group 3   2
      · Performance status 2-4                                 · High intermediate        3
                                                                                                                                                                · Bone marrow                                           · Group 4 3 or 4
      · Stage III or IV                                        · High                   4 or 5
                                                                                                                                                                  involvement
      · Extranodal involvement
        > 1 site

                 AGE-ADJUSTED INTERNATIONAL PROGNOSTIC INDEX a

      PATIENTS £ 60 YEARS:                                   INTERNATIONAL INDEX, PATIENTS £ 60 YEARS:
      · Stage III or IV                                      · Low                 0
      · Serum LDH > 1 x normal                               · Low/intermediate    1
      · Performance status 2-4                               · High/intermediate   2
                                                             · High                3




   a Adapted with permission, The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-hodgkin’s lymphoma.
     N Engl J Med 329:987-994, 1993. Copyright © 1993 Massachusetts Medical Society. All rights reserved.
   b Gallamini A, Stelitano C, Calvi R, et al. Peripheral T-cell lymphoma unspecified (PTCL-U): A new prognostic model from a retrospective multicentric clinical study.
     Blood 2004;103:2474-2479.
      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          TCEL-A
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Peripheral T-Cell Lymphoma                                                                                                                                                     Discussion

                                                                                               SUGGESTED TREATMENT REGIMENS a
                                                                                                     (in alphabetical order)

         First-line therapy: b                                                                                                        Second-line therapy (candidate for transplant):
         · Clinical trial preferred                                                                                                   · Clinical trial preferred
         · CHOP (cyclophosphamide, doxorubicin, vincristine,                                                                          · DHAP (dexamethasone, cisplatin, cytarabine)
           prednisone) appropriate for ALCL, ALK+.                                                                                    · ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin)
         · Other regimens that can be used include:                                                                                   · GDP (gemcitabine, dexamethasone, cisplatin)
           > CHOEP (cyclophosphamide, doxorubicin, vincristine,                                                                       · GemOx (gemcitabine, oxaliplatin)
             etoposide and prednisone)                                                                                                · ICE (ifosfamide, carboplatin, etoposide)
           > CHOP every 2 or 3 wks                                                                                                    · MINE (mesna, ifosfamide, mitoxantrone, etoposide)
           > CHOP followed by ICE (ifosfamide, carboplatin, etoposide)                                                                · Pralatrexate (category 2B) c
           > CHOP followed by IVE (ifosfamide, etoposide and epirubicin)                                                              · Romidepsin
             alternating with intermediate dose methotrexate [New Castle
             Regimen]                                                                                                                 Second-line therapy (non-candidate for transplant):
           > HyperCVAD (cyclophosphamide, vincristine, doxorubicin,                                                                   · Clinical trial preferred
             and dexamethasone) alternating with high-dose methotrexate                                                               · Alemtuzumab d
             and cytarabine                                                                                                           · Bortezomib d
                                                                                                                                      · Cyclosporine for AITL only e
         First-line Consolidation:                                                                                                    · Denileukin diftitox
         · All patients, except low risk (aaIPI), consider consolidation with                                                         · Gemcitabine
           high dose therapy and stem cell rescue.                                                                                    · Pralatrexate c
           (ALCL, ALK positive is a subtype with good prognosis and                                                                   · Radiation therapy
           does not need consolidative transplant if in remission.)                                                                   · Romidepsin




   a See   references for regimens TCEL-B 2 of 2.
   b Standard    induction for PTCL remains undefined with the exception of ALCL, ALK + for which CHOP remains the standard.
      Clinical trial is preferred for all other subtypes.
   c In AITL, pralatrexate has limited activity.
   d Activity has been demonstrated in small clinical trials and additional larger trials are needed.
   e With close follow-up of renal function.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                            TCEL-B
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Peripheral T-Cell Lymphoma                                                                                                                                                     Discussion

                                                                                                SUGGESTED TREATMENT REGIMENS
                                                                                                          References
    First-line therapy                                                                                                                 DHAP (dexamethasone, cisplatin, cytarabine)
    CHOP                                                                                                                               Velasquez WS, Cabanillas F, Salvador P, et al. Effective salvage therapy for lymphoma with
    Savage KJ, Chhanabhai M, Gascoyne RD, Connors JM. Characterization of peripheral T-cell                                            cisplatin in combination with high-dose Ara-C and dexamethasone (DHAP). Blood 1988;71:117-
    lymphomas in a single North American institution by the WHO classification. Ann Oncol                                              122.
    2004;15:1467-1475.                                                                                                                 Mey UJ, Orlopp KS, Flieger D, et al. Dexamethasone, high-dose cytarabine, and cisplatin in
    CHOP or CHOP-14 with or without etoposide                                                                                          combination with rituximab as salvage treatment for patients with relapsed or refractory aggressive
    Pfreundschuh M, Trümper L, Kloess M, Schmits R, et al. German High-Grade Non-Hodgkin's                                             non-Hodgkin's lymphoma. Cancer Invest 2006;24:593-600.
    Lymphoma Study Group. Two-weekly or 3-weekly CHOP chemotherapy with or without                                                     ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin)
    etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive                                          Velasquez WS, McLaughlin P, Tucker S, et al. ESHAP - an effective chemotherapy regimen in
    lymphomas: results of the NHL-B1 trial of the DSHNHL. Blood 2004;104:626-33.                                                       refractory and relapsing lymphoma: a 4-year follow-up study. J Clin Oncol 1994;12:1169-1176.
    Pfreundschuh M, Trümper L, Kloess M, Schmits R, et al. German High-Grade Non-Hodgkin's                                             Gemcitabine
    Lymphoma Study Group. Two-weekly or 3-weekly CHOP chemotherapy with or without                                                     Zinzani PL, Baliva G, Magagnoli M, et al. Gemcitabine Treatment in Pretreated Cutaneous T-Cell
    etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-                                     Lymphoma: Experience in 44 Patients. J Clin Oncol 2000;18:2603-2606.
    B2 trial of the DSHNHL. Blood 2004;104(3):634-41.                                                                                  Zinzani PL, Magagnoli M, Bendandi M, et al. Therapy with gemcitabine in pretreated peripheral T-
    CHOP followed by ICE                                                                                                               cell lymphoma patients. Ann Oncol 1998;9:1351-1353.
    Horwitz S, Moskowitz C, Kewalramani T, et al. Second-line therapy with ICE followed by high                                        GDP (gemcitabine, dexamethasone, cisplatin)
    dose therapy and autologous stem cell transplantation for relapsed/refractory peripheral T-cell                                    Crump M, Baetz T, Couban S, et al. Gemcitabine, dexamethasone, and cisplatin in patients with
    lymphomas: Minimal benefit when analyzed by intent to treat. ASH Annual Meeting Abstracts.                                         recurrent or refractory aggressive histology B-cell non-Hodgkin lymphoma: a Phase II study by the
    2005;106:2679.                                                                                                                     National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG). Cancer 2004;101:1835-
    CHOP followed by IVE                                                                                                               1842.
    Sieniawski M, Lennard J, Millar C, et al. Aggressive primary chemotherapy plus autologous                                          GemOX (gemcitabine, oxaliplatin)
    stem cell transplantation improves outcome for peripheral T cell lymphomas compared with                                           Lopez A, Gutierrez A, Palacios A, et al. GEMOX-R regimen is a highly effective salvage regimen in
    CHOP-like regimens. ASH Annual Meeting Abstracts. 2009;114:1660.                                                                   patients with refractory/relapsing diffuse large-cell lymphoma: a phase II study. Eur J Haematol
    HyperCVAD alternating with high-dose methotrexate and cytarabine                                                                   2008;80:127-132.
    Escalon MP, Liu NS, Yang Y, et al. Prognostic factors and treatment of patients with T-cell non-                                   ICE (ifosfamide, carboplatin, etoposide)
    Hodgkin lymphoma: the M. D. Anderson Cancer Center experience. Cancer 2005;103:2091-                                               Zelenetz AD, Hamlin P, Kewalramani T, et al. Ifosfamide, carboplatin, etoposide (ICE)-based
    2098.                                                                                                                              second-line chemotherapy for the management of relapsed and refractory aggressive non-
    Pozadzides JV et al. Prognosis and treatment of patients with peripheral T-cell lymphoma: The                                      Hodgkin's lymphoma. Ann Oncol 2003;14[suppl 1]:i5-10.
    M. D. Anderson Cancer Center experience. 2010 ASCO Annual Meeting Abstract 8051.                                                   Pralatrexate
                                                                                                                                       O'Connor O, Pro B, Pinter-Brown L, et al. PROPEL: Results of the pivotal,
    Second-line therapy                                                                                                                multicenter, phase II study of pralatrexate in patients with relapsed or
    Alemtuzumab                                                                                                                        refractory peripheral T-cell lymphoma (PTCL). ASCO Meeting Abstracts.
    Enblad G, Hagberg H, Erlanson M, et al. A pilot study of alemtuzumab (anti-CD52 monoclonal                                         2009: 8561.
    antibody) therapy for patients with relapsed or chemotherapy-refractory peripheral T-cell                                          Romdepsin
    lymphomas. Blood 2004;103:2920-2924.                                                                                               Coiffier B, Pro B, Prince HM, et al. Final results from a pivotal, multicenter, international, open-
    Cyclosporine for AILT                                                                                                              label, phase 2 study of romidepsin in progressive or relapsed peripheral T-cell lymphoma (PTCL)
    Advani R, Horwitz S, Zelenetz A, Horning SJ. Angioimmunoblastic T cell lymphoma: treatment                                         following prior systemic therapy. Blood (ASH Annual Meeting Abstracts). 2010;116:114-.
    experience with cyclosporine. Leuk Lymphoma 2007;48:521-525.
    Denileukin diftitox
    Talpur R, Apisarnthanarax N, Ward S, Duvic M. Treatment of refractory peripheral T-cell
    lymphoma with denileukin diftitox (ONTAK). Leuk Lymphoma 2002;43:121-126.
    Dang NH, Pro B, Hagemeister FB, et al. Phase II trial of denileukin diftitox for
    relapsed/refractory T-cell non-Hodgkin lymphoma. Br J Haematol 2007;136:439-447.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                            TCEL-B
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Mycosis Fungoides/Sezary Syndrome                                                                                                                                              Discussion
   DIAGNOSIS                                                          WORKUP                                                                                                                                                   STAGE
   ESSENTIAL:                                                         ESSENTIAL:                                                                                                                                               (MFSS-2)
   · Biopsy of suspicious skin sites                                  · Complete physical examination             > TCR gene rearrangement of                                                                                             See Primary
   · Dermatopathology review of                                         > Examination of entire skin:                                                                                                                           Stage
                                                                                                                     peripheral blood lymphocytes if                                                                                      Treatment
     slides                                                               assessment of %BSA (palm plus digits                                                                                                                  IA
                                                                                                                     Sezary Syndrome suspected                                                                                            (MFSS-4)
   USEFUL UNDER CERTAIN                                                   » 1%BSA) and type of skin lesion        > Comprehensive metabolic panel
   CIRCUMSTANCES:                                                         (patch/plaque, tumor, erythroderma)     > LDH
   · Immunohistochemical studies                                        > Palpation of peripheral lymph node     · Imaging studies
     of skin biopsy a,b (CD2, CD3,                                        regions                                  > Neck/chest/abdominal/pelvic                                                                                          See Primary
                                                                                                                                                                                                                                Stage
     CD4, CD5, CD7, CD8, CD20,                                          > Palpation for organomegaly/masses          contrast-enhanced CT or                                                                                              Treatment
                                                                                                                                                                                                                                IB-IIA
     CD30, CD26, CD56, TIA1,                                          · Laboratory studies: d                        integrated whole body PET-CT                                                                                         (MFSS-5)
     granzyme B, βF1)                                                   > CBC with Sezary screen (manual slide       (³ T2, large cell transformed or
   · Molecular study for T-cell                                           review, "Sezary cell prep")                folliculotropic MF, or with
     receptor (TCR) gene                                                > Sezary flow cytometric study (optional     palpable adenopathy or
     rearrangements (assessment of                                        for T1); CD3, CD4, CD7, CD8, CD26 to       abnormal laboratory studies)                                                                                         See Primary
                                                                                                                                                                                                                                Stage
     clonality) of skin biopsy; a PCR                                     assess for expanded CD4+ cells with · Pregnancy testing in women of                                                                                             Treatment
                                                                                                                                                                                                                                IIB
     methods c                                                            increased CD4/CD8 ratio or with          child-bearing age e                                                                                                    (MFSS-6)
   · Assessment of peripheral blood                                       abnormal immunophenotype including
     for Sezary cells (in cases where                                     loss of CD7 or CD26
     skin is not diagnostic,
     especially T4) including Sezary                                  USEFUL IN SELECTED CASES:
                                                                      · Bone marrow biopsy (not required for staging but used to document visceral                                                                              Stage     See Primary
     cell prep, flow cytometry and                                                                                                                                                                                                        Treatment
     PCR for TCR gene                                                   disease in those suspected to have marrow involvement including B2 blood                                                                                III
                                                                                                                                                                                                                                          (MFSS-7)
     rearrangement                                                      involvement and in patients with unexplained hematologic abnormality)
   · Biopsy of suspicious lymph                                       · Biopsy of suspicious lymph nodes or identical clones (recommend
     nodes (in absence of definitive                                    assessment of clonality for all but particularly NCI LN 2-3) or suspected
                                                                        extracutaneous sites                                                                                                                                    Stage     See Primary
     skin diagnosis)                                                                                                                                                                                                                      Treatment
   · Assessment of ATLL serology                                      · Rebiopsy if suspicious of large cell transformation                                                                                                     IV
                                                                                                                                                                                                                                          (MFSS-8)
     or PCR in at-risk populations
   a Clinically or histologically non-diagnostic cases. Pimpinelli N, Olsen EA, Santucci M, et                                                   all cases of Mycosis Fungoides/Sezary Syndrome. Demonstration of
     al., for the International Society for Cutaneous Lymphoma. Defining early mycosis                                                           identical clones in skin, blood and/or lymph node may be helpful in selected
     fungoides. J Am Acad Dermatol 2005;53:1053-1063.                                                                                            cases.
   b See Use of Immunophenotyping and Genetic Testing in Differential Diagnosis of Mature                                                      d Sezary syndrome (B2) is as defined on MFSS-2.
     B-cell and T/NK-cell Neoplasms (NHODG-A).                                                                                                 e Many skin-directed and systemic therapies are contraindicated or of
   c TCR gene rearrangement results should be interpreted with caution. TCR clonal                                                               unknown safety in pregnancy. Refer to individual drug information.
     rearrangement can be seen in non-malignant conditions or may not be demonstrated in
      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.           MFSS-1
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Mycosis Fungoides/Sezary Syndrome                                                                                                                                              Discussion

         TNMB f                               TNMB Classification and Staging of Mycosis Fungoides and Sezary Syndrome g
         Skin              T1                Limited patches, h papules and/or plaques i covering < 10 % of the skin surface
                           T2                Patches, h papules and/or plaques i covering ³ 10 % of the skin surface
                           T3                One or more tumors j (³ 1 cm in diameter)
                           T4                Confluence of erythema ³ 80 % body surface area
         Node              N0                No clinically abnormal peripheral lymph nodes; biopsy not required k
                           N1                Clinically abnormal peripheral lymph nodes; histopathology Dutch Gr 1 or NCI LN 0-2
                           N2                Clinically abnormal peripheral lymph nodes; histopathology Dutch Gr 2 or NCI LN 3
                           N3                Clinically abnormal peripheral lymph nodes; histopathology Dutch Gr 3-4 or NCI LN 4
                           NX                Clinically abnormal peripheral lymph nodes; no histologic confirmation

         Visceral          M0                No visceral organ involvement
                           M1                Visceral involvement (must have pathology confirmation l and organ involved should be specified)
         Blood             B0                Absence of significant blood involvement: £ 5 % of peripheral blood lymphocytes are atypical (Sezary) cells m
                           B1                Low blood tumor burden: > 5 % of peripheral blood lymphocytes are atypical (Sezary) cells but does not meet
                                             the criteria of B2
                           B2                High blood tumor burden: ³ 1000/mcL Sezary cells l
   f Olsen   E, Vonderheid E, Pimpinelli N, et al. Blood 2007;110:1713-1722.                   of large cell transformation has occurred. Phenotyping for CD30 is encouraged.
   g Sezary    syndrome (B2) is defined as a clonal rearrangement of the TCR in the         k Abnormal peripheral lymph node(s) = any palpable peripheral node that on physical
      blood (clones should be relevant to clone in the skin) and either 1000/mcL or            examination is firm, irregular, clustered, fixed or ³ 1.5 cm in diameter. Node groups
      increased CD4 or CD3 cells with CD4/CD8 of 10 or more or increase in CD4 cells           examined on physical examination = cervical, supraclavicular, epitrochlear, axillary
      with an abnormal phenotype (40% CD4/CD7 or 30% CD4/CD26).                                and inguinal. Central nodes, which are not generally amenable to pathologic
   h Patch = Any size skin lesion without significant elevation or induration.                 assessment, are not currently considered in the nodal classification unless used to
      Presence/absence of hypo- or hyperpigmentation, scale, crusting and/or                   establish N3 histopathologically.
      poikiloderma should be noted.                                                         l Spleen and liver may be diagnosed by imaging criteria.
   i Plaque = Any size skin lesion that is elevated or indurated. Presence or absence       m Sezary cells are defined as lymphocytes with hyperconvoluted cerebriform nuclei. If
      of scale, crusting and/or poikiloderma should be noted. Histological features such       Sezary cells are not able to be used to determine tumor burden for B2, then one of
      as folliculotropism or large cell transformation (³ 25 % large cells), CD30+             the following modified ISCL criteria along with a positive clonal rearrangement of
      or CD30- and clinical features such as ulceration are important to document.             the TCR may be used instead. (1) expanded CD4+ or CD3+ cells with CD4/CD8
   j Tumor = at least one > 1 cm diameter solid or nodular lesion with evidence of depth ratio ³ 10, (2) expanded CD4+ cells with abnormal immunophenotype including
      and/or vertical growth. Note total number of lesions, total volume of lesions, largest loss of CD7 or CD26.
      size lesion, and region of body involved. Also note if histological evidence

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          MFSS-2
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Mycosis Fungoides/Sezary Syndrome                                                                                                                                              Discussion

                                                                                          Clinical Staging/Classification of MF and SS f


                                                                                                          T                       N                      M                          B



                                                                                IA                        1                       0                      0                         0,1
                                                                                IB                        2                       0                      0                         0,1



                                                                                II                      1-2                     1,2                      0                         0,1
                                                                                IIB                      3                      0-2                      0                         0,1


                                                                                III                       4                     0-2                      0                         0,1
                                                                                IIIA                      4                     0-2                      0                          0
                                                                                IIIB                      4                     0-2                      0                          1


                                                                                IVA 1                   1-4                     0-2                      0                          2
                                                                                IVA 2                   1-4                      3                       0                         0-2
                                                                                IVB                     1-4                     0-3                      1                         0-2




   f OlsenE, Vonderheid E, Pimpinelli N, et al. Revisions to the Staging and Classification of Mycosis Fungoides and Sezary Syndrome: A Proposal of the International
     Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC).
     Blood 2007;110:1713-1722.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          MFSS-3
Printed by Eric Kirkendall on 7/17/2011 6:41:14 PM. For personal use only. Not approved for distribution. Copyright © 2011 National Comprehensive Cancer Network, Inc., All Rights Reserved.




                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Mycosis Fungoides/Sezary Syndrome                                                                                                                                              Discussion

   STAGE                                                           PRIMARY TREATMENT o
   (MFSS-2)

                                                                                                                                      CR/PR p or
                                                                                                                                                                                                      Relapse with or persistent
                                                                                                                                      inadequate
                                                                   Skin-directed therapies (may                                                                                                       T1 skin disease
                                                                                                                                      response
                                                                   be alone or in combination
                                                                   with other skin-directed
                                                                   therapies):
                                                                   See Suggested Treatment
                                                                                                                                                                                                      Systemic therapy ± skin-
                                                                   Regimens "Skin-directed
   Stage IA                                                                                                                                                                                           directed therapy
                                                                   therapies (skin-limited/local)"                                    Refractory disease q                                            (see Stage IB on page MFSS-5)
                                                                   (MFSS-A)                                                           or progression to                                               or
                                                                                                                                      > stage IA on skin-                                             Total skin electron beam
                                                                   If B1 blood involvement,
                                                                                                                                      directed therapies                                              therapy (TSEBT)
                                                                   consider primary treatment
                                                                                                                                                                                                      or
                                                                   for Stage III, B1 MFSS-7                                                                                                           Clinical trial
                                                                   (category 2B)




   Histologic evidence of
                                                                   See Primary Treatment for
   folliculotropic or large
                                                                   Stage IIB on page MFSS-6
   cell transformed MF n




   n Folliculotropic, large cell transformed MF, or B1 involvement has been associated with worse outcome, thus, may be managed as "tumor (IIB)" disease (MFSS-6) or
     stage III with B1 involvement (MFSS-7), respectively.
   o It is preferred that treatment occur at centers with expertise in the management of the disease.
   p Patients achieving a response should be considered for maintenance or taper regimens to optimize response duration. Patients who relapse often respond well to the
     same treatment. Patients with a PR should be treated with the other options in the primary treatment list to improve response before moving onto treatment for
     refractory disease. Patients with relapse or persistent disease after initial primary treatment may be candidates for clinical trials.
   q Refractory or intolerant to multiple previous therapies.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          MFSS-4
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Mycosis Fungoides/Sezary Syndrome                                                                                                                                              Discussion

   STAGE                        PRIMARY TREATMENT o
   (MFSS-2)
                                                                                                                                Relapse with or persistent T1-
                                                                                           CR/PR p or                           T2 disease:
                                                                                           inadequate                           · T1 (see stage IA on MFSS-4)
                                 Generalized skin treatment                                response                             · T2 (see generalized skin
                                 · See Suggested Treatment                                                                        treatment) (MFSS-A)
                                   Regimens "Skin-directed
                                   therapies (Skin-                                                                                                                                                                     · Clinical trial
                                   generalized)” (MFSS-A)                                                                                                                                  CR/PR p or                   · TSEBT (if not
                                   ± adjuvant local skin                                                                        See Suggested Treatment                                    inadequate
    Stage IB-IIA                                                                                                                Regimens                                                                                  previously
                                   treatment r                                             Refractory                                                                                      response
                                                                                                                                · Clinical trial                                                                          administered)
                                   (see stage IA on MFSS-4)                                disease q or
                                                                                                                                · Systemic Therapies                                                                    · Systemic chemotherapy
                                                                                           progression to                                                                                 Refractory
                                 If blood B1 involvement,                                                                         (SYST-CAT A) (MFSS-A)                                                                   agents used in ³ stage
                                                                                           > stage IB-IIA                                                                                 disease q or
                                 consider primary treatment                                                                     · Combination Therapies                                                                   IIB disease
                                                                                                                                                                                          progression
                                 for Stage IIIB B1 MFSS-7                                                                         ± skin-directed therapy                                                                 > See Suggested
                                 (category 2B)                                                                                                                                                                               Treatment Regimens
                                                                                                                                                                                                                             "Systemic Therapies
                                                                                                                                                                                                                             (SYST-CAT B)"
                                                                                                                                                                                                                             (MFSS-A)
   Histologic evidence of
                                                         See Primary Treatment for
   folliculotropic or large
                                                         Stage IIB on page MFSS-6
   cell transformed MF n


   n Folliculotropic, large cell transformed MF, or B1 involvement has been associated with worse outcome, thus, may be managed as "tumor (IIB)" disease (MFSS-6) or
      stage III with B1 involvement (MFSS-7), respectively.
   o It is preferred that treatment occur at centers with expertise in the management of the disease.
   p Patients achieving a response should be considered for maintenance or taper regimens to optimize response duration. Patients who relapse often respond well to the
      same treatment. Patients with a PR should be treated with the other options in the primary treatment list to improve response before moving onto treatment for
      refractory disease. Patients with relapse or persistent disease after initial primary treatment may be candidates for clinical trials.
   q Refractory or intolerant to multiple previous therapies.
   r For patients with recalcitrant sites after generalized skin treatment, additional local treatment may be needed.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          MFSS-5
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Mycosis Fungoides/Sezary Syndrome                                                                                                                                              Discussion

   STAGE                                                                                     PRIMARY TREATMENT o
   (MFSS-2)
                                                                                                                                                                                                Relapse with or persistent T1-
                                                                                                                                                             CR/PR p or                         T3 limited:
                                                                                            · Local RT for limited extent                                    inadequate                         · T1-2 (see stage IA on MFSS-4
                                             Limited extent                                   tumor, transformed, and/or                                     response                             or stage IB-IIA on MFSS-5)
                                             tumor disease ±                                  folliculotrophic disease u                                                                        · T3 limited extent
                                             patch/plaque                                   · Systemic Therapies (SYST-
                                                                                                                                                             Refractory
                                             disease                                          CAT A) (MFSS-A) ± skin-
    Stage     IIB s                                                                                                                                          disease q or
                                                                                              directed therapies v ± RT
    and/or                                                                                                                                                   progression
    histologic
    evidence of
    folliculotropic or                                                                                                                                     Relapse with or persistent T1-T3:
                                                                                             · TSEBT w                               CR/PR p or
    large cell                                                                                                                                             · T1-2 (see stage IA on MFSS-4 or
                                                                                             · See Suggested Treatment               inadequate
    transformation                                                                                                                                           stage IB-IIA on MFSS-5)
                                                                                               Regimens t                            response
    (LCT)                                                                                                                                                  · T3
                                           Generalized extent                                  > Systemic Therapies
                                           tumor, transformed,                                   (SYST-CAT A) (MFSS-A)
                                           and/or folliculotropic                              > Systemic Therapies
                                           disease t                                             (SYST-CAT B) (MFSS-A)               Refractory            · Multi-agent chemotherapy x
                                                                                               > Systemic Therapies                  disease   q or        · Consider allogeneic transplant y
                                                                                                 (SYST-CAT C) (MFSS-A) t             progression           · Clinical trial
                                                                                               > Combination Therapies
                                                                                             ± skin-directed     t Histologic evidence of LCT often, but not always corresponds to a more aggressive
                                                                                             therapy               growth rate. If there is no evidence of more aggressive growth, choosing systemic
                                                                                           therapies from SYST-CAT A or SYST-CAT B are appropriate. If aggressive growth is
   o Itis preferred that treatment occur at centers with expertise in the management       seen, then agents listed in SYST-CAT C are preferred.
     of the disease.                                                                     u For non-radiated sites, see Stage I-IIA. After patient is rendered disease free by RT,
   p Patients achieving a response should be considered for maintenance or taper           may consider adjuvant systemic biologic therapy (SYST-CAT A) after RT to improve
     regimens to optimize response duration. Patients who relapse often respond            response duration.
     well to the same treatment. Patients with a PR should be treated with the other     v Skin-directed therapies are for patch or plaque lesions and not for tumor lesions.
     options in the primary treatment list to improve response before moving onto        w May consider adjuvant systemic biologic therapy (SYST-CAT A) after TSEBT to
     treatment for refractory disease. Patients with relapse or persistent disease after improve response duration.
     initial primary treatment may be candidates for clinical trials.                    x Most patients are treated with multiple SYST-CAT A/B or Combination therapies
   q Refractory or intolerant to multiple previous therapies.                              before receiving multiagent chemotherapy.
   s Rebiopsy if suspect large cell transformation.                                      y The role of allogeneic HSCT is controversial. See discussion for further details.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          MFSS-6
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Mycosis Fungoides/Sezary Syndrome                                                                                                                                              Discussion

   STAGE                      PRIMARY TREATMENT o
   (MFSS-2)



                              If no blood involvement,
                              consider skin-directed                               CR/PR p or                        Relapse or
                              therapy                                              inadequate                        persistent
                              See Suggested
                                                                                   response                          disease
                              Treatment Regimens
                              Skin-directed therapies                                                                                                                                          CR/PR p or
                                                                                                                                                                                                                                 Relapse or
                              (Skin-generalized)                                                                                                                                               inadequate
                                                                                                                                                                                                                                 persistent disease
                                (MFSS-A)                                                                                                                                                       response
   Stage III z                or                                                                                                            · Combination therapies
                              If blood B1 involvement,                                                                                        > See Suggested
                                                                                    Refractory                                                                                                                             · Clinical trial
                              systemic therapies                                                                                                Treatment Regimens -
                                                                                    disease q or                                                                                                                           · See Suggested
                              See Suggested                                                                                                     Combination
                                                                                    progression                                                                                                                              Treatment Regimens
                              Treatment Regimens                                                                                                Therapies bb (MFSS-A)
                                                                                                                                                                                               Refractory                    "Systemic Therapies
                              "Systemic Therapies                                                                                           · Clinical trial
                                                                                                                                                                                               disease q or                  (SYST-CAT B)"
                              (SYST-CAT A)" ± skin-                                                                                                                                            progression                 · Alemtuzumab cc
                              directed therapy aa                                                                                                                                                                          · Consider non-ablative
                                                                                                                                                                                                                             allogeneic transplant, y
                                                                                                                                                                                                                             as appropriate
   o Itis preferred that treatment occur at centers with expertise in the management
     of the disease.
   p Patients achieving a response should be considered for maintenance or taper
     regimens to optimize response duration. Patients who relapse often respond
     well to the same treatment. Patients with a PR should be treated with the other                                                 aa Mid-potency   topical steroids should be included (± occlusive modality) with any of
     options in the primary treatment list to improve response before moving onto                                                      the primary treatment modalities to reduce skin symptoms. Erythrodermic patients
     treatment for refractory disease. Patients with relapse or persistent disease                                                     are at increased risk for secondary infection with skin pathogens and systemic
     after initial primary treatment may be candidates for clinical trials.                                                            antibiotic therapy should be considered.
   q Refractory or intolerant to multiple previous therapies.                                                                        bb Combination therapy options can be considered earlier (primary treatment)
   y The role of allogeneic HSCT is controversial. See discussion for further details.
                                                                                                                                       depending on treatment availability or symptom severity.
   z Generalized skin-directed therapies (other than topical steroids) may not be                                                    cc Alemtuzumab can be administered by IV or subcutaneously. Lower doses
     well-tolerated in stage III and should be used with caution. Phototherapy                                                         administered subcutaneously have shown lower incidence of infectious
     (PUVA or UVB) or TSEBT can be used successfully.                                                                                  complications.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.           MFSS-7
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Mycosis Fungoides/Sezary Syndrome                                                                                                                                              Discussion

   STAGE                                                                      PRIMARY TREATMENT o
   (MFSS-2)

                                                                                                                                                CR/PR p or                       Relapse or persistent disease
                                                                                                                                                inadequate                       · Consider allogeneic transplant, y
                                                                              · See Suggested Treatment                                         response                           as appropriate
                                                                                Regimens
                                   Sezary syndrome                              > Systemic Therapies
                                                                                  (SYST-CAT A) (MFSS-A)                                                                          · See Suggested Treatment Regimens -
                                                                                                                                                 Refractory
                                                                                > Combination Therapies                                                                            Systemic Therapies (SYST-CAT B) (MFSS-A)
                                                                                                                                                 disease q or
                                                                                                                                                                                 · Alemtuzumab cc
                                                                                                                                                 progression
                                                                                                                                                                                 · Clinical trial
   Stage IV



                                                                                                                                                CR/PR p or                       Relapse or persistent disease
                                    Non Sezary
                                                                              See Suggested Treatment                                           inadequate                       · Consider allogeneic transplant, y
                                                                              Regimens - Systemic                                               response                           as appropriate
                                    or
                                    Visceral                                  Therapies (SYST-CAT B) or
                                    disease                                   (SYST-CAT C) dd or multi-
                                    (solid organ)                             agent chemotherapy
                                                                               ± RT for local control ee                                         Refractory
                                                                                                                                                 disease q or                    Clinical trial
                                                                                                                                                 progression

   o Itis preferred that treatment occur at centers with expertise in the management of the disease.
   p Patients  achieving a response should be considered for maintenance or taper regimens to optimize response duration. Patients who relapse often respond well to the
     same treatment. Patients with a PR should be treated with the other options in the primary treatment list to improve response before moving onto treatment for
     refractory disease. Patients with relapse or persistent disease after initial primary treatment may be candidates for clinical trials.
   q Refractory or intolerant to multiple previous therapies.
   y The role of allogeneic HSCT is controversial. See discussion for further details.
   cc Alemtuzumab can be administered by IV or subcutaneously. Lower doses administered subcutaneously has shown lower incidence of infectious complications.
   dd Patients with stage IV non-Sezary/visceral disease may present with more aggressive growth characteristics. If there is no evidence of more aggressive growth,
     systemic therapies from SYST-CAT B are appropriate. If aggressive growth is seen, then agents listed in SYST-CAT C are preferred.
   ee Consider adjuvant systemic biologic therapy (SYST-CAT A) after chemotherapy to improve response duration.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          MFSS-8
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Mycosis Fungoides/Sezary Syndrome                                                                                                                                              Discussion
                                                                                             SUGGESTED TREATMENT REGIMENS a
      SKIN-DIRECTED THERAPIES                                                                   SYSTEMIC THERAPIES                                                                         SYSTEMIC THERAPIES (continued)
                                                                                                                                                                                           Category C (SYST-CAT C) g
      For limited/localized skin involvement (Skin-                                                  Category A (SYST-CAT A)
                                                                                                                                                                                           · Liposomal doxorubicin
      Limited/Local)                                                                                 · Retinoids (bexarotene, all-trans retinoic                                           · Gemcitabine
      · Topical corticosteroids b                                                                      acid, isotretinoin [13-cis-retinoic acid],                                          · Denileukin diftitox
      · Topical chemotherapy (mechlorethamine                                                          acitretin)                                                                          · Romidepsin
        [nitrogen mustard], carmustine)                                                              · Interferons (IFN-alpha, IFN-gamma)                                                  · Low or standard dose pralatrexate
      · Local radiation (particularly unilesional                                                    · HDAC-inhibitors (vorinostat, romidepsin) e                                          · See regimens listed on TCEL-B h
        presentation, 24-36 Gy)                                                                      · Extracorporeal photopheresis f
      · Topical retinoids (bexarotene, tazarotene)                                                   · Denileukin diftitox                                                                 COMBINATION THERAPIES
      · Phototherapy (UVB, nbUVB for patch/thin                                                      · Methotrexate (£ 100 mg q week)
                                                                                                                                                                                           Skin-directed + Systemic
        plaques; PUVA for thicker plaques) c
                                                                                                                                                                                           · Phototherapy + retinoid e
      · Topical imiquimod                                                                            Category B (SYST-CAT B)
                                                                                                     · First-line therapies                                                                · Phototherapy + IFN
      For generalized skin involvement (Skin-                                                          > Liposomal doxorubicin                                                             · Phototherapy + photopheresis f
      Generalized)                                                                                     > Gemcitabine                                                                       · Total skin electron beam +
      · Topical corticosteroids b                                                                    · Second-line therapies                                                                 photopheresis f
      · Topical chemotherapy (mechlorethamine                                                          > Chlorambucil
                                                                                                       > Pentostatin                                                                       Systemic + Systemic
        [nitrogen mustard], carmustine)
                                                                                                       > Etoposide                                                                         · Retinoid + IFN
      · Phototherapy (UVB, nbUVB, for patch/thin
                                                                                                       > Cyclophosphamide                                                                  · Bexarotene + denileukin diftitox
        plaques; PUVA for thicker plaques) c
                                                                                                       > Temozolomide                                                                      · Photopheresis f + retinoid
      · Total skin electron beam therapy (30-36 Gy) d
                                                                                                       > Methotrexate (>100 mg q week)                                                     · Photopheresis f + IFN
        (reserved for those with severe skin symptoms                                                  > Bortezomib                                                                        · Photopheresis f + retinoid + IFN
        or generalized thick plaque or tumor disease, or                                               > Low dose pralatrexate
        poor response to other therapies)                                               e Safety of combining TSEBT with systemic retinoids or HDAC-inhibitors, such as
   a See   references for regimens MFSS-A 2 of 4, MFSS-A 3 of 4, and MFSS-A 4 of 4        vorinostat or romidepsin or combining phototherapy with vorinostat or romidepsin is
   b Long-term use of topical steroid may be associated with skin atrophy and/or striae
                                                                                          unknown.
     formation. This risk worsens with increased potency of the steroid. High-potency f Photopheresis may be more appropriate as systemic therapy in patients with some
     steroid used on large skin surfaces may lead to systemic absorption.                 blood involvement (B1 or B2).
   c Cumulative dose of UV is associated with increased risk of UV-associated skin      g Patients with large cell transformed (LCT) MF and stage IV non-Sezary/visceral
     neoplasms; thus, phototherapy may not be appropriate in patients with history of disease may present with more aggressive growth characteristics. In general,
     extensive squamoproliferative skin neoplasms or basal cell carcinomas or who         agents listed in SYST-CAT C are preferred in these circumstances.
     have had melanoma.                                                                 h Combination regimens are generally reserved for patients with relapsed/refratory or
   d It is common practice to follow TSEBT with systemic therapies such as interferon
                                                                                          extracutaneous disease.
     or bexarotene to maintain response.
      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                            MFSS-A
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Mycosis Fungoides/Sezary Syndrome                                                                                                                                              Discussion

                                                                                                SUGGESTED TREATMENT REGIMENS
                                                                                                          References
    Skin-directed therapies
    Topical corticosteroids
    Zackheim HS, Kashani Sabet M, Amin S. Topical corticosteroids for mycosis fungoides. Experience in 79 patients. Arch Dermatol 1998;134(8):949-954.
    Zackheim HS. Treatment of patch stage mycosis fungoides with topical corticosteroids. Dermatol Ther 2003;16:283- 287.
    Carmustine
    Zackheim HS. Topical carmustine (carmustine) in the treatment of mycosis fungoides. Dermatol Ther 2003;16:299-302.
    Nitrogen mustard (mechlorethamine hydrochloride)
    Kim YH, Martinez G, Varghese A, Hoppe RT. Topical nitrogen mustard in the management of mycosis fungoides: update of the Stanford experience. Arch Dermatol
    2003;139:165-173.
    Local radiation
    Wilson LD, Kacinski BM, Jones GW. Local superficial radiotherapy in the management of minimal stage IA cutaneous T-cell lymphoma (Mycosis Fungoides).
    International Journal of Radiation Oncology, Biology, Physics 1998;40:109-115.
    Topical bexarotene
    Breneman D, Duvic M, Kuzel T, et al. Phase 1 and 2 trial of bexarotene gel for skin directed treatment of patients with cutaneous T cell lymphoma. Arch Dermatol
    2002;138:325-332.
    Heald P, Mehlmauer M, Martin AG, et al. Topical bexarotene therapy for patients with refractory or persistent early stage cutaneous T cell lymphoma: results of the
    phase III clinical trial. J Am Acad Dermatol 2003;49:801-815.
    Tazarotene Gel
    Apisarnthanarax N, Talpur R, Ward S, Ni X, Kim HW, Duvic M. Tazarotene 0.1% gel for refractory mycosis fungoides lesions: an open-label pilot study. J Am Acad
    Dermatol 2004;50:600-607.
    Topical imiquimod
    Deeths MJ, Chapman JT, Dellavalle RP, Zeng C, Aeling JL. Treatment of patch and plaque stage mycosis fungoides with imiquimod 5% cream. J Am Acad Dermatol
    2005;52:275-280.
    Phototherapy (UVB and PUVA)
    Gathers RC, Scherschun L, Malick F, Fivenson DP, Lim HW. Narrowband UVB phototherapy for early stage mycosis fungoides. J Am Acad Dermatol 2002;47:191-197.
    Querfeld C, Rosen ST, Kuzel TM, et al. Long term follow up of patients with early stage cutaneous T cell lymphoma who achieved complete remission with psoralen
    plus UV A monotherapy. Arch Dermatol 2005;141:305-311.
    Total skin electron beam therapy (TSEBT)
    Chinn DM, Chow S, Kim YH, Hoppe RT. Total skin electron beam therapy with or without adjuvant topical nitrogen mustard or nitrogen mustard alone as initial
    treatment of T2 and T3 mycosis fungoides. Int J Radiat Oncol Biol Phys 1999;43:951-958.
    Ysebaert L, Truc G, Dalac S et al. Ultimate results of radiation therapy for T1-T2 mycosis fungoides. Int J Radiat Oncol Biol Phys 2004;58:1128-1134

                                                                                                                                                                                                                      Continued on next page




      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                            MFSS-A
   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.            2 of 4
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Mycosis Fungoides/Sezary Syndrome                                                                                                                                              Discussion

                                                                                                SUGGESTED TREATMENT REGIMENS
                                                                                                          References
   Systemic therapies                                                                                                              Whittaker SJ, Demierre MF, Kim EJ, et al. Final results from a multicenter, international,
   Alemtuzumab for Sezary Syndrome ± lymph node disease                                                                            pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J Clin Oncol 2010;
   Lundin J, Hagberg H, Repp R, et al. Phase 2 study of alemtuzumab (anti-CD52                                                     28:4485-4491.
   monoclonal antibody) in patients with advanced mycosis fungoides/Sezary                                                         Extracorporeal photopheresis (ECP)
   syndrome. Blood 2003;101:4267-4272.                                                                                             Edelson R, Berger C, Gasparro F, et al. Treatment of cutaneous T-cell lymphoma by
   Bernengo MG, Quaglino P, Comessatti A, et al. Low-dose intermittent alemtuzumab                                                 extracorporeal photochemotherapy. Preliminary results. N Engl J Med 1987;316:297-
   in the treatment of Sezary syndrome: clinical and immunologic findings in 14                                                    303.
   patients. Haematologica 2007;92:784-794.                                                                                        Zic JA, Stricklin GP, Greer JP, et al. Long-term follow-up of patients with cutaneous T-cell
   Gautschi O, Blumenthal N, Streit M, et al. Successful treatment of chemotherapy-                                                lymphoma treated with extracorporeal photochemotherapy. J Am Acad Dermatol
   refractory Sezary syndrome with alemtuzumab (Campath-1H). Eur J Haematol                                                        1996;35:935-945.
   2004;72:61-63.                                                                                                                  Denileukin diftitox
   Retinoids                                                                                                                       Olsen E, Duvic M, Frankel A, et al. Pivotal phase III trial of two dose levels of denileukin
   Zhang C, Duvic M. Treatment of cutaneous T-cell lymphoma with retinoids.                                                        diftitox for the treatment of cutaneous T-cell lymphoma. J Clin Oncol 2001;19:376-388.
   Dermatol Ther 2006;19:264-271.                                                                                                  Prince HM, Duvic M, Martin A, et al. Phase III placebo-controlled trial of denileukin
   Duvic M, Martin AG, Kim Y, et al. Phase 2 and 3 clinical trial of oral bexarotene                                               diftitox for patients with cutaneous T-cell lymphoma. J Clin Oncol 2010;28:1870-1877.
   (Targretin capsules) for the treatment of refractory or persistent early-stage                                                  Methotrexate
   cutaneous T-cell lymphoma. Arch Dermatol 2001;137:581-593.                                                                      Zackheim HS, Kashani-Sabet M, Hwang ST. Low-dose methotrexate to treat
   Duvic M, Hymes K, Heald P, et al. Bexarotene is effective and safe for treatment of                                             erythrodermic cutaneous T-cell lymphoma: results in twenty-nine patients. J Am Acad
   refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II-III                                                 Dermatol 1996;34:626-631.
   trial results. J Clin Oncol.2001;19:2456-2471.                                                                                  Zackheim HS, Kashani-Sabet M, McMillan A. Low-dose methotrexate to treat mycosis
   Interferon                                                                                                                      fungoides: a retrospective study in 69 patients. J Am Acad Dermatol 2003;49:873-878.
   Olsen EA. Interferon in the treatment of cutaneous T-cell lymphoma. Dermatol Ther                                               Liposomal doxorubicin
   2003;16:311-321.                                                                                                                Wollina U, Dummer R, Brockmeyer NH, et al. Multicenter study of pegylated liposomal
   Kaplan EH, Rosen ST, Norris DB, et al. Phase II study of recombinant human                                                      doxorubicin in patients with cutaneous T-cell lymphoma. Cancer 2003;98(5):993-1001.
   interferon gamma for treatment of cutaneous T-cell lymphoma. J Natl Cancer Inst                                                 Quereux G, Marques S, Nguyen J-M, et al. Prospective multicenter study of pegylated
   1990;82:208-212.                                                                                                                liposomal doxorubicin treatment in patients with advanced or refractory mycosis
   Vorinostat                                                                                                                      fungoides or Sezary syndrome. Arch Dermatol 2008;144:727-733.
   Duvic M, Talpur R, Ni X, et al. Phase 2 trial of oral vorinostat (suberoylanilide                                               Gemcitabine
   hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood                                                   Duvic M, Talpur R, Wen S, Kurzrock R, David CL, Apisarnthanarax N. Phase II
   2007;109:31-39.                                                                                                                 evaluation of gemcitabine monotherapy for cutaneous T-cell lymphoma. Clin Lymphoma
   Olsen EA, Kim YH, Kuzel TM, et al. Phase IIb multicenter trial of vorinostat in                                                 Myeloma 2006;7(1):51-58.
   patients with persistent, progressive, or treatment refractory cutaneous T-cell                                                 Marchi E, Alinari L, Tani M, et al. Gemcitabine as frontline treatment for cutaneous T-cell
   lymphoma. J Clin Oncol 2007;25:3109-3115.                                                                                       lymphoma: phase II study of 32 patients. Cancer 2005;104(11):2437-2441.
   Duvic M, Olsen EA, Breneman D, et al. Evaluation of the long-term tolerability and                                              Zinzani PL, Baliva G, Magagnoli M, et al. Gemcitabine treatment in pretreated
   clinical benefit of vorinostat in patients with advanced cutaneous T-cell lymphoma.                                             cutaneous T-cell lymphoma: experience in 44 patients. J Clin Oncol 2000;18:2603-2606.
   Clin Lymphoma Myeloma. 2009;9:412-416.                                                                                          Zinzani PL, Venturini F, Stefoni V, et al. Gemcitabine as single agent in pretreated T-cell
   Romidepsin                                                                                                                      lymphoma patients: evaluation of the long-term outcome. Ann Oncol 2010;21:860-863.
   Piekarz RL, Frye R, Turner M, et al. Phase II Multi-Institutional Trial of the Histone
   Deacetylase Inhibitor Romidepsin As Monotherapy for Patients With Cutaneous T-                                                                                                                                     Continued on next page
   Cell Lymphoma. J Clin Oncol 2009;27:5410-5417.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                            MFSS-A
   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.            3 of 4
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Mycosis Fungoides/Sezary Syndrome                                                                                                                                              Discussion

                                                                                               SUGGESTED TREATMENT REGIMENS
                                                                                                         References
   Systemic therapies continued                                                                                                Combination therapies
   Pentostatin                                                                                                                 Skin-directed + Systemic
   Cummings FJ, Kim K, Neiman RS, et al. Phase II trial of pentostatin in refractory                                           Rupoli S, Goteri G, Pulini S, et al. Long term experience with low dose interferon
   lymphomas and cutaneous T-cell disease. J Clin Oncol 1991;9(4):565-571.                                                     alpha and PUVA in the management of early mycosis fungoides. Eur J Haematol
   Temozolomide                                                                                                                2005;75(2):136-145.
   Tani M, Fina M, Alinari L, Stefoni V, Baccarani M, Zinzani PL. Phase II trial of                                            Kuzel TM, Roenigk HH Jr, Samuelson E, et al. Effectiveness of interferon alfa-2a
   temozolomide in patients with pretreated cutaneous T-cell lymphoma.                                                         combined with phototherapy for mycosis fungoides and the Sézary syndrome. J Clin
   Haematologica 2005;90(9):1283-1284.
                                                                                                                               Oncol 1995;13(1):257-263.
   Bortezomib
                                                                                                                               McGinnis KS, Shapiro M, Vittorio CC, et al. Psoralen plus long wave UV A (PUVA)
   Zinzani PL, Musuraca G, Tani M, et al. Phase II trial of proteasome inhibitor
   bortezomib in patients with relapsed or refractory cutaneous T-cell lymphoma. J                                             and bexarotene therapy: An effective and synergistic combined adjunct to therapy
   Clin Oncol 2007;25(27):4293-4297.                                                                                           for patients with advanced cutaneous T cell lymphoma. Arch Dermatol
   Low dose Pralatrexate                                                                                                       2003;139(6):771-775.
   Horwitz SM, Duvic M, Kim Y, et al. Pralatrexate is active in cutaneous T-cell                                               Wilson LD, Jones GW, Kim D, et al. Experience with total skin electron beam
   lymphoma (CTCL): Results of a multicenter, dose-finding trial. ASH Annual                                                   therapy in combination with extracorporeal photopheresis in the management of
   Meeting Abstracts. 2009;114:910.                                                                                            patients with erythrodermic (T4) mycosis fungoides. Journal of the American
   Liposomal doxorubicin                                                                                                       Academy of Dermatology. 2000;43(1):54-60.
   Quereux G, Marques S, Nguyen J-M, et al. Prospective multicenter study of                                                   Stadler R, Otte H-G, Luger T, et al. Prospective randomized multicenter clinical trial
   pegylated liposomal doxorubicin treatment in patients with advanced or                                                      on the use of interferon alpha -2a plus acitretin versus interferon alpha -2a plus
   refractory mycosis fungoides or Sezary syndrome. Arch Dermatol 2008;144:727-
                                                                                                                               PUVA in patients with cutaneous T-cell lymphoma stages I and II. Blood
   733.
   Gemcitabine                                                                                                                 1998;92:3578-3581.
   Awar O, Duvic M. Treatment of transformed mycosis fungoides with intermittent
   low-dose gemcitabine. Oncology 2007;73:130-135.                                                                             Systemic + Systemic
   Pralatrexate                                                                                                                Foss F, Demierre MF, DiVenuti G. A phase 1 trial of bexarotene and denileukin
   O'Connor O, Pro B, Pinter-Brown L, et al. PROPEL: Results of the pivotal,                                                   diftitox in patients with relapsed or refractory cutaneous T cell lymphoma. Blood
   multicenter, phase II study of pralatrexate in patients with relapsed or refractory                                         2005;106(2):454-457.
   peripheral T-cell lymphoma (PTCL). ASCO Meeting Abstracts. 2009;27:8561.                                                    Straus DJ, Duvic M, Kuzel T, et al. Results of a phase II trial of oral bexarotene
   Romidepsin                                                                                                                  (Targretin) combined with interferon alfa 2b (Intron A) for patients with cutaneous T
   Piekarz R, Wright J, Frye R, et al. Final results of a phase 2 NCI multicenter                                              cell lymphoma. Cancer 2007;109(9):1799-1803.
   study of romidepsin in patients with relapsed peripheral T-cell lymphoma                                                    Talpur R, Ward S, Apisarnthanarax N, Breuer Mcham J, Duvic M. Optimizing
   (PTCL). ASH Annual Meeting Abstracts. 2009;114:1657-.                                                                       bexarotene therapy for cutaneous T cell lymphoma. J Am Acad Dermatol.
   Denileukin diftitox                                                                                                         2002;47(5):672-684.
   Talpur R, Jones DM, Alencar AJ, et al. CD25 expression is correlated with                                                   Suchin KR, Cucchiara AJ, Gottleib SL, et al. Treatment of cutaneous T-cell
   histological grade and response to denileukin diftitox in cutaneous T-cell
                                                                                                                               lymphoma with combined immunomodulatory therapy: a 14-year experience at a
   lymphoma. J Invest Dermatol 2006;126:575-583.
                                                                                                                               single institution. Arch Dermatol. 2002;138(8):1054-1060.
                                                                                                                               Richardson SK, Lin JH, Vittorio CC, et al. High clinical response rate with
                                                                                                                               multimodality immunomodulatory therapy for Sezary syndrome. Clin Lymphoma
                                                                                                                               Myeloma 2006;7:226-232.


      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                            MFSS-A
   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.            4 of 4
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Adult T-cell Leukemia/Lymphoma                                                                                                                                                 Discussion

    DIAGNOSIS                                                                                                             WORKUP                                                                                                     DIAGNOSTIC
                                                                                                                                                                                                                                     CATEGORY
                                                                                                                                                                                                                                     see ATLL-A
                                                                                                                           ESSENTIAL:
                                                                                                                           · Complete history and physical examination-
                                                                                                                                                                                                                                     See Primary
                                                                                                                             including complete skin exam
                                                                                                                                                                                                                                     Therapy
                                                                                                                           · CBC and blood smear: lymphocytosis (ALC
    ESSENTIAL: a                                                                                                                                                                                                                     Chronic/
                                                                                                                             > 4000/μL in adults) in acute and chronic subtypes
    · HTLV-1 serology: ELISA and confirmatory Western Blot                                                                                                                                                                           Smoldering
                                                                                                                           · Electrolytes, BUN, creatinine, serum calcium,
      if ELISA is positive                                                                                                                                                                                                           (ATLL-2)
                                                                                                                             serum LDH
    · Peripheral blood smear analysis for atypical cells b
                                                                                                                           · Chest/abdominal/pelvic/neck CT scan
    · Flow cytometry on peripheral blood c
                                                                                                                           · Pregnancy testing in women of child-bearing age
                                                                                                                             (if chemotherapy planned)                                                                               See Primary
    USEFUL IN CERTAIN CIRCUMSTANCES:
                                                                                                                                                                                                                                     Therapy Acute
    · Biopsy of lymph nodes (excisional), skin biopsy, GI
                                                                                                                           USEFUL IN SELECTED CASES:                                                                                 (ATLL-3)
      tract, or bone marrow biopsy d is required if:
                                                                                                                           · Upper gastrointestinal endoscopy
      > Diagnosis is not established on peripheral blood, or
      > Ruling out an underlying infection (tuberculosis,                                                                  · Skeletal survey in symptomatic patients
        histoplasmosis, toxoplasmosis, etc.)                                                                               · Stool examination for parasites (strongyloides is
                                                                                                                             most likely)                                                                                            See Primary
      > If biopsy performed, the recommended panel for
        paraffin section immunohistochemistry: e,f CD3, CD4,                                                               · PET-CT scan                                                                                             Therapy
        CD7, CD8, and CD25                                                                                                 · Central nervous system evaluation: CT scan, MRI                                                         Lymphoma
                                                                                                                             and/or lumbar puncture in all patients with acute or                                                    (ATLL-3)
                                                                                                                             lymphoma subtypes or in patients with neurologic
                                                                                                                             manifestations


   a The  diagnosis of ATLL requires histopathology and immunophenotyping of tumor
     lesion, or morphology and immunophenotying of peripheral blood, and/or HTLV
     serology.
   b Typical ATL cells (“flower cells”) have distinctly polylobated nuclei with
     homogeneous and condensed chromatin, small or absent nucleoli and agranular d Bone marrow involvement is an independent poor prognostic factor.
     and basophilic cytoplasm but multiple morphological variations can be          e See Use of Immunophenotyping and Genetic Testing in Differential Diagnosis of
     encountered. Presence of ³ 5% atypical cells by morphology in peripheral blood   Mature B-cell and T/NK-cell Neoplasms (NHODG-A).
     is required for diagnosis in the absence of other criteria.                    f Usually CD4+ T-cells with expression of CD2, CD5, CD25, CD45RO, CD29, T-cell
   c Presence of ³ 5% T-lymphocytes with an abnormal immunophenotype in               receptor αβ and HLA-DR. Most cases are CD7 - and CD26 - with low CD3
     peripheral blood is required for diagnosis.                                      expression. Rare cases are CD8 + or CD4/CD8 double positive or double negative.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.           ATLL-1
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Adult T-cell Leukemia/Lymphoma                                                                                                                                                 Discussion

    ATLL SUBTYPE g                                                 PRIMARY THERAPY h                                                            INITIAL RESPONSE                                        ADDITIONAL
                                                                                                                                                (at 2 mo)                                               THERAPY



                                                                  Clinical trial
                                                                  or
                                                                  Observation
                                                                  or
    Chronic/Smoldering                                            Skin-directed therapies as clinically
                                                                  indicated (See Mycosis Fungoides/                                                Complete                                             Continue treatment with
                                                                  Sezary Syndrome MFSS-A)                                                          response k                                           zidovudine and interferon
                                                                  or
                                                                  Zidovudine and interferon i,j
                                                                                                                                                                                                        Chemotherapy
                                                                                                                                                                                                        (See Suggested Treatment
                                                                                                                                                                                                        Regimens ATLL-C)
                                                                                                                                                   Persistent or                                        or
                                                                                                                                                   progressive disease k                                Clinical trial
                                                                                                                                                                                                        or
                                                                                                                                                                                                        Best supportive care




   g See  Diagnostic Criteria for Clinical Subtype of ATLL (ATLL-A).
   h Supportive   care: anti-infectious prophylaxis with sulfamethoxazole/trimethoprim + strongyloidosis prophylaxis is recommended.
   i Outside of a clinical trial, if a patient is not responding or is progressing, treatment with zidovudine and interferon should be stopped. If there is evidence of clinical
      benefit, treatment should continue until best response is achieved. If life threatening manifestations, treatment can be discontinued before the two months period.
   j See references for zidovudine and interferon (ATLL-D).
   k See Response Criteria for ATLL (ATLL-B).

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          ATLL-2
Printed by Eric Kirkendall on 7/17/2011 6:41:14 PM. For personal use only. Not approved for distribution. Copyright © 2011 National Comprehensive Cancer Network, Inc., All Rights Reserved.




                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Adult T-cell Leukemia/Lymphoma                                                                                                                                                 Discussion

   ATLL SUBTYPE g                                     PRIMARY THERAPY h                                                             INITIAL RESPONSE                                       ADDITIONAL
                                                                                                                                     (after 2 cycles)                                      THERAPY
                                                                                                                                                                                           Continue treatment with zidovudine and
                                                                                                                                    Complete                                               interferon
                                                                                                                                    response k                                             or
                                                     Clinical trial
                                                     or                                                                                                                                    Consider allogeneic stem cell transplant
                                                     Zidovudine and interferon i,j
   Acute l                                                                                                                                                                                 Clinical trial
                                                     or
                                                     Chemotherapy (See Suggested                                                                                                           or
                                                     Treatment Regimens (ATLL-C)                                                                                                           Best supportive care
                                                                                                                                    Persistent or                                          or
                                                                                                                                    progressive disease k                                  Chemotherapy (See Suggested
                                                                                                                                                                                           Treatment Regimens ATLL-C)
                                                                                                                                                                                           or
                                                                                                                                                                                           Consider allogeneic stem cell transplant

                                                                                                                                    Complete
                                                                                                                                                                                           Consider allogeneic stem cell transplant
                                                                                                                                    response k
                                                     Clinical trial
                                                     or
    Lymphoma l,m,n                                                                                                                                                                         Clinical trial
                                                     Chemotherapy (See Suggested
                                                     Treatment Regimens ATLL-C)                                                                                                            or
                                                                                                                                                                                           Best supportive care
                                                                                                                                    Persistent or                                          or
                                                                                                                                    progressive disease k                                  Chemotherapy (See Suggested
                                                                                                                                                                                           Treatment Regimens ATLL-C)
                                                                                                                                                                                           or
                                                                                                                                                                                           Consider allogeneic stem cell transplant
   g See    Diagnostic Criteria for Clinical Subtype of ATLL (ATLL-A).                                                              j See  References for zidovudine and interferon (ATLL-D).
   h Supportive    care: anti-infectious prophylaxis with sulfamethoxazole/trimethoprim                                             k See   Response Criteria for ATLL (ATLL-B).
      + strongyloidosis prophylaxis is recommended.                                                                                 l Efficacy of long term treatment is limited. There are small series where transplant
   i Outside of a clinical trial, if a patient is not responding or is progressing,                                                    is beneficial. There is no defined treatment.
      treatment with zidovudine and interferon should be stopped. If there is evidence                                              m Antiviral therapy is not effective.
      of clinical benefit, treatment should continue until best response is achieved. If                                            n CNS prophylaxis: intrathecal chemotherapy is recommended (methotrexate and
      life threatening manifestations, treatment can be discontinued before the two                                                    cytarabine and corticosteroids).
      months period.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          ATLL-3
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Adult T-cell Leukemia/Lymphoma                                                                                                                                                 Discussion

                                                        DIAGNOSTIC CRITERIA AND CLASSIFICATION OF CLINICAL SUBTYPES OF ATLL a


                                                                                                                        Smoldering                                                                                                 ATL
                                                                                 Healthy carrier                                                          Chronic ATL                        Acute ATL
                                                                                                                          ATL                                                                                                   Lymphoma

              Anti-HTLV-1 serology                                                           +                                   +                                  +                                 +                                 +

                                                                                           -                                   +                                  +                                +                               +
              Clonal intergration of provirus
                                                                                        (blood)                             (blood)                            (blood)                          (blood)                      (lymph nodes)

              Lymphocyte count                                                          Normal                              Normal                           Elevated                          Elevated                              Elevated

              Abnormal cells (%)                                                          < 5%                                > 5%                               > 5%                             > 5%                                < 1%

              Hypercalcemia                                                                   -                                   -                                  -                                +                                 +

              LDH                                                                       Normal                              £ 1.5 N                              £2N                              >2N                                 >2N


              Skin and lung involvement                                                       -                                  +                                  +                                 +                                 +

               Bone marrow or spleen
                                                                                              -                                   -                                 +                                 +                                 +
               involvement

              Bone, GI or CNS involvement                                                     -                                   -                                  -                                +                                 +




   a Modifiedfrom Shimoyama M and members of The Lymphoma Study Group. Diagnostic criteria and classification of clinical subtypes of adult T-cell
     leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87). Br J Haematol 1991;79:428-437.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.              ATLL-A
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Adult T-cell Leukemia/Lymphoma                                                                                                                                                 Discussion

                                                                                                   RESPONSE CRITERIA FOR ATLL a

                                                                       Lymph                           Extranodal                                                                              Peripheral
             Response                 Definition                                                                                     Spleen, Liver                      Skin                                                   Bone Marrow
                                                                       Nodes                           Masses                                                                                  Blood

           Complete                   Disappearance
                                                                        Normal                         Normal                            Normal                      Normal                     Normal †                     Normal
           remission*                 of all disease

           Uncertified                Stable residual
                                                                        ³ 75%                          ³ 75%
           complete                   mass in bulky                                                                                      Normal                      Normal                     Normal †                     Normal
                                                                        decrease ‡                     decrease ‡
           remission*                 lesion

           Partial                    Regression of                     ³ 50%                          ³ 50%                                                         ³ 50%                      ³ 50%
                                                                                                                                         No increase                                                                         Irrelevant
           remission*                 disease                           decrease ‡                     decrease ‡                                                    decrease                   decrease

                                      Failure to attain
                                      complete/partial
           Stable                                                       No change                      No change                         No change                   No change
                                      remission and                                                                                                                                             No change                    No change
           disease*                                                     in size                        in size                           in size                     in size
                                      no progressive
                                      disease

           Relapsed
                                      New or
           disease or                                                   New or ³ 50%                   New or ³ 50%                    New or ³ 50%                  ³ 50%                      New or ³ 50%
                                      increased                                                                                                                                                                              Reappearance
           progressive                                                  increase §                     increase §                      increase                      increase                   increase #
                                      lesions
           disease

         *Required that each criterion to be present for a period of at least 4 weeks.                                                  § Defined by ³ 50% increase from nadir in the sum of the products of measurable
         † Provided  that < 5% of flower cells remain, complete remission is judged to have                                               disease.
           been attained if the absolute lymphocyte count, including flower cells,                                                      # Defined by ³ 50% increase from nadir in the count of flower cells and an
           is < 4 x 10 9/L.                                                                                                               absolute lymphocyte count, including flower cells, of > 4 x10 9/L.
         ‡ Calculated by the sum of the products of the greatest diameters of measurable
           disease.
   a TsukasakiK, Hermine O, Bazarbachi A, et al. Definition, prognostic factors, treatment, and response criteria of adult T-cell leukemia-lymphoma:
     A proposal from an international consensus meeting. J Clin Oncol 2009;27:453-459.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.           ATLL-B
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Adult T-cell Leukemia/Lymphoma                                                                                                                                                 Discussion

                                                                                                SUGGESTED TREATMENT REGIMENS


                                              · Chemotherapy a
                                                > CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)
                                                > Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin)
                                                > HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating
                                                  with high-dose methotrexate and cytarabine




   a There    is not published data regarding the use of these regimens, however, they are used at NCCN member institutions for the treatment of ATLL.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          ATLL-C
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Adult T-cell Leukemia/Lymphoma                                                                                                                                                 Discussion

                                                                                  REFERENCES FOR ZIDOVUDINE AND INTERFERON
                          Zidovudine and interferon
                          Bazarbachi A, Hermine O. Treatment with a combination of zidovudine and alpha-interferon in naive and pretreated adult T-cell
                          leukemia/lymphoma patients. J Acquir Immune Defic Syndr Hum Retrovirol 1996;13 Suppl 1:S186-190.

                          Bazarbachi A, Panelatti G, Ramos JC, et al. A worldwide meta-analysis on the use of zidovudine and interferon-alpha for the treatment of
                          adult T cell leukemia/lymphoma. ASH Annual Meeting Abstracts. 2007;110:2049.

                          Hermine O, Allard I, Levy V, Arnulf B, Gessain A, Bazarbachi A. A prospective phase II clinical trial with the use of zidovudine and interferon-
                          alpha in the acute and lymphoma forms of adult T-cell leukemia/lymphoma. Hematol J 2002;3:276-282.

                          White JD, Wharfe G, Stewart DM, et al. The combination of zidovudine and interferon alpha-2B in the treatment of adult T-cell
                          leukemia/lymphoma. Leuk Lymphoma 2001;40:287-294.




      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          ATLL-D
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Extranodal NK/T-cell Lymphoma, nasal type                                                                                                                                      Discussion

    DIAGNOSIS a                                                                                         SUBTYPES                                               WORKUP
    ESSENTIAL:                                                                                                                                                 ESSENTIAL:
    · Hematopathology review of all slides with a                                                                                                              · Physical exam; attention to complete ENT
      least one paraffiin block representative of the                                                                                                            evaluation nasopharynx involvement
      tumor. Rebiopsy if consult material is non-                                                                                                                (including Waldeyer's ring), testicles and
                                                                                                                                                                 skin
      diagnostic.
                                                                                                                                                               · Performance status
    · A FNA or core needle biopsy alone is not
                                                                                                                                                               · B symptoms
      suitable for the initial diagnosis of lymphoma. b
                                                                                                                                                               · CBC, differential platelets
    · In certain circumstances, when a lymph node
                                                                                                                                                               · LDH
      is not easily accessible for excisional or
                                                                                                        Subtypes included:                                     · Comprehensive metabolic panel
      incisional biopsy, a combination of core biopsy
                                                                                                        · Extranodal NK/T-cell,                                · Uric acid
      and FNA biopsies in conjunction with                                                                                                                                                                                                See
                                                                                                          nasal type                                           · Bone marrow biopsy + aspirate e
      appropriate ancillary techniques for the                                                                                                                                                                                            Induction
                                                                                                                                                               · Chest/abdominal/pelvic CT with contrast
      differential diagnosis (immunohistochemistry,                                                     Subtypes not included:                                                                                                            Therapy
                                                                                                                                                                 of diagnostic quality or PET-CT scan with
      flow cytometry, PCR for IgH and TCR gene                                                          · NK-cell leukemias                                                                                                               (NKTL-2)
                                                                                                                                                                 diagnostic quality CT
      rearrangements and FISH for major                                                                 · Precursor NK-cell                                    · Dedicated CT of the nasal cavity, hard
      translocations) may be sufficient for diagnosis.                                                    neoplasm                                               palate, anterior fossa or MRI nasopharynx
    · Adequate immunophenotyping to establish                                                                                                                  · Calculation of NK/T-cell PI f
      diagnosis c                                                                                                                                              · MUGA scan/echocardiogram if treatment
      > Recommended immunohistochemistry (IHC)
                                                                                                                                                                 includes regimens containing
         panel: B cell: CD20; T lineage antigens: CD2,                                                                                                           anthracyclines or anthracenediones
         CD7, CD8, CD4, CD5. cCD3ε; NK lineage                                                                                                                 · EBV viral load g
         markers: CD56; Ki-67 (nuclear antigen                                                                                                                 USEFUL IN SELECTED CASES:
         marker)                                                                                                                                               · Pregnancy testing in women of child-
      > in situ hybridization (ISH) for (EBER-1/2) d                                                                                                             bearing age
   a Itis preferred that treatment occur at centers with expertise in the management of this                                                                   · Discussion of fertility and sperm banking
     disease.                                                                                                                                                  · HIV
   b Necrosis is very common in diagnostic biopsies and may delay diagnosis significantly.                                                  d Negative   result should prompt pathology review for alternative diagnosis.
     Biopsy should include the edges of lesions, to increase the odds of having viable                                                      e BM   aspirate - lymphoid aggregates rare, considered involved if EBER-1
     tissue. Useful to perform multiple nasopharyngeal biopsies even in areas not clearly                                                      positive, hemophagoctosis may be present.
     involved.                                                                                                                              f See NK/T-cell Lymphoma Prognostic Index (NKTL-A).
   c Typical NK/T-cell immunophenotype: CD20-, CD2+, cCD3ε+ (surface CD3-), CD7+,                                                           g EBV viral load is important in diagnosis and possibly in monitoring of disease.
     CD8+ CD45RO+, CD43+, CD56+, T-cell receptor (TCR)αβ-, TCR-, TCRγδ, TCR and Ig                                                             A positive result is consistent with NK/T-cell, nasal type. Lack of normalization
     genes are usually germline (NK lineage).                                                                                                  of EBV viremia should be considered indirect evidence of persistent disease.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          NKTL-1
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Extranodal NK/T-cell Lymphoma, nasal type                                                                                                                                      Discussion

                              STAGE                                                                                                                         INDUCTION THERAPY

                                                                                                                                                            Clinical trial
                                                                                                  No risk factors                                           or
                                                                                                  present                                                   RT alone (³ 50 Gy)
                                                                                                                                                            or
                                                            Assess risk                                                                                     Concurrent chemoradiotherapy h
                              Stage I
                                                            factors


                                                                                                 Presence of ANY
                                                                                                 risk factor                                                Clinical trial
    Nasal                                                                                                                                                   or                                                                       See Post-RT
                                                                                                                                                            Concurrent chemoradiotherapy h                                           Evaluation
                              Stage II                                                                                                                                                                                               (NKTL-3)


                                                                                                                                                            Clinical trial
                              Stage III/IV                                                                                                                  or
                                                                                                                                                            Concurrent chemoradiotherapy h
                                                                                                                                                            or
                                                                                                                                                            Combination chemotherapy
    Extranasal                  Stage I- IV                                                                                                                 regimen (L-asparaginase
                                                                                                                                                            based) h ± RT


                                                                                                                                                                                  Risk factors
                                                                                                                                                            (includes elements of NK/T-cell Lymphoma PI on NKTL-A)
                                                                                                                                                            · Age > 60 y                                             · Local tumor invasion
                                                                                                                                                            · B symptoms                                               (LTI); bone or skin
                                                                                                                                                            · ECOG PS ³ 2                                            · Histological evidence of
   Adapted with permission from Kohrt H, Lee M, Advani R. Risk stratification in extranodal                                                                 · Elevated LDH                                             high Ki-67 staining
     natural killer/T-cell lymphoma. Expert Rev Anticancer Ther 2010;10:1395-1405.                                                                          · Regional node involvement                              · EBV DNA titer
   h See Suggested Treatment Regimens (NKTL-B).                                                                                                                                                                        ³ 6.1 x 10 7 copies/ml

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          NKTL-2
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Extranodal NK/T-cell Lymphoma, nasal type                                                                                                                                      Discussion

   POST RT                                                                                                                    RESPONSE                                   ADDITIONAL
   EVALUATION                                                                                                                 ASSESSMENT j                               THERAPY

                                                                                                                             CR k                                        Observe



                                                                                      Stage I, with                                                                      Hematopoietic stem cell
                                                                                      or without                             PR
                                                                                                                                                                         transplant, l if eligible
                                                                                      risk factors

                                                                                                                                                                                                                                 Hematopoietic stem
                                                                                                                                                                         Salvage        chemotherapy m                           cell transplant, l if
                                                                                                                             Refractory
                                                          Nasal                                                                                                          or                                                      eligible
                                                                                                                             disease
                                                                                                                                                                         Best supportive care

   Post-RT evaluation i
   · Repeat initial imaging
     of CT, MRI, or PET-CT
     scan                                                                             Stage II- IV
   · Endoscopy with visual                                                                                                                                               Consider hematopoietic stem
                                                                                                                              CR or PR
     inspection and repeat                                                                                                                                               cell transplant l
     biopsies
   · EBV viral load                                                                                                                                                      Salvage chemotherapy m
                                                                                                                              Refractory
                                                                                                                                                                         or
                                                                                                                              disease
                                                                                                                                                                         Best supportive care
                                                          Extranasal                    Stage I- IV


    i The  role of PET scan in this disease is not well established.
    j See  Response Criteria for Lymphoma (NHODG-C).                          Adapted with permission from Kohrt H, Lee M, Advani R. Risk stratification in extranodal
    k Includes a negative ENT evaluation.                                      natural killer/T-cell lymphoma. Expert Rev Anticancer Ther 2010;10:1395-1405.
    l Allogeneic preferred, if matched donor available.
    m Combination chemotherapy regimen (L-asparaginase based) See Suggested Treatment Regimens (NKTL-B).

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.             NKTL-3
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Extranodal NK/T-cell Lymphoma, nasal type                                                                                                                                      Discussion

                                                                                         NK/T CELL LYMPHOMA PROGNOSTIC INDEX a


                                                                                               ALL PATIENTS
                                                                                               Serum LDH > 1 x normal
                                                                                               B symptoms
                                                                                               Lymph nodes, N1 to N3, not M1
                                                                                               Ann Arbor Stage III

                                                                                                                               Number of risk factors
                                                                                               Low                                               0
                                                                                               Low intermediate                                  1
                                                                                               High intermediate                                 2
                                                                                               High                                              3 or 4




   a Lee J, Suh C, Park YH, et al. Extranodal natural killer T-cell lymphoma, nasal-type: A prognostic model from a retrospective multicenter
     study. J Clin Oncol. 2006;24:612-618.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          NKTL-A
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Extranodal NK/T-cell Lymphoma, nasal type                                                                                                                                      Discussion

                                                                                               SUGGESTED TREATMENT REGIMENS a



        Combination chemotherapy regimen (L-asparaginase based)
        · SMILE (steroid [dexamethasone], methotrexate, ifosfamide, L-asparaginase, and etoposide)

        Concurrent chemoradiotherapy (CCRT)
        · CCRT (radiation 50 Gy and 3 courses of DeVIC [dexamethasone, etoposide, ifosfamide, and carboplatin])

        · CCRT (radiation 40 to 52.8 Gy and cisplatin) followed by 3 cycles of VIPD (etoposide, ifosfamide, cisplatin, and dexamethasone)

        Radiotherapy alone (or in sequence with chemotherapy)
        · Early or up-front RT had an essential role in improved OS and DFS in patients with localized extranodal NK/T-cell lymphoma, nasal-
          type, in the upper aerodigestive tract. The recommended tumor dose was ³ 50 Gy. Up-front RT may yield more benefits on survival in
          patients with stage I disease.




   a See   references for regimens NKTL-B 2 of 2.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                            NKTL-B
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Extranodal NK/T-cell Lymphoma, nasal type                                                                                                                                      Discussion

                                                                                               SUGGESTED TREATMENT REGIMENS
                                                                                                                         References

              Combination chemotherapy regimen (L-asparaginase based)
              Jaccard A GN, Coppo P, Morschhauser F, et al. A prospective phase II trial of an L-asparaginase containing regimen in patients with refractory or relapsing
              extra nodal NK/T-cell lymphoma. ASH Annual Meeting Abstracts. 2008;112:79.
              Yamaguchi M KY, Maeda Y, Hashimoto C, et al and The NK-Cell Tumor Study Group Phase II study of SMILE chemotherapy for newly-diagnosed stage
              IV, relapsed or refractory extranodal NK/T-cell lymphoma, nasal type: NKTSG study. J Clin Oncol (Meeting Abstract). 2010;28:8044.

              Concurrent chemoradiotherapy
              Yamaguchi M TK, Oguchi M, Isobe Y, et al, Japan Clinical Oncology Group Lymphoma Study Group (JCOG-LSG) Phase I/II study of concurrent
              chemoradiotherapy for localized nasal NK/T-cell lymphoma: Final results of JCOG0211. J Clin Oncol (Meeting Abstract). 2009;27:8549.
              Kim SJ, Kim K, Kim BS, et al. Phase II trial of concurrent radiation and weekly cisplatin followed by VIPD chemotherapy in newly diagnosed, stage IE to
              IIE, nasal, extranodal NK/T-cell lymphoma: Consortium for Improving Survival of Lymphoma study. J Clin Oncol 2009;27:6027-6032.

              Radiotherapy alone
              Huang MJ, Jiang Y, Liu WP, et al. Early or up-front radiotherapy improved survival of localized extranodal NK/T-cell lymphoma, nasal-type in the upper
              aerodigestive tract. Int J Radiat Oncol Biol Phys 2008;70:166-174.




      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                            NKTL-B
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                                                            NCCN Guidelines™ Version 3.2011                                                                                                                                   NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                            Post-Transplant Lymphoproliferative Disorder                                                                                                                                  Discussion

   DIAGNOSIS                                                                                                  WORKUP

   ESSENTIAL:
   · Histopathology and adequate immunophenotype
     to establish diagnosis. Rebiopsy if consult
     material is nondiagnostic.                                                                              ESSENTIAL:
     > Recommended panel for paraffin section                                                                · Performance status                                                           Early lesions
       immunohistochemistry: CD3, CD5, CD10, BCL6,                                                           · Albumin
       BCL2, IRF4/MUM1, CD20, CD79a, PAX5, Ki67                                                              · Immunosuppressive regimen
     > Cell surface marker analysis by flow cytometry:                                                       · LDH, electrolytes, BUN, creatinine
       CD3, CD5, CD7, CD4, CD8, CD19, CD20, CD10,                                                            · CBC, differential                                                            Polymorphic
       Kappa, lambda                                                                                         · Hepatitis B testing b
   · Epstein-Barr virus (EBER-ISH). If the less                                                              · Chest/abdomen/pelvis CT
                                                                                                                                                                                                                                       See Primary
     sensitive EBV-LMP1 stain is positive, EBER in situ
                                                                                                                                                                                                                                       Treatment
     hybridization is not required.                                                                          USEFUL IN SELECTED CASES:
                                                                                                             · MUGA scan/echocardiogram if                                                                                             (PTLD-2)
   USEFUL UNDER CERTAIN CIRCUMSTANCES:                                                                         treatment includes regimens
   · Panel for paraffin section immunohistochemistry:                                                          containing anthracyclines or                                                 Monomorphic
     CD15, CD30, CD45, CD7, CD4, CD8, ALK, TIA-1,                                                              anthracenediones
     Granzyme B, CD57, CD56, CD138                                                                           · Bone marrow evaluation
   · Cell surface marker analysis by flow cytometry:                                                         · PET-CT scan
     CD138, cytoplasmic Kappa and lambda, CD30,                                                              · EBV PCR, CMV PCR                                                             Classic Hodgkin
     CD57, CD56, CD16, CD25, CD52.                                                                           · Brain MRI                                                                    lymphoma
   · Molecular genetic analysis to detect gene
     rearrangements: IgH by PCR
   · BCL6 gene mutation analysis a




   a BCL6  gene mutation positivity has been associated with a poor response to reduction in immunosuppressive therapy.
   b HepatitisB testing is indicated because of the risk of reactivation with immunotherapy + chemotherapy. Tests include hepatitis B surface antigen and core antibody for a
     patient with no risk factors. For patients with risk factors or previous history of hepatitis B, add e-antigen. If positive, check viral load and consult with gastroenterologist.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          PTLD-1
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                                                            NCCN Guidelines™ Version 3.2011                                                                                                                                   NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                            Post-Transplant Lymphoproliferative Disorder                                                                                                                                  Discussion

   PTLD                                      PRIMARY TREATMENT                                                                            INITIAL RESPONSE                                        SECOND-LINE
   SUBTYPE                                                                                                                                                                                        TREATMENT

                                                                                                                                          Complete                                                Continue RI and
                                                                                                                                          response                                                monitor EBV PCR
                                             · Reduction of immunosuppressive (RI)
   Early lesions
                                             · If EBV positive, treat with gancyclovir
                                                                                                                                          Persistent or                                           Rituximab and
                                                                                                                                          progressive disease                                     monitor EBV PCR

                                                                    · RI, if possible
                                                                    · If EBV positive, treat with                                                                                                 Continue RI and monitor
                                   Systemic                           gancyclovir                                                         Complete                                                EBV PCR
                                                                    · Rituximab                                                           response                                                or
                                                                    · Chemoimmunotherapy e                                                                                                        Maintenance rituximab
   Polymorphic
                                                                   RT                                                                                                                             Chemoimmunotherapy e
                                                                   or                                                                     Persistent or                                           or
                                   Localized                                                                                                                                                      Clinical trial
                                                                   Surgery                                                                progressive disease
                                                                                                                                                                                                  or
                                                                   or
                                                                                                                                                                                                  EBV specific cytotoxic T- cell
                                                                   Rituximab alone
                                                                                                                                                                                                  immunity (if EBV driven)

                                                                                                                                          Complete                                               See appropriate histology
                                             RI d
                                                                                                                                          response                                               guidelines for followup
                                             or
   Monomorphic c                             Chemoimmunotherapy e                                                                                                                                 If RI was initial therapy, then rituximab
                                             or                                                                                                                                                   or chemoimmunotherapy e
                                             Rituximab alone f                                                                            Persistent or                                           or
                                                                                                                                          progressive disease                                     If rituximab monotherapy was initial
   Classic Hodgkin                           Treat as Hodgkin lymphoma
                                                                                                                                                                                                  therapy, then chemoimmunotherapy e
   lymphoma                                  (See NCCN Hodgkin Lymphoma Guidelines)                                                                                                               or
   c Treatment                                                                                                                                                                                    Clinical trial
                 is based on the unique histology.
   d Response    to RI therapy is variable and patients need to be closely monitored.
                                                                                                                                                                                                  or
   e See Suggested Treatment Regimens PTLD-A.                                                                                                                                                     EBV specific cytotoxic T-cell immunity
   f In patients unable to tolerate chemotherapy.                                                                                                                                                 (if EBV driven)

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          PTLD-2
Printed by Eric Kirkendall on 7/17/2011 6:41:14 PM. For personal use only. Not approved for distribution. Copyright © 2011 National Comprehensive Cancer Network, Inc., All Rights Reserved.




                                                            NCCN Guidelines™ Version 3.2011                                                                                                                                   NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                            Post-Transplant Lymphoproliferative Disorder                                                                                                                                  Discussion

                                                                                                SUGGESTED TREATMENT REGIMENS
                                                                                                     (in alphabetical order)


                                   RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)

                                   RCHOEP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide)

                                   RCVP (rituximab, cyclophosphamide, vincristine, prednisone) (for frail patients who cannot tolerate anthracycline)


                                   See Monoclonal Antibody Directed at CD20 and Viral Reactivation (NHODG-D)




      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.          PTLD-A
Printed by Eric Kirkendall on 7/17/2011 6:41:14 PM. For personal use only. Not approved for distribution. Copyright © 2011 National Comprehensive Cancer Network, Inc., All Rights Reserved.




                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Non-Hodgkin’s Lymphomas                                                                                                                                                        Discussion
      USE OF IMMUNOPHENOTYPING/GENETIC TESTING IN DIFFERENTIAL DIAGNOSIS OF MATURE B-CELL AND T/NK-CELL NEOPLASMS a
                            (TO BE USED IN CONJUNCTION WITH CLINICAL PATHOLOGICAL CORRELATION)
   B-CELL ANTIGENS POSITIVE (CD19, CD20, CD79a, PAX5)
                                                                        cyclin D1 -
                                                   CD23 +   CLL
                                                                        t(11;14) -
                                                                                  CD5 +                                          cyclin D1 +
                                                                                                                                                                   MCL
                                                                                                                                 t(11;14) +
                                                                                                        CD23 -
                                                                                                                                 cyclin D1 - c
                                 Panel: CD5, CD10,                                                                                                                 CLL
                                                                                                                                 t(11;14) -
                                 CD23, cyclin D1,
    Small cells:
                                 BCL2, BCL6                                                                                                              BCL6 +
                                 (CD25, CD103) b                                                        CD10 +                  FL                       BCL2 + d
                                                                                                                                                         t(14;18) + d

                                                                                 CD5 -                                          CD103 +
                                                                                                                                                         HCL                  annexin 1 +
                                                                                                                                CD25 +
                                                                                                                                                                                                · Morphology (MZ pattern)
                                                                                                                                                                                                · Clinical features                         MZL
                                                                                                        CD10 -
                                                                                                                                                       Cytoplasmic Ig -                           (extranodal, splenic)

                                                                                                                                                                                                Pseudofollicular pattern,                  CD5 -
                                                                                                                                CD103 -                                                         clinical features (BM)                     CLL

                                                                                                                                                                                                                      · Morphology (MZ pattern,
                                                                                                                                                                                                                        plasmacytoid features),
   Small cells:                                                                                                                                                                                                         genetics (del 7q)
   · Chronic lymphocytic leukemia/ small lymphocytic                                                                                                                                            LPL vs
                                                                                                                                                       Cytoplasmic Ig +                                               · Clinical features
     lymphoma (CLL/SLL)                                                                                                                                                                         MZL
                                                                                                                                                                                                                        (splenomegaly, bone
   · Mantle cell lymphoma (MCL)                                                                                                                                                                                         marrow involvement,
   · Splenic marginal zone lymphoma                                                                                                                                                                                     paraprotein)
                                                                                                            a These
   · Hairy cell leukemia (HCL)                                                                                       are meant to be general guidelines. Interpretation of results should be based on
   · Lymphoplasmacytic lymphoma (LPL)                                                                         individual circumstances and may vary. Not all tests will be required in every case.
                                                                                                            b Flow cytometry, blood or bone marrow, if HCL is in differential diagnosis.
   · Extranodal marginal zone lymphoma (MALT lymphoma)                                                      c Rare cases of both cyclin D1 and t(11;14) negative MCL have been reported. This diagnosis
   · Nodal marginal zone lymphoma                                                                             should be made with extreme caution and with expert consultation.
   · Follicular lymphoma (FL)                                                                               d 85% of Follicular Lymphoma will be BCL2 + or t(14;18) +.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                          NHODG-A
   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.           1 of 8
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Non-Hodgkin’s Lymphomas                                                                                                                                                        Discussion
      USE OF IMMUNOPHENOTYPING/GENETIC TESTING IN DIFFERENTIAL DIAGNOSIS OF MATURE B-CELL AND T/NK-CELL NEOPLASMS a
                             (TO BE USED IN CONJUNCTION WITH CLINICAL PATHOLOGICAL CORRELATION)
    B-CELL ANTIGENS POSITIVE (CD19, CD20, CD79a, PAX5)

                                                                                                            cyclin D1 +                            blastoid MCL

                                                                                     CD5 +
                                                                                                            cyclin D1 -
                                                                                                            BCL6 +/-                               CD5 + DLBCL                                            MYC +
                                                                                                            IRF4/MUM1 +/-                                                                                 BCL2 -                     BL
                                                                                                                                                                                                          BCL6 -
                                                                                                                                    BCL6 +
                                      Panel: CD5, CD10,                                                                                                              Fish for MYC,
                                                                                                                                    BCL2 -
    Medium cells                      BCL2, BCL6,                                                                                                                    BCL2, BCL6                           MYC +/-
                                                                                                                                    Ki67 95%
                                      cyclin D1, Ki67                                                                                                                                                     BCL2 +                     U-DLBCL/BL
                                                                                                            CD10+
                                                                                                                                                                                                          BCL6 +/-

                                                                                                                                    BCL6 +                                                                      Fish for MYC, BCL2, BCL6
                                                                                                                                                                     U-DLBCL/BL
                                                                                                                                    BCL2 +                                                                      to check for “double hit”
                                                                                     CD5 -                                                                                                                 MYC +
                                                                                                                                                                                                           BCL2 -                    BL ?
                                                                                                                                    BCL6 +                                                                 BCL6 -
                                                                                                                                    BCL2 -                           Fish for MYC,
                                                                                                                                    IRF4/MUM1 -                      BCL2, BCL6                            MYC +/-
                                                                                                                                    Ki67 > 90%                                                             BCL2 +                    U-DLBCL/BL
                                                                                                            CD10-
                                                                                                                                                                                                           BCL6 +/-

                                                                                                                                   BCL6 +/-
                                                                                                                                   BCL2 +                                                                 Fish for MYC, BCL2, BCL6
                                                                                                                                                                     U-DLBCL/BL
   Medium cells                                                                                                                    IRF4/MUM1 +/-                                                          to check for “double hit”
   · Burkitt lymphoma (BL)                                                                                                         Ki67 60- 90%
   · Diffuse large B-cell lymphoma (DLBCL)
   · Mantle cell lymphoma (MCL), blastoid variant
   · B-cell lymphoma (BCL), unclassifiable, intermediate                                                                     a These  are meant to be general guidelines. Interpretation of results should be based on
     between DLBCL and BL (U-DLBCL/BL)                                                                                         individual circumstances and may vary. Not all tests will be required in every case.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                            NHODG-A
   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.             2 of 8
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Non-Hodgkin’s Lymphomas                                                                                                                                                        Discussion
      USE OF IMMUNOPHENOTYPING/GENETIC TESTING IN DIFFERENTIAL DIAGNOSIS OF MATURE B-CELL AND T/NK-CELL NEOPLASMS a
                             (TO BE USED IN CONJUNCTION WITH CLINICAL PATHOLOGICAL CORRELATION)
    B-CELL ANTIGENS POSITIVE (CD19, CD20, CD79a, PAX5)

                                                                                               cyclin D1 +                              pleomorphic MCL

                                                                        CD5 +
                                                                                               cyclin D1 -
                                                                                               BCL6 +/-                                 CD5 + DLBCL, NOS
                                    Panel: CD5,                                                IRF4/MUM1 +/-
    Large cells:                    CD10, BCL6,
                                    IRF4/MUM1                                                                                     CD10+                    DLBCL, NOS GCB type (BCL6+)

                                                                                            DLBCL or                                                     BCL6 +
                                                                        CD5 -                                                                                                            DLBCL, NOS GCB type
                                                                                            U-DLBCL/CHL                                                  IRF4/MUM1 -

                                                                                                                                                         BCL6 +                                                      Panel: CD20, PAX5,
                                                                                                                                  CD10-                                                  Non-GCB
                                                                                                                                                         IRF4/MUM1 +                                                 CD138, ALK1, CD30,
    Large cells:
                                                                                                                                                                                                                     CD15, EBV-EBER,
    · Diffuse large B-cell lymphoma (DLBCL), NOS
                                                                                                                                                         BCL6 -                                                      HHV8, Ig light and
      > T-cell/histiocyte rich large B-cell lymphoma (THRLBCL)                                                                                                                           Post-GCB
                                                                                                                                                         IRF4/MUM1 +                                                 heavy chains
      > Primary DLBCL of the CNS
      > Primary cutaneous DLBCL, leg type
      > EBV positive DLBCL of the elderly (EBV + DLBCL)
    · DLBCL associated with chronic inflammation
    · Lymphomatoid granulomatosis                                                                                                                                                                          Continued on next page
    · Primary mediastinal (thymic) large B-cell lymphoma (PMBL)
    · Intravascular large B-cell lymphoma
    · ALK positive large B-cell lymphoma
    · Plasmablastic lymphoma
    · Large B-cell lymphoma arising in HHV8-associated
      multicentric Castleman disease (LBCL in HHV8 + MCD)
    · Primary effusion lymphoma                                                                                                    GCB= Germinal center B-cell like
    · B-cell lymphoma, unclassifiable, intermediate between
      DLBCL (U-DLBCL) and classical Hodgkin lymphoma (CHL)                                                                   a These  are meant to be general guidelines. Interpretation of results should be based on
    · Mantle cell lymphoma (MCL), pleomorphic variant                                                                          individual circumstances and may vary. Not all tests will be required in every case.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                          NHODG-A
   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.           3 of 8
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Non-Hodgkin’s Lymphomas                                                                                                                                                        Discussion
      USE OF IMMUNOPHENOTYPING/GENETIC TESTING IN DIFFERENTIAL DIAGNOSIS OF MATURE B-CELL AND T/NK-CELL NEOPLASMS a
                             (TO BE USED IN CONJUNCTION WITH CLINICAL PATHOLOGICAL CORRELATION)
   Large cells (continued)                      T-cell-rich       THRLBCL (May be BCL6 +, IRF4/MUM1 -)
                                  CD30 -
                                                DLBCL, non-GCB
                      EBER -                                                        MAL + d
                      HHV8 -                                                                     (May be
                                                Mediastinal             PMBL        TRAF + d
                                                                                                 BCL6 +, IRF4/MUM1 -)
                                                                                    REL +(nuc) d
                                  CD30 +                                                          MAL + d
                                                Morphologically         CD15 -      PMBL          TRAF + d
                                                                                                  REL + (nuc) d
                                                borderline with CHL
                                                                        CD15 +      U-DLBCL/CHL
                                   Elderly or
                                                              EBV + DLBCL
    CD20 +                         immunosuppressed
    (PAX5 +)
                      EBER +       Extranodal, T-cell
                      HHV8 -                                  Lymphomatoid granulomatosis
                                   rich, angiocentric
                                                                    Chronic
                                                                                                                     DLBCL associated with chronic inflammation
                                                                    inflammation


                                    EBER -                                                  LBCL in HHV8 + multicentric Castleman disease
                                    HHV8 +                                                  (IgM lambda +) confirm by morphology
                                                                       EBV +
                                                                                                   Plasmablastic lymphoma
                                                                       HHV8 -
                                                                       EBV +/-
                                                                                                   PEL (CD30+)
                                                                       HHV8 +
     CD20 -
                                     CD138 +/-
     (PAX5 -)                                                          EBV -
                                                                                                   ALK + DLBCL                           IgA lambda + EMA +
                                                                       ALK+
                                                                       EBV -                       Anaplastic/Plasmablastic
                                                                       ALK -                                                                                    IgG, A, kappa or lambda
                                                                                                   myeloma/plasmacytoma
                                                                       HHV8 -
   a These  are meant to be general guidelines. Interpretation of results should be based on
                                                                                                                                                  d These     stains/studies are not routinely available.
     individual circumstances and may vary. Not all tests will be required in every case.
      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                          NHODG-A
   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.           4 of 8
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Non-Hodgkin’s Lymphomas                                                                                                                                                        Discussion
      USE OF IMMUNOPHENOTYPING/GENETIC TESTING IN DIFFERENTIAL DIAGNOSIS OF MATURE B-CELL AND T/NK-CELL NEOPLASMS a
                            (TO BE USED IN CONJUNCTION WITH CLINICAL PATHOLOGICAL CORRELATION)
   B-CELL ANTIGENS POSITIVE (CD19, CD20, CD79a, PAX5)

                                                                                             CD10 +                              PCFCL
                                                                                                                                                       BCL6 +
                                                                                                                                                       IRF4/MUM1 -
                                                                                                                                                                                                                          PCFCL
                                                                                                                                                       (FDC +/-)
                                                                                                                                                       Small/medium/large cells
                                      Panel: CD10, BCL2,
    Cutaneous                                                                                                         BCL2 -
                                      BCL6, IRF4/MUM1,
    localization
                                      CD21/23 (FDC markers)
                                                                                                                                                       BCL6 -
                                                                                                                                                       IRF4/MUM1 +/-
                                                                                                                                                                                                                          PCMZL
                                                                                                                                                       (FDC +)
                                                                                                                                                       Small/medium cells

                                                                                             CD10 -
                                                                                                                                                       BCL6 +/-
                                                                                                                                                       IRF4/MUM1 +
                                                                                                                                                                                                                          PC-DLBCL, leg type
                                                                                                                                                       (FDC -)
                                                                                                                                                       Large round cells

                                                                                                                                                       BCL6 -
                                                                                                                      BCL2 +                           IRF4/MUM1 +/-
                                                                                                                                                                                                                          PCMZL
                                                                                                                                                       (FDC +)
                                                                                                                                                       Small/medium cells

                                                                                                                                                       BCL6 +
                                                                                                                                                       IRF4/MUM1 -
                                                                                                                                                                                                                          PCFCL
                                                                                                                                                       (FDC +, follicular)
                                                                                                                                                       Small/medium/large cells


   · Primary cutaneous marginal zone lymphoma (PCMZL)                                                                            FDC = Follicular dendritic cells
   · Primary cutaneous follicle center lymphoma (PCFCL)                                                                      a These  are meant to be general guidelines. Interpretation of results should be based on
   · Primary cutaneous DLBCL, leg type (PC-DLBCL, leg type)                                                                    individual circumstances and may vary. Not all tests will be required in every case.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                          NHODG-A
   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.           5 of 8
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Non-Hodgkin’s Lymphomas                                                                                                                                                        Discussion
       USE OF IMMUNOPHENOTYPING/GENETIC TESTING IN DIFFERENTIAL DIAGNOSIS OF MATURE B-CELL AND T/NK-CELL NEOPLASMS a
                             (TO BE USED IN CONJUNCTION WITH CLINICAL PATHOLOGICAL CORRELATION)
    T-CELL ANTIGENS POSITIVE (CD2, CD3, CD5, CD7) [and B-cell antigens negative]

                                                                                                         ALK +                    ALCL, ALK +

                                                                                                                                                          DLBCL (T-cell antigen expression artifactual)
                                                                              CD30 +                                             PAX5 +

                                                                                                                                                          CD15 +                    Classical Hodgkin lymphoma
                                                                                                                                                          EBER +/-
                                     Panel: CD30,                                                        ALK -
   Anaplastic
                                     CD15, Pax5,                                                                                                                   · Cutaneous = Primary cutaneous CD30+ T-cell LPD
   morphology
                                     ALK, EBV-EBER                                                                                                                   > Polymorphous, regressing = LyP
                                                                                                                                                                     > Monomorphous, progressing = PC-ALCL
                                                                                                                                 PAX5 -                            · Non-cutaneous = ALCL, ALK -
                                                                                                                                                                   · Intestinal = EATL (eosinophils: clinical history of
                                                                              CD30 -                    PTCL- NOS                                                    celiac disease or antibodies)
                                                                                                                                                                   · HTLV1 + = ATLL, anaplastic large cell type (CD25+)




   Anaplastic morphology
   · Anaplastic large cell lymphoma (ALCL), ALK positive
   · Anaplastic large cell lymphoma (ALCL), ALK negative
   · Adult T-cell leukemia/lymphoma (ATLL), anaplastic large cell type
   · Enteropathy associated T-cell lymphoma (EATL)
   · Primary cutaneous CD30 positive T-cell lymphoproliferative disorders                                                                  a These  are meant to be general guidelines. Interpretation of results should be
     > Lymphomatoid papulosis (LyP)                                                                                                          based on individual circumstances and may vary. Not all tests will be required
     > Primary cutaneous anaplastic large cell lymphoma (PC-ALCL)                                                                            in every case.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                          NHODG-A
   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.           6 of 8
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Non-Hodgkin’s Lymphomas                                                                                                                                                        Discussion
      USE OF IMMUNOPHENOTYPING/GENETIC TESTING IN DIFFERENTIAL DIAGNOSIS OF MATURE B-CELL AND T/NK-CELL NEOPLASMS a
                             (TO BE USED IN CONJUNCTION WITH CLINICAL PATHOLOGICAL CORRELATION)
   T-CELL ANTIGENS POSITIVE (CD2, CD3, CD5, CD7) [and B-cell antigens negative (Pax5)]

                                                                                            CD30 +                  CD30+ Cutaneous LPD e
                                                                                                                                                                              MF, SS e (CD2+ CD5+ CD7- CD8- βF1+ CGP-)
                                                                                                                                                      CD4 +
                                        Panel: CD2, CD5, CD7,                                                                                                                 HTLV1 + = ATLL
   Cutaneous                            CD4, CD8, CD30, CD56,                                                   Epidermotropic                                                              CD8 + AECTCL e,f (CD2- CD5- CD7+/-
   localization                         βF1, cytotoxic granule                                                                                                           CD8 +              CD56 - βF1+ CGP+)
   (non-anaplastic                      proteins (CGP = perforin,                                                                                     CD4 -
   morphology)                          granzyme B, TIA1), EBV-                                                                                                              cutaneous γδTCL (CD2+ CD5- CD7+/-
                                        EBER; Optional: CD25                                                                                                       CD8 -     CD56+/- βF1- CGP+) (dermis and
                                                                                                                                                                             subcutis often involved)
                                                                                             CD30 -                                                                      Consider myeloid sarcoma (may be CD2+
                                                                                                                                                               CD56 +    CD7+ CD56+) or
                                                                                                                                             CD4 +                       BPDC (CD3- CD5- CD123+ CD68+ TCL1+)
                                                                                                                                                                                    Small/med cells = CD4+ small/medium CTCL
                                                                                                                                                               CD56 -
                                                                                                                                                                                    Med/large cells = PTCL, NOS
                                                                                                                 Dermis and
                                                                                                                                                                                                            SCPTCL (CD2+ CD5-
                                                                                                                 subcutis                                                            βF1 +
                                                                                                                                                                                                            CD7+ CD56- CGP+)
                                                                                                                                                                 CD8 +
                                                                                                                                                                                                            Cutaneous γδTCL (CD2+
                                                                                                                                                                                     βF1 -
                                                                                                                                                                                                            CD5- CD7+/- CD56+/- CGP+)
                                                                                  CD4 -
   Cutaneous localization (non-anaplastic morphology)
                                                                                                          βF1 +          PTCL-NOS
   · Primary cutaneous CD30 positive T-cell lymphoproliferative disorders (LPD)
   · Mycosis fungoides, Sézary syndrome (MF, SS)                                              CD8 -                                 NK/T nasal type CD2+
                                                                                                                     EBV +
   · Subcutaneous panniculitis-like T-cell lymphoma (SCPTCL)                                                                        CD7- CD56+ CGP+)
   · Primary cutaneous gamma-delta T-cell lymphoma (γδTCL)                                                βF1 -
                                                                                                                                    cutaneous γδTCL
   · Primary cutaneous CD8 positive aggressive epidermotropic cytotoxic T-cell
                                                                                                                     EBV -          (CD2+ CD5- CD7+/-
     lymphoma (AECTCL)
                                                                                                                                    CD56+/- CGP+)
   · Primary cutaneous CD4 positive small/medium T-cell lymphoma       a These are meant to be general guidelines. Interpretation of results should be based
   · Extranodal NK/T-cell lymphoma, nasal type                            on individual circumstances and may vary. Not all tests will be required in every case.
   · Peripheral T-cell lymphoma, NOS                                   e A minority of MF cases can be CD30+, CD4 - and either CD8 +/-, TIA1 +.
   · Blastic plasmacytoid dendritic cell neoplasm (BPDC)               f AECTCL has distinctive morphology and clinical presentation.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                          NHODG-A
   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.           7 of 8
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Non-Hodgkin’s Lymphomas                                                                                                                                                        Discussion
         USE OF IMMUNOPHENOTYPING/GENETIC TESTING IN DIFFERENTIAL DIAGNOSIS OF MATURE B-CELL AND T/NK-CELL NEOPLASMS a
                             (TO BE USED IN CONJUNCTION WITH CLINICAL PATHOLOGICAL CORRELATION)
                                                                  ENK/TCL (CD5- CD4- CD8- CD30- CD56+ CGP+, midline
                                                   EBER +
                                                                  face, upper aerodigestive tract, testis, GI tract)
    Extranodal,                          Panel: ALK1, CD5, CD7, CD4,
    noncutaneous                         CD8, CD30, C56, βF1,                                                                                          ALK +               ALCL, ALK+ small cell or histiocyte-rich variants
    localization                         cytotoxic granule proteins
                                                                                                                                                                           · Intestinal, other abdominal/visceral sites,
    (non-anaplastic                      (CGP = perforin, granzyme B,                                                           CD30 +
                                                                                                                                                                             celiac disease or markers positive =
    morphology)                          TIA1), EBV-EBER
                                                                                                                                                                             EATL (CD 5- CD7- CD4- CD8-/+ CD56-/+
                                                                                                                                                       ALK -
                                                                                                                                                                             TIA1+ GRB+ Perf+)
                                                                                                          EBER -
                                                                                                                                                                           · Other sites, celiac disease markers
   Extranodal, noncutaneous localization                                                                                                                                     negative = PTCL, NOS
   · Extranodal NK/T cell lymphoma, nasal type (ENKTCL)                                                                                                  · Liver, spleen, bone marrow sinuses, immune
   · Enteropathy-associated T-cell lymphoma (EATL)
                                                                                                                                                           suppression = HSTCL (CD5- CD7- CD4- CD8-
   · Hepatosplenic T-cell lymphoma (HSTCL)                                                                                      CD30 -
                                                                                                                                                           CD56+ TIA1+ GRB- Perf-)
   · Peripheral T-cell lymphoma, NOS (PTCL, NOS)
                                                                                                                                                         · Other sites = PTCL, NOS
   · ALCL, ALK+ small cell and histiocyte-rich variants

                                                                                            CD30 +
                                                                                                                           ALCL, ALK+ small cell or histiocyte-rich variants
                                                                                            ALK +
                                               Panel: CD5, CD4,
   Nodal localization                          CD8, CD30, ALK1,                                                         CD10 +
   (non-anaplastic                             CD10, BCL6, PD1,                                                         BCL6 +                         · Vascular proliferation, expanded CD21+ CD23+ FDC = AITL
   morphology)                                 CD21, CD23, EBV-
                                                                                                                        PD1 +                          · Nodular CD21+ CD23+ FDC = Nodular PTCL
                                                                                                                        CD4 +/-
                                               EBER
                                                                                            CD30 +/-
                                                                                            ALK -
                                                                                                                                                       HTLV1 + = ATLL (CD2+ CD5+ CD7- CD 25+ CD56-)
                                                                                                                        CD10 -
   Nodal localization                                                                                                   BCL6 -
   · Adult T-cell leukemia/lymphoma (ATLL)
   · Angioimmunoblastic T-cell lymphoma (AITL)                                                                                                         HTLV1 - = PTCL, NOS
   · Peripheral T-cell lymphoma, NOS (PTCL, NOS)                                                                             a These  are meant to be general guidelines. Interpretation of results should be based on
   · ALCL, ALK+ small cell and histiocyte-rich variants                                                                        individual circumstances and may vary. Not all tests will be required in every case.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                          NHODG-A
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Non-Hodgkin’s Lymphomas                                                                                                                                                        Discussion

                                                                                                          TUMOR LYSIS SYNDROME

       Laboratory hallmarks of TLS:                                                                                                    Treatment of TLS:
       · High potassium                                                                                                                · TLS is best managed if anticipated and treatment started prior to
       · High uric acid                                                                                                                  chemotherapy.
       · High phosphorous                                                                                                              · Centerpiece of treatment includes
       · Low calcium                                                                                                                     > Rigorous hydration
                                                                                                                                         > Management of hyperuricemia
       Symptoms of TLS:                                                                                                                  > Frequent monitoring of electrolytes and aggressive correction
       · Nausea and vomiting, shortness of breath, irregular heartbeat,                                                                    is essential
         clouding of urine, lethargy, and/or joint discomfort.                                                                         · First-line and at retreatment
                                                                                                                                         > Allopurinol beginning 2-3 days prior to chemotherapy and
       High risk features                                                                                                                  continued for 10-14 days
       · Histologies of Burkitt Lymphoma and Lymphoblastic Lymphoma;                                                                        or
         occasionally patients with DLBCL and CLL                                                                                           Rasburicase is indicated for patients with any of the following
       · Spontaneous TLS                                                                                                                   risk factors:
                                                                                                                                           7 presence of any high risk feature
       · Elevated WBC
                                                                                                                                           7 urgent need to initiate therapy in a high-bulk patient
       · Bone marrow involvement                                                                                                           7 situations where adequate hydration may be difficult or
       · Pre-existing elevated uric acid
                                                                                                                                              impossible
       · Ineffectiveness of allopurinol                                                                                                    7 Acute renal failure
       · Renal disease or renal involvement by tumor                                                                                     > One dose of rasburicase is frequently adequate. Redosing
                                                                                                                                           should be individualized.

                                                                                                                                       · If TLS is untreated, its progression may cause acute kidney
                                                                                                                                         failure, cardiac arrhythmias, seizures, loss of muscle control, and
                                                                                                                                         death.




      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Non-Hodgkin’s Lymphomas                                                                                                                                                        Discussion

                                                                                               RESPONSE CRITERIA FOR LYMPHOMA
                                                                                                      (not including PET)


                            Response                                      Physical                                    Lymph Nodes                                Lymph Node                              Bone Marrow
                            Category                                     Examination                                                                             Masses


                            CR                                                Normal                                        Normal                                     Normal                                  Normal


                             CRu                                              Normal                                        Normal                                     Normal                            Indeterminate
                             (unconfirmed)
                                                                                                                                                                                                         Normal or
                                                                              Normal                                        Normal                             > 75% decrease
                                                                                                                                                                                                         indeterminate

                            PR                                                Normal                                        Normal                                     Normal                                 Positive


                                                                              Normal                                 ³ 50% decrease                             ³ 50% decrease                               Irrelevant


                                                                          Decrease in
                                                                          liver/spleen                               ³ 50% decrease                             ³ 50% decrease                               Irrelevant


                             Relapse/                           Enlarging liver/spleen,
                                                                                                                   New or increased                          New or increased                           Reappearance
                             Progression                              new sites


                        Source: Table 2 from Cheson BD, Horning SJ, Coiffier B et al: Report of an International Workshop to Standardize Response Criteria for
                         Non-Hodgkin’s Lymphoma. J Clin Oncol 1999; 17:1244. Reprinted with permission from the American Society of Clinical Oncology.



                                                                                                                                                                                                          See Response Designations and
                                                                                                                                                                                                          PET findings NHODG-C 2 of 2
      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                          NHODG-C
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Non-Hodgkin’s Lymphomas                                                                                                                                                        Discussion
                                                                                REVISED RESPONSE CRITERIA FOR LYMPHOMA
                                                                                             (including PET) a
          Response                      Definition                        Nodal Masses                         Spleen, Liver                                                                        Bone Marrow

          CR                            Disappearance                     (a) FDG-avid or PET positive prior                                               Not palpable,                            Infiltrate cleared on repeat
                                        of all evidence                   to therapy; mass of any size                                                     nodules                                  biopsy; if indeterminate by
                                        of disease                        permitted if PET negative                                                        disappeared                              morphology,
                                                                          (b) Variably FDG-avid or PET                                                                                              immunohistochemistry
                                                                          negative; regression to normal                                                                                            should be negative
                                                                          size on CT

          PR                            Regression of                     ³ 50% decrease in SPD of up to 6                                                 ³ 50% decrease in                        Irrelevant if positive prior to
                                        measurable                        largest dominant masses; no                                                      SPD of nodules(for                       therapy; cell type should be
                                        disease and no                    increase in size of other nodes                                                  single nodule in                         specified
                                        new sites                         (a) FDG-avid or PET positive prior                                               greatest transverse
                                                                          to therapy; one or more PET                                                      diameter); no
                                                                          positive at previously involved site                                             increase in size of
                                                                          (b) Variably FDG-avid or PET                                                     liver or spleen
                                                                          negative; regression on CT

          SD                            Failure to attain                 (a) FDG-avid or PET positive prior to
                                        CR/PR or PD                       therapy; PET positive at prior sites of
                                                                          disease and no new sites on CT or PET
                                                                          (b) Variably FDG-avid or PET negative; no
                                                                          change in size of previous lesions on CT

          Relapsed                      Any new lesion                    Appearance of a new lesion(s) > 1.5 cm in > 50% increase from New or recurrent
          disease or PD                 or increase by                    any axis, ³ 50% increase in SPD of more     nadir in the SPD of  involvement
                                        ³ 50% of                          than one node, or ³ 50% increase in         any previous lesions
                                        previously                        longest diameter of a previously identified
                                        involved sites                    node > 1 cm in short axis
                                        from nadir                        Lesions PET positive if FDG-avid
                                                                          lymphoma or PET positive prior to therapy
   Source: Table 2 from Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma.                                                                       a Recommended for use with Diffuse Large B-Cell
    J Clin Oncol 2007;25(5):579-586. Reprinted with permission from the American Society of Clinical Oncology.                                                                             Lymphoma and Hodgkin Disease/Lymphoma.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
                                                                                                                                                                                                                                          NHODG-C
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Non-Hodgkin’s Lymphomas                                                                                                                                                        Discussion

                                                            MONOCLONAL ANTIBODY DIRECTED AT CD20 AND VIRAL REACTIVATION

          · Hepatitis B surface antigen (HBSAg) and Hepatitis B core antibody (HBCAb) testing for all patients receiving rituximab
            > Quantitative hepatitis B viral load by PCR only if one of the screening tests positive
            > In areas with high prevalence/ population or prevalence is HBV not known, recommend testing all patients receiving
              immunotherapy, chemotherapy, or chemoimmunotherapy

          Note: Patients receiving IV immunoglobin may be HBCAb positive as a consequence of IVIG therapy.

          · Empiric antiviral therapy with oncologic treatment for any patient who is HBSAg or HBCAb positive
            > Monitor hepatitis B viral load with PCR monthly through treatment and every 3 months thereafter
              7 If viral load is consistently undetectable, treatment is considered prophylactic
              7 If viral load fails to drop, consult hepatologist
            > Maintain prophylaxis for at least 6 months after oncologic treatment ends
              7 Consult with hepatologist for duration of therapy in patient with active hepatitis B virus


          Progressive multifocal leukoencephalopathy (PML)
          · Caused by the JC virus and is usually fatal
            > Diagnosis made by PCR of CSF and in some cases brain biopsy
          · No known effective treatments
          · Check for changes in behavior such as confusion, dizziness or loss of balance, difficulty talking or walking, and vision problems




      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Non-Hodgkin’s Lymphomas                                                                                                                                                        Discussion

                                                                                              PRINCIPLES OF RADIATION THERAPY a
   Field:
   Options: Involved-Field or Reduced Involved-Field

   For extra nodal sites:
   · Organ involvement: The field includes the involved organ alone (example: Gastric MALT- the whole stomach; Parotid- the total unilateral
     parotid gland).
   · Bone/spine involvement: Only the involved part of the organ is irradiated (with margins). No radiation is required to uninvolved adjacent
     lymph nodes.
   For nodal sites:
   · Field: In most cases an involved-field is appropriate. Regional fields or extended-field are not recommended unless there is significant
     concern that adjacent nodes are involved.
     > In DLBCL, RT consolidation following chemotherapy, RT may be limited to the originally involved lymph node(s). In the mediastinum,
       abdomen and pelvis treating only the post-chemotherapy volume in the transverse diameter is recommended.
     > When RT is the primary treatment, involved-field or reduced-IFRT (involved nodal radiation therapy) is recommended.
     > Margins are influenced by the quality of imaging and clinical information.
   Dose:
   · RT for follicular lymphoma: 24-30 Gy (36 only if bulky)
   · RT for MALT lymphoma: Stomach- 30 Gy. Other organs 24-30 Gy
   · RT for early stage mantle cell lymphoma: 30-36 Gy
   · Consolidation dose in DLBCL following CR to chemotherapy: 30-36 Gy
     > RT dose for residual disease (PR) after chemotherapy: 40-50 Gy.
   · Mini-RT for palliation of advanced-stage low-grade lymphomas (FL, SLL, MZL, MCL): 2 GyX2 (may be repeated)
   a References:
   Horning SJ, Weller E, Kim K, et al. Chemotherapy with or without radiotherapy in limited-stage diffuse aggressive non-Hodgkin's lymphoma: Eastern Cooperative
    Oncology Group study 1484. J Clin Oncol 2004;22:3032-3038.
   Miller TP, Dahlberg S, Cassady JR, et al. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's
    lymphoma. N Engl J Med 1998;339:21-26.
   Haas RL, Poortmans P, de Jong D, et al. High response rates and lasting remissions after low-dose involved field radiotherapy in indolent lymphomas, J Clin Oncol
    2003;21: 2474-2480.
   Campbell BA, Voss N, Woods R, et al. Long-term outcomes for patients with limited stage follicular lymphoma: involved regional radiotherapy versus involved node
    radiotherapy. Cancer 2010;116:3797-3806.
   Goda JS, Gospodarowicz M, Pintilie M, et al. Long-term outcome in localized extranodal mucosa-associated lymphoid tissue lymphomas treated with radiotherapy
    Cancer 2010;116:3815-3824.
   Phan J, Mazloom A, Medeiros LJ, et al: The benefit of consolidative radiation therapy in patients with diffuse large B-cell lymphoma treated with R-CHOP chemotherapy.
    J Clin Oncol 2010;28:4170-4176.

      Note: All recommendations are category 2A unless otherwise indicated.
      Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

   Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.        NHODG-E
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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Non-Hodgkin’s Lymphomas                                                                                                                                                        Discussion

    Classification
         Table 1
         WHO Classification of the mature B-cell, T-cell, and NK-cell neoplasms (2008)
         Mature B-Cell Neoplasms                                                                                                             Diffuse large B-cell lymphoma (DLBCL), NOS
         · Chronic lymphocytic leukemia/small lymphocytic lymphoma                                                                             > T-cell/histiocyte rich large B-cell lymphoma
         · B-cell prolymphocytic leukemia                                                                                                      > Primary DLBCL of the CNS
         · Splenic marginal zone lymphoma                                                                                                      > Primary cutaneous DLBCL, leg type
         · Hairy cell leukemia                                                                                                                 > EBV positive DLBCL of the elderly*
         · Splenic lymphoma/leukemia, unclassifiable *                                                                                       · DLBCL associated with chronic inflammation
           > Splenic diffuse red pulp small B-cell lymphoma*                                                                                 · Lymphamatoid granulomatosis
           > Hairy cell leukemia-variant*                                                                                                    · Primary mediastinal (thymic) large B-cell lymphoma
         · Lymphoplasmacytic lymphoma                                                                                                        · Intravascular large B-cell lymphoma
           > Waldenström’s macroglobinemia                                                                                                   · ALK positive large B-cell lymphoma
         · Heavy chain diseases                                                                                                              · Plasmablastic lymphoma
           > Alpha heavy chain disease                                                                                                       · Large B-cell lymphoma arising in HHV8-associated multicentric
           > Gamma heavy chain disease                                                                                                         Castleman disease
           > Mu heavy chain disease                                                                                                          · Primary effusion lymphoma
         · Plasma cell myeloma                                                                                                               · Burkitt lymphoma
         · Solitary plasmacytoma of bone                                                                                                     · B-cell lymphoma, unclassifiable, with features intermediate
         · Extraosseous plasmacytoma                                                                                                           between diffuse large B-cell lymphoma and Burkitt lymphoma
         · Extranodal marginal zone lymphoma of mucosa-associated                                                                            · B-cell lymphoma, unclassifiable, with features intermediate
           lymphoid tissue (MALT type)                                                                                                         between diffuse large B-cell lymphoma and classical Hodgkin
         · Nodal marginal zone lymphoma                                                                                                        lymphoma
           > Pediatric nodal marginal zone lymphoma*
         · Follicular lymphoma
           > Pediatric follicular lymphoma*
         · Primary cutaneous follicle center lymphoma
         · Mantle cell lymphoma                                                                                                                                                                           Continued on next page




         *The italicized histologic types are provisional entities, for which the WHO Working Group felt there was insufficient evidence to recognize as distinct diseases at
          this time.




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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Non-Hodgkin’s Lymphomas                                                                                                                                                        Discussion

   Classification
         Table 1 continued
          Mature T-Cell and NK-Cell Neoplasms                                                                                              Hodgkin Lymphoma
          · T-cell prolymphocytic leukemia                                                                                                 · Nodular lymphocyte predominant Hodgkin lymphoma
                                                                                                                                           · Classical Hodgkin lymphoma
          · T-cell large granular lymphocytic leukemia
                                                                                                                                             > Nodular sclerosis classical Hodgkin lymphoma
            > Chronic lymphoproliferative disorder of NK-cells *
                                                                                                                                             > Lymphocyte-rich classical Hodgkin lymphoma
          · Aggressive NK cell leukemia
                                                                                                                                             > Mixed cellularity classical Hodgkin lymphoma
          · Systemic EBV positive T-cell lymphoproliferative disorder of
                                                                                                                                             > Lymphocyte-depleted classical Hodgkin lymphoma
            childhood
          · Hydroa vaccineforme-like lymphoma
          · Adult T-cell leukemia/lymphoma                                                                                                 Post-Tranplant Lymphoproliferative Disorders (PTLD)
          · Extranodal NK/T-cell lymphoma, nasal type                                                                                      · Early lesions
          · Enteropathy-associated T-cell lymphoma                                                                                           > Plasmacytic hyperplasia
          · Hepatosplenic T-cell lymphoma                                                                                                    > Infectious mononucleosis-like PTLD
          · Subcutaneous panniculitis-like T-cell lymphoma                                                                                 · Polymorphic PTLD
          · Mycosis fungoides                                                                                                              · Monomorphic PTLD (B- and T/NK-cell types) #
          · Sézary syndrome                                                                                                                · Classical Hodgkin lymphoma type PTLD #
          · Primary cutaneous CD30 positive T-cell lymphoproliferative
            disorders
            > Lymphomatoid papulosis                                                                                                       From Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J,
            > Primary cutaneous anaplastic large cell lymphoma                                                                             Vardiman JW (Eds): World Health Organization Classification of Tumours of the
          · Primary cutaneous gamma-delta T-cell lymphoma                                                                                  Haematopoietic and Lymphoid Tissues. IARC Press: Lyon 2008.
          · Primary cutaneous CD8 positive aggressive epidermotropic
            cytotoxic T-cell lymphoma*
          · Primary cutaneous CD4 positive small/medium T-cell lymphoma *
          · Peripheral T-cell lymphoma, NOS
          · Angioimmunoblastic T-cell lymphoma
          · Anaplastic large-cell lymphoma, ALK positive
          · Anaplastic large-cell lymphoma, ALK negative*


         *The italicized histologic types are provisional entities, for which the WHO Working Group felt there was insufficient evidence to recognize as distinct diseases at
           this time.
         # These lesions are classified according to the leukemic or lymphoma to which they correspond.




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                                                           NCCN Guidelines™ Version 3.2011                                                                                                                                    NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                           Non-Hodgkin’s Lymphomas                                                                                                                                                        Discussion

   Staging

          Table 2
          Cotswolds Modification of Ann Arbor Staging System
          Stage Area of Involvement
          I           Single lymph node group
          II          Multiple lymph node groups on same side of diaphragm
          III         Multiple lymph node groups on both sides of diaphragm
          IV          Multiple extranodal sites or lymph nodes and extranodal disease
          X           Bulk > 10 cm
          E           Extranodal extension or single isolated site of extranodal disease
          A/B         B symptoms: weight loss > 10%, fever, drenching night sweats

          From: Lister TA, Crowther D, Sutcliffe SB, et al.: Report of a committee
          convened to discuss the evaluation and staging of patients with Hodgkin's
          disease: Cotswolds meeting. J of Clin Onc 1989;7(11): 1630-1636.




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                                                                                                                                                                                                                               NHL Table of Contents
                                                                 Non-Hodgkin’s Lymphomas                                                                                                                                                  Discussion


      Discussion                                                                                                                     been attributed partly to the human immunodeficiency virus (HIV)
                                                                                                                                     epidemic and the development of AIDS-related NHL. However, much of
      NCCN Categories of Evidence and Consensus                                                                                      the increase in incidence has been observed in patients in their sixth
                                                                                                                                     and seventh decades; a large part of this increase incidence has
      Category 1: The recommendation is based on high-level evidence                                                                 paralleled a major decrease in mortality from other causes. The median
      (e.g. randomized controlled trials) and there is uniform NCCN                                                                  age of individuals with NHL has risen in the last two decades.2 As a
      consensus.                                                                                                                     result, patients with NHL may also have significant comorbid conditions,
                                                                                                                                     which complicate treatment options.
      Category 2A: The recommendation is based on lower-level evidence
      and there is uniform NCCN consensus.
                                                                                                                                     Classification
      Category 2B: The recommendation is based on lower-level evidence
                                                                                                                                     In the 1956, Rappaport et al. proposed a lymphoma classification that
      and there is nonuniform NCCN consensus (but no major
                                                                                                                                     was based on the pattern of cell growth (nodular or diffuse), and size
      disagreement).                                                                                                                 and shape of the tumor cells.3,4 This classification, though widely used
      Category 3: The recommendation is based on any level of evidence                                                               in the Unites states, quickly became outdated with the discovery and
      but reflects major disagreement.                                                                                               the existence of distinct types of lymphocytes (B, T and NK). The Kiel
                                                                                                                                     classification became the first and most significant classification that
      All recommendations are category 2A unless otherwise noted.
                                                                                                                                     applied this new information to the classification of lymphomas.5,6, 7
                                                                                                                                     According to the Kiel classification, the lymphomas were divided into
      Overview                                                                                                                       low-grade and high-grade based on the histological features. This
      Non-Hodgkin’s lymphomas (NHL) are a heterogeneous group of                                                                     classification was widely used in Europe. The use of different
      lymphoproliferative disorders originating in B-lymphocytes,                                                                    classification systems in clinical studies made it difficult to compare
      T-lymphocytes or natural killer (NK) lymphocytes. In the United States,                                                        results from clinical studies. Hence, the International Working
      B-cell lymphomas represent 80-85% of the cases with 15-20% being                                                               Formulation (IWF) for NHLs was developed to standardize the
      T-cell lymphomas. NK-cell lymphomas are very rare. In 2010, an                                                                 classification of lymphomas.
      estimated 65,540 new cases of NHL will be diagnosed and 20,210 will
                                                                                                                                     International Working Formulation classification
      die of their disease.1 NHL is the sixth leading site of new cancer cases
      among men and women, accounting for 4% of new cancer cases and                                                                 The IWF classified NHL into three major categories as low,
      4% of cancer-related deaths.1                                                                                                  intermediate and high grade, based on the morphology and natural
                                                                                                                                     history.8 This classification divided diffuse large B-cell lymphoma
      The incidence of NHL has increased dramatically between 1970 and                                                               (DLBCL) into intermediate and high grade groups. However, these
      1995; the increase has moderated since the mid-90s. This increase has                                                          distinctions were not reproducible. Since this classification did not

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                                                                 NCCN Guidelines™ Version 3.2011                                                                                                                              NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                                 Non-Hodgkin’s Lymphomas                                                                                                                                                  Discussion


      include immunophenotyping, the categories were not reproducible.9 In                                                           includes many entities not recognized by the IWF.13,14 After
      addition, after this classification was published many new diseases                                                            consideration of cell of origin (B, T, or NK), the classification subdivides
      were described that were not included in the IWF classification.                                                               lymphomas into those derived from precursor lymphocytes versus
                                                                                                                                     those derived from mature lymphocytes. The classification is further
      Revised European American Classification                                                                                       refined based on immunophenotype, genetic, and clinical features.
      In 1994, the International Lymphoma Study Group (ILSG) developed                                                               These considerations have aided in defining active treatment for
      the REAL classification, which classified lymphomas based on the cell                                                          specific subtypes of lymphoma.
      of origin (B, T, or NK) and included morphology, immunophenotype,
                                                                                                                                     In 2008, the International T-cell lymphoma Project evaluated the WHO
      genetic and clinical features to define diseases.10 In 1997, the
                                                                                                                                     classification of T-cell lymphoma in a cohort of 1,314 cases of PTCL
      International Lymphoma Classification Project performed a clinical
                                                                                                                                     and natural killer/T-cell lymphomas (NKTCL). The diagnosis of PTCL or
      evaluation of the Revised European American Classification (REAL)
                                                                                                                                     NKTCL was confirmed in 1,1,53 cases (88%). The most common
      classification in a cohort of 1,403 cases of NHL.11,12 The diagnosis of
                                                                                                                                     subtypes were PTCL-not otherwise specified (NOS; 25.9%),
      NHL was confirmed in 1,378 (98.2%) of the cases. This study identified
                                                                                                                                     angioimmunoblastic lymphoma (18.5%), NKTCL (10.4%), adult T-cell
      the thirteen most common histological types, comprising about 90% of
                                                                                                                                     leukemia/lymphoma (ATLL; 9.6%), anaplastic large cell lymphoma
      the cases of NHL in the United States. The findings were as follows:
                                                                                                                                     (ALCL), ALK-positive (6.6%) and ALCL, ALK-negative (5.5%).15 The
      DLBCL, 31%; follicular lymphoma (FL), 22%; small lymphocytic
                                                                                                                                     findings of this study validated the utility of the WHO classification for
      lymphoma/chronic lymphocytic leukemia (SLL/CLL), 6%; mantle cell
                                                                                                                                     defining subtypes of T-cell lymphomas.
      lymphoma (MCL), 6%; peripheral T-cell lymphoma (PTCL), 6%; and
      mucosa associated lymphoid tissue (MALT) lymphoma, 5%. The                                                                     The WHO classification was updated again in September 2008 to add
      remaining subtypes each occurred in less than 2% of cases.                                                                     new diseases and subtypes that have been recognized in the past
      Importantly, in the United States more than 50% of cases of lymphoma                                                           decade, and to better define some of the heterogeneous and
      are either DLBCL or FL. The study investigators concluded that the                                                             ambiguous categories based on the recent advances.16,17 Genetic
      REAL classification can be readily applied and identifies clinically                                                           features, detected by cytogenetics or fluorescence in-situ hybridization
      distinctive types of NHL.                                                                                                      (FISH) are increasingly important in defining specific NHL subtypes. In
                                                                                                                                     addition, detection of viruses, particularly Epstein-Barr virus, HHV8 and
      World Health Organization Classification
                                                                                                                                     HTLV1, is often necessary to establish a specific diagnosis.
      In 2001, the World Health Organization (WHO) updated the
      classification of hematopoietic and lymphoid neoplasms.13,14 The 2001                                                          2008 WHO Classification of Mature B-cell Lymphomas
      WHO classification applied the principles of REAL classification and                                                           CLL/SLL
      represented the first international consensus on classification of
                                                                                                                                     The updated classification includes the new definition issued by the
      hematologic malignancies. The REAL/WHO classification of NHL
                                                                                                                                     International Working Group on CLL (IWCLL).18 In the absence of nodal
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                                                                 NCCN Guidelines™ Version 3.2011                                                                                                                              NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                                 Non-Hodgkin’s Lymphomas                                                                                                                                                  Discussion


      or organ involvement, disease-related cytopenias, the diagnosis of CLL                                                         Pediatric FL, primary intestinal FL, other extranodal FLs and
      requires the presence of at least 5,000 clonal B lymphocytes per                                                               intrafollicular neoplasia (“in situ” FL) are the other variants that are
      microliter in the peripheral blood for the duration of at least 3 months.                                                      included under FL.
      The presence of fewer than 5,000 lymphocytes per microliter in the
      absence of lymphadenopathy, organomegaly or other clinical features                                                            Pediatric follicular lymphoma: Children with FL typically have early
      is defined as monoclonal B lymphocytosis (MBL). CLL requiring                                                                  stage disease, lack BCL2 expression and the t(14;18). Pediatric FL has
      treatment develops in subjects with CLL-phenotype MBL and with                                                                 a better prognosis than adult FL and is often cured with minimal
      lymphocytosis at the rate of 1.1% per year.19                                                                                  therapy.

      Follicular Lymphoma                                                                                                            Primary Intestinal follicular lymphoma: FL of the gastrointestinal tract is
                                                                                                                                     a recently described entity which is common in the small intestine, with
      In FL, pathological grading according to the number of centroblasts is
                                                                                                                                     the vast majority occurring in the duodenum. The morphology,
      considered to be a clinical predictor of outcome. In the 2001 WHO
                                                                                                                                     immunophenotype, and genetic features are similar to those of nodal
      classification, 3 grades were recommended: FL1, FL2, and FL3; FL3
                                                                                                                                     follicular lymphoma. However, most patients have clinically indolent and
      could be optionally stratified into 3A (centrocytes still present) or 3B
                                                                                                                                     localized disease. Survival appears to be excellent even without
      (sheets of centroblasts). However, clinical outcomes for patients with
                                                                                                                                     treatment.
      FL1 and FL2 do not differ and classification is unreliable. Therefore, in
      the updated 2008 WHO classification these are grouped into one grade                                                           Other Extranodal Follicular Lymphoma: In many of the other
      (FL1-2). Hans et al reported that there was no difference in survival                                                          extranodal sites, the morphology, immunophenotype, and genetic
      between Grade 3A and 3B, whereas patients with FL3 with more than                                                              features are similar to those of nodal FL. Patients usually have
      50% diffuse component have an inferior survival that is similar to the                                                         localized disease and systemic relapses are rare.
      survival of those with DLBCL.20 FL3B with cytogenetic abnormalities of
      BCL6 (at 3q27) are thought to be genetically more akin to germinal                                                             Intrafollicular Neoplasia or “In situ” Follicular Lymphoma: This is
      center type DLBCL than FL1-3A and has a more aggressive clinical                                                               defined as a morphologically normal lymph node or other lymphoid
      course. Patients with FL3B with BCL2 translocation appear to have                                                              tissues with a few follicles that are BCL2-positive. Some of these
      similar clinical behavior to patients with FL1-3A.21 Since FL3B is rare, in                                                    patients are found to have either a history of FL or FL elsewhere in the
      most studies clinical behavior of FL3 is based mainly on FL 3A cases.                                                          body and some have no evidence of FL.22 Intrafollicular neoplasia may
      The 2008 WHO classification mandates stratifying FL3 into either 3A or                                                         represent the nodal equivalent of circulating clonal B-cells that have
      3B. FL is thus still divided into three grades (FL1-2, FL3A and FL3B)                                                          BCL2 rearrangement, but lack the other genetic abnormalities required
      based on the number of centroblasts. Any diffuse areas in FL should be                                                         for the development of a progressive lymphoma. In some cases, this
      given a separate diagnosis of DLBCL, if it meets the criteria for FL3A or                                                      may represent the earliest evidence of a true FL that will progress to an
      3B.                                                                                                                            overt lymphoma. A diagnosis of lymphoma should not be made in such

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                                                                 NCCN Guidelines™ Version 3.2011                                                                                                                              NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                                 Non-Hodgkin’s Lymphomas                                                                                                                                                  Discussion


      cases, and careful staging and follow-up are recommended; patients                                                             2008 classification also has new category of large B-cell lymphoma
      should not be treated for lymphoma based on this finding.                                                                      arising in HHV8-associated multicentric Castleman’s disease.

      Primary cutaneous follicle center lymphoma (PCFCL)                                                                             DLBCL, not otherwise specified (NOS)
      This is a new category in the 2008 classification and is defined as a                                                          The 2008 classification has included DLBCL, NOS as a new category
      tumor of neoplastic follicle center cells, including centrocytes and                                                           to include GCB and ABC subtypes as well as other DLBCL cases that
      variable numbers of centroblasts, with a follicular, follicular and diffuse                                                    do not belong to any of the four specific subtypes (T-cell/histiocyte
      or a diffuse growth pattern. PCFCL is the most common B-cell                                                                   rich large B-cell lymphoma, primary CNS DLBCL, primary cutaneous
      lymphoma of the skin and it is classified as a distinct entity in the                                                          DLBCL (“leg type”) or EBV+ DLBCL of the elderly).
      EORTC classification of cutaneous lymphomas.23 Gene expression
                                                                                                                                     Gene expression profiling (GEP) has been used to identify three
      profiling studies have also provided evidence in support of this
                                                                                                                                     different subtypes of DLBCL: germinal center B-cell (GCB) subtype,
      classification.24 PCFCL presents as a solitary or localized skin lesion on
                                                                                                                                     activated B-cell (ABC) subtype and type 3 which includes PBML and
      the scalp, forehead or the trunk. It is characterized by an indolent
                                                                                                                                     cases that cannot be classified as GCB or ABC subtype.27 GEP is not
      course and rarely disseminates to extracutaneous sites. PCFCL is
                                                                                                                                     yet recommended for routine clinical use. Immunostaining algorithms
      consistently BCL6-positive, may be CD10-positive in cases with a
                                                                                                                                     have been developed to differentiate between these two subtypes
      follicular growth pattern. BCL2 is either negative or dim (predominantly
                                                                                                                                     using a combination of CD10, BCL6, IRF4/MUM1, GCET1 and
      seen in cases with a follicular growth pattern). PCFCL has an excellent
                                                                                                                                     FOXP1.28, 29 However, studies based on immunohistochemistry (IHC)
      prognosis with a 5-year survival rate of 95%. PCFCL must be
                                                                                                                                     have produced conflicting results regarding the outcome of GCB and
      distinguished from primary cutaneous diffuse large B-cell lymphoma,
                                                                                                                                     ABC subtypes.30, 31
      leg type, which is typically IRF4/MUM1+ and strongly BCL2+ and has a
      more unfavorable prognosis.25, 26                                                                                              Primary Cutaneous DLBCL, leg type
                                                                                                                                     Primary cutaneous DLBCL leg type (PCDLBCL, leg type) is an
      Diffuse Large B-cell Lymphomas
                                                                                                                                     unusual form of DLBCL composed of large transformed B cells most
      Some of the new categories of DLBCL are defined by extranodal
                                                                                                                                     commonly arising on the leg (85%) though can arise at other sites
      primary sites and the association with viruses such as EBV or HHV8.
                                                                                                                                     (15%). These tumors arise from post germinal center B-cell with
      Two borderline categories have also been included to incorporate
                                                                                                                                     expression of CD20, IRF4/MUM1, FOXP1, and BCL2; many cases
      cases in which it is not possible distinguish between adult Burkitt
                                                                                                                                     express BCL6 and lack expression of CD10.32 These tumors can
      lymphoma (BL) and DLBCL, and primary mediastinal large B-cell
                                                                                                                                     disseminate to non-cutaneous sites particularly the central nervous
      lymphoma (PBML) and nodular sclerosis classical Hodgkin lymphoma
                                                                                                                                     system. Clinically the prognosis is poor particularly when the
      (NSCHL). The ALK-positive DLBCL, plasmablastic lymphoma and
                                                                                                                                     presentation is with multiple subcutaneous nodules.
      primary effusion lymphoma are considered as distinct entities. The


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                                                                 NCCN Guidelines™ Version 3.2011                                                                                                                              NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                                 Non-Hodgkin’s Lymphomas                                                                                                                                                  Discussion

      B-cell lymphoma, intermediate between BL and DLBCL                                                                             were more highly expressed in PMBL were also characteristically
      BL is characterized by t(8;14), which results in the juxtaposition of                                                          expressed in CHL cells.37 Traverse-Glehen, et al., reported borderline
      MYC gene from chromosome 8 with the immunoglobulin heavy chain                                                                 cases with biologic and morphologic features of both CHL and B-cell
      variable (IGHV) region on chromosome14 and variant translocations                                                              NHL, known as "mediastinal gray zone lymphomas" (MGZL)’’.38
      involving MYC and the immunoglobulin light chain genes.33
                                                                                                                                     This provisional category includes lymphomas with overlapping
      Nevertheless, MYC translocations also occur in DLBCL. Recent GEP
                                                                                                                                     features between CHL and DLBCL, especially PBML. Those cases
      studies have confirmed that the distinction between BL and DLBCL is
                                                                                                                                     that morphologically resemble NSCHL have a strong expression of
      not reliably reproducible with the use of the current criteria of
                                                                                                                                     CD20 and other B-cell-associated markers. Those cases that
      morphology, immunophenotype, and genetic abnormalities.34, 35
                                                                                                                                     resemble PBML may have dim or no expression of CD20, strong
      Mature aggressive B-cell lymphomas without a molecular BL
                                                                                                                                     expression of CD30 and CD15. These lymphomas have a more
      signatures (non-mBL) with MYC rearrangements35 as well as those
                                                                                                                                     aggressive course and poorer outcome than either CHL or PBML.
      with both t(8;14) and t(14;18) translocations are associated with a
      poor prognosis.36                                                                                                              2008 WHO Classification of Mature T-cell and NK-cell
                                                                                                                                     Lymphomas
      This provisional category replaces the “Atypical Burkitt Lymphoma”
      that was included in the 2001 WHO classification. The new category                                                             The 2008 WHO classification has adapted the EOTRC classification
      includes lymphomas with features of both DLBCL and BL, but or                                                                  for cutaneous T-cell lymphomas.23 The new categories include
      biological and clinical reasons should not be diagnosed as DLBCL or                                                            primary cutaneous gamma-delta T-cell lymphoma, primary cutaneous
      BL. Lymphomas in this provisional category include those that are                                                              aggressive epidermotropic CD9-positive cytotoxic T-cell lymphoma
      morphologically intermediate between BL and DLBCL with                                                                         and primary cutaneous small/medium CDE4-positive T-cell
      immunophenotype suggestive of BL (CD10-positive, BCL6-positive,                                                                lymphoma. Anaplastic large cell lymphoma (ALCL), ALK-negative is
      BCL2-negative and IRF4/MUM1-negative or weakly positive),                                                                      now separated out from PTCL-NOS as a provisional entity.
      lymphomas that are morphologically similar to BL but are strongly
      BCL2-positive and those with both MYC and BCL2 rearrangements                                                                  ALCL
      (double hit) and complex karyotypes.                                                                                           ALCL accounts for less than 5% of all cases of NHL. There are now
                                                                                                                                     three distinctly recognized subtypes of ALCL: ALCL, ALK-positive,
      B-cell lymphoma intermediate between PMBL and NSCHL
                                                                                                                                     ALCL, ALK-negative and primary cutaneous ALCL. Primary
      PMBL has been recognized as a subtype of DLBCL based on its                                                                    cutaneous ALCL is a distinct subtype of mature T-cell lymphoma.
      distinctive clinical and morphological features. NSCHL is the most                                                             ALK-positive ALCL is most common in children and young adults. It is
      common form of HL. Both tumors occur in the mediastinum and affect                                                             characterized by the over expression of anaplastic lymphoma kinase
      adolescents and young adults. GEP studies strongly support a                                                                   (ALK1) protein, resulting from t(2;5) in 40-60% of patients.39, 40
      relationship between PMBL and CHL. About a third of the genes that

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                                                                 NCCN Guidelines™ Version 3.2011                                                                                                                              NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                                 Non-Hodgkin’s Lymphomas                                                                                                                                                  Discussion


      Although clinically aggressive, it is highly curable with CHOP                                                                 measured by CT scan and the extent of bone marrow involvement
      chemotherapy. The distinction between ALK-positive and                                                                         that is determined by bone marrow aspirate and biopsy.43 These
      ALK-negative ALCL was not required in the 2001 WHO classification.                                                             guidelines were revised in 2007 by the International Harmonization
      It is now clear that ALK-positive ALCL is a well-defined                                                                       Project to incorporate IHC, flow cytometry and 18flourodeoxyglucose
      clinicopathologic entity. The International Peripheral T-Cell Lymphoma                                                         (FDG)-positron emission tomography (PET) scans in the definition of
      Project reported that patients with ALK-positive ALCL had a superior                                                           response for lymphoma.44 In the revised guidelines, the response
      outcome compared with those with ALK-negative ALCL [5-year                                                                     category of complete response uncertain (CRu) was essentially
      failure-free survival (FFS): 60% vs. 36%; and 5-year overall survival                                                          eliminated because residual masses were defined as a partial
      (OS): 70% vs. 49%].41 Contrary to prior reports, ALK-negative ALCL                                                             response (PR) or a complete response (CR) based on the result of a
      was associated with a better outcome than PTCL-NOS. The 5-year                                                                 PET scan. Using the revised system, response is categorized as CR,
      FFS (36% vs. 20%) and OS (49% vs. 32%) were superior compared                                                                  PR, stable disease (SD) and relapsed disease or progressive disease
      with PTCL-NOS. A recent analysis from the GELA found that age and                                                              (PD). However, the application of PET to responses is limited to
      beta-2 microglobulin, not ALK1 expression, was the most significant                                                            histologies where there is reliable FDG uptake in active tumor.
      variable in the outcome of ALCL; however, age was very closely                                                                 However, the revised response criteria have thus far only been
      associated with ALK1 expression.42 Patients with primary cutaneous                                                             validated for DLBCL and Hodgkin lymphoma. The application of the
      ALCL had a very favorable 5-year OS (90%) despite being negative                                                               revised response criteria to other histologies requires validation and
      for ALK1; the 5-year FFS rate was 55%. The findings of this study                                                              the original IWG guidelines should be used.
      confirmed that ALK-negative ALCL should be separated from both
      ALK-positive ALCL and PTCL-NOS.                                                                                                Diagnosis

      Based on the recent findings, the 2008 WHO classification has                                                                  In all cases, the most important first step is to make an accurate
      included a provisional category for ALK-negative ALCL. It is                                                                   pathologic diagnosis. The basic pathological evaluation is the same in
      morphologically identical to ALK-positive ALCL, with a strong and                                                              each guideline though some further evaluation may be useful in
      diffuse expression of CD30, no expression of B-cell antigens and                                                               certain circumstances to clarify a particular diagnosis; these are
      absence of ALK1. The prognosis is intermediate between that of                                                                 outlined in the pathological evaluation of the individual guideline.
      ALK-positive ALCL and PTCL-NOS.
                                                                                                                                     An incisional or excisional lymph node biopsy is recommended to
                                                                                                                                     establish the diagnosis of NHL. Core needle biopsy is discouraged
      Response Criteria
                                                                                                                                     unless the clinical situation dictates that this is the only safe means of
      The International Working Group (IWG) published the guidelines for                                                             obtaining diagnostic tissue. Fine needle aspiration (FNA) biopsy is
      response criteria for lymphoma in 1999. These response criteria are                                                            widely used in the diagnosis of malignant neoplasms, but its role in
      based on the reduction in the size of the enlarged lymph node as                                                               the diagnosis of lymphoma is still controversial.45, 46 Since the revised

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                                                                 NCCN Guidelines™ Version 3.2011                                                                                                                              NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                                 Non-Hodgkin’s Lymphomas                                                                                                                                                  Discussion


      REAL/WHO classification is based on both morphology and                                                                        Immunophenotyping/Genetic testing algorithm
      immunophenotyping, FNA alone is not acceptable as a reliable
                                                                                                                                     After the publication of the 2008 WHO Classification, the NHL panel
      diagnostic tool for NHL. However, its use in combination with ancillary
                                                                                                                                     has developed a series of algorithms for the use of
      techniques may provide precise diagnosis thereby obviating the need
                                                                                                                                     immunophenotyping in the diagnosis of mature lymphoid neoplasms.
      for a more invasive biopsy in highly selected circumstances. Recent
                                                                                                                                     These algorithms should be used in conjunction with clinical and
      studies have shown that the diagnostic accuracy of FNA improves
                                                                                                                                     pathological correlation. They were developed to provide guidance for
      significantly when it is used in combination with IHC and flow
                                                                                                                                     surgical pathologists as well as an aid to the clinician in the
      cytometry.47-49
                                                                                                                                     interpretation of pathology reports.
      In the NCCN guidelines, FNA alone is not suitable for an initial
                                                                                                                                     The initial assessment begins with morphologic, clinical, and
      diagnosis of NHL, though it may be sufficient to establish relapse.
                                                                                                                                     immunophenotypic analysis. Morphologic assessment involves
      However, in certain circumstances, when a lymph node is not easily
                                                                                                                                     determining the cell size (small cells, medium-sized cells, or large
      accessible, a combination of core biopsy and FNA in conjunction with
                                                                                                                                     cells), with or without anaplastic morphology. Clinical features include
      appropriate ancillary techniques [PCR for IGHV and/or T-cell receptor
                                                                                                                                     patient’s age and the location (nodal, extranodal, and among
      (TCR) gene rearrangements; FISH for major translocations;
                                                                                                                                     extranodal sites skin vs. other specific sites). The initial
      immunophenotypic analysis] may be sufficient for diagnosis. This is
                                                                                                                                     immunophenotyping panel should include Pan-B and Pan-T-cell
      particularly true for the diagnosis of CLL. In other entities presenting
                                                                                                                                     antigens. Based on the morphologic and clinical features, some of the
      in leukemic phase, such as FL or MCL, a biopsy is still preferred to
                                                                                                                                     B-cell and T-cell subset antigens may also be added in the initial
      clarify histological subtype.
                                                                                                                                     panel.
      Immunophenotypic analysis is essential for the differentiation of
                                                                                                                                     B-cell Lymphomas (expression of one or more B-cell antigens
      various subtypes of NHL to establish the proper diagnosis. It can be
                                                                                                                                     (CD20, Pax5, CD79a, CD19, CD22)
      performed by flow cytometry and/or IHC; the choice depends on the
      antigens as well as the expertise and resources available to the                                                               Small Cells
      hematopathologist. In some cases flow cytometry and IHC are                                                                    In the differential diagnosis of small cell lymphomas [CLL/SLL, mantle
      complementary diagnostic tools.50 Cytogenetic or molecular genetic                                                             cell lymphoma (MCL), hairy cell leukemia (HCL), splenic marginal
      analysis may be necessary under certain circumstances to identify the                                                          zone lymphoma, extra- nodal marginal zone lymphoma, nodal
      specific chromosomal translocations that are characteristic of some                                                            marginal zone lymphoma and follicular lymphoma], the panel for
      NHL subtypes or to establish clonality.                                                                                        immunophenotyping includes CD5, CD10, CD23, cyclin D1, BCL6,
                                                                                                                                     BCL2, and may include CD25 and CD103 if HCL is suspected.




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                                                                 NCCN Guidelines™ Version 3.2011                                                                                                                              NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                                 Non-Hodgkin’s Lymphomas                                                                                                                                                  Discussion


      Both CLL and MCL are CD5+ B-cell lymphomas. CLL is usually                                                                     CD103-negative small B-cell neoplasms can be further stratified by
      CD5+, CD23+ and cyclin D1-. However, some cases of CLL have an                                                                 staining for cytoplasmic immunoglobulin light chains. If cytoplasmic
      atypical immunophenotype (CD 23 dim or negative). Dysregulated                                                                 light chains are negative the most likely diagnosis is one of the MZLs,
      expression of cyclin D1, a cell cycle protein that results from the                                                            which are further classified by a combination of morphological and
      chromosomal translocation, t(11;14) is seen in the vast majority of                                                            clinical features (extranodal, nodal, and splenic). If cytoplasmic
      cases of MCL.51, 52 This translocation is not seen in other NHLs                                                               immunoglobulin is positive, the differential diagnosis includes MZL or
      though it can be seen in multiple myeloma.                                                                                     lymphoplasmacytic lymphoma (LPL). This distinction is based on a
                                                                                                                                     combination of morphology, clinical and laboratory (monoclonal
      The initial stratification is based on the expression of CD5. If CD5 is                                                        gammopathy) features and may be aided by cytogenetics (deletion 7q
      positive, confirmatory studies should be done with CD23 and cyclin                                                             in splenic MZL, t(11;18) in some extranodal MZL, vs. deletion 6q in
      D1 to differentiate between CLL and MCL. CD23 is often helpful but                                                             LPL).
      cyclin D1 expression is the most reliable marker for differentiating
      between CLL and MCL. Thus, immunophenotypic analysis of cyclin                                                                 Medium-sized Cells
      D1 or cytogenetic analysis of t(11;14) using FISH is helpful in                                                                For medium-sized cell lymphomas [BL, DLBCL, blastoid variant of
      confirming the diagnosis of MCL. Rare cases of both cyclin D1 and                                                              MCL, B-cell lymphoma, intermediate between BLBCL and BL
      t(11;14) negative MCL have been reported.53 This diagnosis should be                                                           (U-DLBCL/BL)], the immunophenotyping panel includes CD5, CD10,
      made with extreme caution and with expert consultation.                                                                        BCL2, BCL6, cyclin D1 and Ki-67.

      If CD5 is negative, then the next stratification is based on CD10.                                                             As with small cell lymphomas, the initial stratification is based on CD5.
      CD10 positivity (which must be confirmed by morphology to be on                                                                If CD5 is positive, the differential diagnosis is MCL vs. DLBCL and it
      tumor cells and not on residual reactive or colonized follicles)                                                               can be confirmed based on the analysis of cyclin D1, BCL6 and
      indicates follicular lymphoma, and this diagnosis can be confirmed                                                             IRF4/MUM1. BCL6 rearrangements associated with various
      further by staining for BCL6, BCL2 and detection of t(14;18) by FISH                                                           chromosomal translocations involving chromosome 3q27 are
      or PCR, since BCL2 resulting from t(14;18) is over-expressed in 90%                                                            observed in about 28-35% of DLBCL.55 IRF4/MUM1 is an oncogene
      of cases of FL.54 FL is also CD20+, CD5- and cyclin D1-, and nodular                                                           associated with myeloma, activated as a result of chromosomal
      aggregates of CD21+ or CD23+ FDC will usually be found. When                                                                   translocation, t(6;14) and it is observed in 73% of DLBCLs.56 Cyclin
      CD10 is negative, the differential diagnosis includes MZLs, LPL, and                                                           D1 positivity confirms the diagnosis of blastoid MCL. If cyclin D1 is
      HCL; immunophenotypic analysis of CD103 and CD25 can be used to                                                                negative, the diagnosis is confirmed as CD5+ DLBCL, irrespective of
      identify hairy cell leukemia (HCL). If both are positive, the suggested                                                        the expression of BCL6 and IRF4/MUM1.
      diagnosis would be HCL, which can be confirmed by the staining of
      annexin-1 since HCL is characterized by a strong expression of                                                                 If CD5 is negative, the stratification is based on the expression of
      annexin-1.                                                                                                                     CD10. If CD10 is positive, the differential diagnosis includes BL vs.

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                                                                 NCCN Guidelines™ Version 3.2011                                                                                                                              NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                                 Non-Hodgkin’s Lymphomas                                                                                                                                                  Discussion


      U-DLBCL/BL. These can be further stratified by Ki-67, BCL2 and                                                                 inflammation, ALK1+ DLBCL, plasmablastic lymphoma) often have
      BCL6. BCL6+, BCL2- and Ki-67 (95% or greater) would support the                                                                immunophenotypic profiles consistent with non-GCB origin; therefore,
      diagnosis of BL especially in pediatric cases. In adults, when BL is                                                           non-GCB immunophenotype should prompt further analysis to detect
      suspected, FISH for MYC, BCL2 and possibly BCL6 should be done                                                                 these subtypes in the appropriate clinical setting.
      to confirm the presence of MYC rearrangement and assess for the
      presence of a dual rearrangement of MYC and BCL2 (double hit),                                                                 Additional markers (CD20, PAX5, CD30, ALK1, CD138 and
      particularly if BCL2 is expressed.54 If MYC is positive and BCL2 and                                                           cytoplasmic immunoglobulin, as well as detection of HHV8 and EBV)
      BCL6 are not rearranged, one may make a diagnosis of BL. If BCL2                                                               may be useful for the further classification of large B-cell lymphomas.
      or BCL6 is rearranged, with or without MYC, the diagnosis could be                                                             In a tumor that is positive for both CD20 and PAX5, CD30 positivity
      U-DLBCL/BL. CD10-negative medium-sized B-cell neoplasms                                                                        supports the diagnosis of PMBL. If CD30 is positive and the
      generally fall into the category of U-DLBCL/BL. If both BCL2 and                                                               morphology overlaps with CHL, CD15 may be helpful: if it is positive,
      BCL6 are positive by IHC, FISH for MYC, BCL2 and BCL6 should be                                                                this supports either U-DLBCL/CHL or CHL, depending on the
      done to check for double hit U-DLBCL/BL, which have a poor                                                                     morphologic features. Absence of CD15 would support PMBL.
      prognosis.                                                                                                                     Absence of both CD20 and PAX5 and expression of IRF4/MUM1 and
                                                                                                                                     CD138 suggest terminal B-cell differentiation, and the differential
      Large Cells                                                                                                                    diagnosis would include ALK-positive DLBCL, plasmablastic
      DLBCL-NOS and the newly described subtypes of DLBCL as well as                                                                 lymphoma and primary effusion lymphoma. ALK-positive DLBCL is
      the pleomorphic variant of MCL are characterized by large cells. The                                                           characterized by the expression of ALK protein and absence of CD30.
      immunophenotyping panel for large cell lymphomas includes CD5,                                                                 It has an aggressive clinical course and poor outcome.57 If ALK is
      CD10, BCL6, and IRF4/MUM1 The first stratification is based on the                                                             negative, the stratification is now based on the staining for EBV and
      expression of CD5. If CD5 is positive, cyclin D1 expression should be                                                          HHV. EBV+ and HHV8- indicate plasmablastic lymphoma. Primary
      assessed to distinguish between pleomorphic MCL and CD5+ DLBCL,                                                                effusion lymphoma is HHV8+ with or without EBV and is CD30+.
      NOS, which has a variable expression of BCL6 and IRF4/MUM1. If                                                                 DLBCL associated with HHV8+ multicentric Castleman’s disease is
      CD5 is negative, the differential diagnosis is DLBCL which can be                                                              CD20+/-, HHV8+ and has characteristic morphologic features. Many
      stratified again based on the expression of CD10. CD10 positivity                                                              of these DBLCL subtypes have plasmacytic differentiation, and will
      confirms the diagnosis of DLBCL, NOS (GCB subtype). If CD10 is                                                                 have detectable cytoplasmic immunoglobulin.
      negative, confirmatory studies can be done with BCL6 and IRF4/MUM1
                                                                                                                                     Cutaneous B-cell lymphomas
      to differentiate GCB subtype (BCL6+ and IRF4/MUM1-) from non-GCB
      subtypes. For clinical purposes, it is not necessary to distinguish                                                            In the WHO classification, three main types of primary cutaneous
      between GCB and non-GCB subtypes. Recently described DLBCL                                                                     B-cell lymphomas are recognized: PCFCL, PCDLBCL, leg type, and
      subtypes (EBV+ DLBCL of the elderly, DLBCL associated with chronic                                                             primary cutaneous MZL (PCMZL). PCMZL express CD20 and BCL2
                                                                                                                                     but are negative for CD5, CD10 and BCL6.58 PCFCL, which is an

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                                                                 NCCN Guidelines™ Version 3.2011                                                                                                                              NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                                 Non-Hodgkin’s Lymphomas                                                                                                                                                  Discussion


      indolent disease, has a germinal center phenotype; whereas, most                                                               is PAX5-negative whereas CHL typically shows expression of CD15
      PCDLBCL, leg type which is an aggressive tumor, have an activated                                                              as well as dim expression of PAX5.
      B cell phenotype.59
                                                                                                                                     Cutaneous-T-cell lymphomas (non-anaplastic morphology)
      The immunophenotyping panel includes CD10, BCL2, BCL6,                                                                         Mycosis fungoides (MF) and Sezary syndrome (SS) are the most
      IRF4/MUM1 and follicular dendritic cell (FDC) markers (CD21 or                                                                 common types of cutaneous T-cell lymphomas (CTCLs) lacking
      CD23) to detect neoplastic follicles or colonized germinal centers.                                                            anaplastic morphology. Primary CTCLs are very rare. In the WHO
      Initial stratification is based on CD10. CD10 positivity on the                                                                classification, three rare provisional entities are included under
      neoplastic cells indicates PCFCL; however, many cases of PCFCL                                                                 primary CTCL- primary cutaneous gamma-delta T-cell lymphoma,
      are CD10-. If CD10 is negative, the differential diagnosis is based on                                                         primary cutaneous CD8-positive aggressive epidermotropic cytotoxic
      the expression of BCL2. BCL-2 is usually negative in PCFCL but                                                                 T-cell lymphoma (AECTCL) and primary cutaneous CD4-positive
      strongly expressed in PCDLBCL. When BCL2 is negative,                                                                          small/medium T-cell lymphoma.
      immunophenotypic analysis of BCL6 and IRF4/MUM1 is necessary to
      distinguish between PCFCL and PCMZL. PCFCL is consistently                                                                     The immunophenotyping panel for the diagnosis of cutaneous T-cell
      BCL6-positve and IRF4/MUM1-negative, whereas PCMZL is                                                                          lymphomas includes CD2, CD5, CD7,CD4, CD8, CD30, CD56, βF1,
      BCL6-negative and IRF4/MUM1 can be either positive or negative. If                                                             cytotoxic granule proteins (CGP). Initial stratification can be based on
      BCL2 is positive, IRF4/MUM1 is helpful to differentiate between                                                                CD30. Strong and uniform CD30 positivity favors primary cutaneous
      PCFCL and PCDLBCL, leg type, since PCFCL is usually                                                                            CD30-positive T-cell lymphoproliferative disorders (LPD), even if the
      IRF4/MUM1-negative while PCDLBCL, leg type is usually                                                                          morphology is not obviously anaplastic; however some CD30+ cells
      IRF4/MUM1-positive.                                                                                                            can be seen in MF and ATLL. In an epidermotropic cutaneous T-cell
                                                                                                                                     lymphoma, if CD30 is negative, then the differential diagnosis is
      T-cell Lymphomas (expression of one or more pan-T antigens                                                                     based on the expression of CD4 and CD8. If CD4 is positive, then the
      (CD2, CD3, CD5, CD7, CD43, CD45RO)                                                                                             differential diagnosis is MF/SS vs. adult T-cell leukemia and
                                                                                                                                     lymphoma (ATLL). ATLL and MF/SS both lack CGP. ATLL is CD25+
      T-cell lymphomas (anaplastic morphology)
                                                                                                                                     while MF/SS is CD25-; it is suggested by epidemiologic factors and
      In cases with anaplastic morphology, the immunophenotyping panel                                                               can be confirmed by serologic testing for HTLV1. If CD4 is negative
      includes CD30, CD15, PAX5, ALK, EBV-EBER. ALCL has a strong,                                                                   and CD8 is positive, then the diagnosis is more likely AECTCL which
      diffuse expression of CD30. If CD30 is positive, evaluation of ALK1                                                            has an aggressive clinical course.60 Since a minority of MF cases can
      status is used to identify ALK-positive ALCL. If ALK1 is negative,                                                             be CD30+, CD4 - and CD8 +/-, AECTCL should be confirmed further
      analysis of CD15 and PAX5 are essential in the differential diagnosis                                                          by its characteristic immunophenotype (CD4-, CD3+, CD8+, CD5- and
      of non-cutaneous ALK-negative ALCL and CHL. ALK-negative ALCL                                                                  CD45RO-). Cutaneous gamma-delta T-cell lymphoma may be
                                                                                                                                     epidermotropic, but typically also involves dermis and subcutis; is

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                                                                 NCCN Guidelines™ Version 3.2011                                                                                                                              NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                                 Non-Hodgkin’s Lymphomas                                                                                                                                                  Discussion


      typically CD4- CD8- CD5- CD56+, but may express CD8. Staining for                                                              expression of CD30 and ALK1. If ALK is negative, expression of βF1,
      βF1 is negative, and CGP are strongly expressed. Subcutaneous                                                                  CD4, CD5, CD8, and CD30 may be useful in further classification:
      panniculitis-like T-cell lymphoma is typically CD3+ CD7+ CD8+ βF1+                                                             EATL is βF1+ CD30+ CD56-/+, while HSTCL is usually βF1-, CD30-,
      and expresses CGP.                                                                                                             and is CD56+.

      Nodal Localization (Non-Anaplastic Morphology)                                                                                 Work-up
      Angioimmunoblastic T-cell lymphoma (AITL), ATLL and PTCL-NOS
                                                                                                                                     Essential work-up procedures include a complete physical exam with
      are included in this category, as well as small cell variants of ALCL.
                                                                                                                                     particular attention to node bearing areas and the size of liver and
      The immunophenotypic panel includes CD5, CD4, CD8, CD30, ALK1,
                                                                                                                                     spleen, symptoms present, performance status, laboratory studies
      CD10, BCL6, PD1, CD21, CD23 and EBV-EBER. Follicular helper T
                                                                                                                                     including CBC, serum lactate dehydrogenase (LDH), hepatitis B
      cell markers CD10, BCL6, PD1, and CD4 are helpful to differentiate
                                                                                                                                     testing (see below), comprehensive metabolic panel, and CT
      between AITL and PTCL-NOS and ATLL. The initial stratification is
                                                                                                                                     chest/abdominal/pelvic with oral and intravenous contrast (unless
      based on ALK and CD30 expression. If CD30 and ALK are negative
                                                                                                                                     co-existent renal insufficiency). MUGA scan or echocardiograms are
      and CD10, BCL6, PD1 and CD4 are positive, the likely diagnosis is
                                                                                                                                     recommended when anthracyclines and anthracenedione containing
      AITL; this can be confirmed by detection of FDCs expressing CD21
                                                                                                                                     regimens are used. Bone marrow biopsy with or without aspirate is
      and CD23, and typically some EBV+ large B cells. If follicular helper T
                                                                                                                                     essential in all cases where treatment is considered; however, there
      cell markers are absent, the differential diagnosis includes ATLL and
                                                                                                                                     are circumstances where it may be deferred (see below). Due the risk
      PTCL-NOS; expression of CD25, clinical features and assessment for
                                                                                                                                     of hepatitis B reactivation, the panel has included hepatitis B testing
      HTLV1 antibodies can confirm the diagnosis of ATLL.
                                                                                                                                     (hepatitis B surface antigen and hepatitis B core antibody) as part of
      Extranodal non-cutaneous localization (non-anaplastic morphology)                                                              essential work-up prior to initiation of treatment in all patients who will
      Extranodal NK T-cell lymphoma (ENKTCL), nasal type,                                                                            receive anti CD20 monoclonal antibody-based regimens.
      enteropathy-associated T-cell lymphoma (EATL), hepatosplenic T-cell                                                            Furthermore, hepatitis B reactivation has been reported with
      lymphoma (HSTCL), extranodal involvement by PTCL-NOS and                                                                       chemotherapy alone and testing should be considered in anyone with
      ALCL, ALK+ small-cell histiocyte-rich variants are included in this                                                            a risk factor (e.g. blood transfusion, IV drug abuse) or if from a region
      category. The differential diagnosis will be affected by the specific                                                          with a non-negligible prevalence of hepatitis B infection. For further
      clinical presentation. Initial stratification may be based on the EBV                                                          discussion see “Hepatitis B Reactivation” in the Supportive Care
      EBER status. If EBER is positive, ENKTCL is suggested and can be                                                               section of this manuscript. Hepatitis C testing is needed in high-risk
      confirmed by CD56 expression. If EBER is negative, the differential                                                            patients and patients with splenic marginal zone lymphoma.
      diagnosis may include EATL, HSTCL, ALCL, ALK+ small-cell
                                                                                                                                     Optional procedures (depending on specific lymphoma type) include
      histiocyte-rich variants and extranodal PTCL-NOS, depending on the
                                                                                                                                     beta-2-microglobulin, CT or PET-CT scans, endoscopic ultrasound
      clinical features. The stratification can then be based on the

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                                                                 NCCN Guidelines™ Version 3.2011                                                                                                                              NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                                 Non-Hodgkin’s Lymphomas                                                                                                                                                  Discussion


      (gastric MALT lymphoma), head CT or brain MRI and lumbar puncture                                                              early stage indolent lymphoma (stage I or II), bone marrow biopsy is
      to analyze cerebrospinal fluid (MCL and DLBCL). Discussion of                                                                  essential; some panel members advocate bilateral core biopsies in
      fertility issues and sperm banking should be addressed in the                                                                  this situation.66 Bilateral cores are recommended if
      appropriate circumstances.61                                                                                                   radioimmunotherapy is considered.

      Bone marrow biopsy is usually included in the work-up for all patients                                                         FDG-PET scan has been used for initial staging, restaging and
      with NHL with the exception of SLL/CLL when there is a clonal                                                                  follow-up of patients with NHL.67 In a recent meta-analysis, PET
      lymphocytosis identified by flow cytometry. Bone marrow involvement                                                            showed a high positivity and specificity when used for the staging and
      occurs in 39% of low-grade, 36% of intermediate grade and 18% of                                                               restaging of patients with lymphoma.68 FDG-PET is nearly universally
      high-grade lymphomas. Bone marrow involvement was associated                                                                   positive at diagnosis in Hodgkin lymphoma, DLBCL, and follicular
      with significantly shorter survivals in patients with intermediate or                                                          lymphoma,69 about 90% in T-cell lymphoma70 and nodal MZL but less
      high-grade lymphomas.62 In a recent retrospective analysis, the                                                                sensitive for extra-nodal MZL.71 However, a number of benign
      incidence of bone marrow involvement and the parameters predicting                                                             conditions including sarcoid, infection, and inflammation can result in
      bone marrow involvement were analyzed in 192 patients with stage I                                                             false-positive PET scans complicating the interpretation. Lesions
      and II in DLBCL. Overall incidence of BM involvement was 3.6%. The                                                             smaller than 1 cm are not reliably visualized with PET scans. PET
      authors concluded that bone marrow biopsy may be safely omitted in                                                             scan is now part of pre-treatment evaluation in Hodgkin lymphoma
      selected patients with early stage DLBCL.63 In cutaneous B-cell                                                                and DLBCL and may be useful in selected cases in other histologies.
      lymphomas, bone marrow biopsy is essential for PCDLBCL, leg type                                                               The pre-treatment PET is particularly important to aid in the
      since this is an aggressive lymphoma that will probably require                                                                interpretation of post treatment response evaluation according to new
      systemic treatment, whereas the role of bone marrow biopsy in the                                                              response criteria (see above). At diagnosis, though PET scans may
      PCFCL and PCMZL is less clear. Recent studies have indicated that                                                              detect additional disease sites, the clinical stage is modified only in
      bone marrow biopsy is an essential component of staging in patients                                                            15-20% of patients and a change in treatment in only 8% of patients.
      with PCFCL first presenting in the skin, whereas it appears to have                                                            PET scan has generally been used in conjunction with a diagnostic
      limited value in patients with MZL presenting in the skin, and may be                                                          CT scans.
      considered only in selected cases.64, 65
                                                                                                                                     Integrated PET-CT as a largely replaced the dedicated CT scans in
      In the NCCN guidelines, bone marrow biopsy with or without aspirate                                                            the United States. This diagnostic study has distinct advantages in
      is included as part of essential work-up for all lymphomas. However,                                                           both staging and restaging compared to full dose diagnostic CT or
      in patients with low bulk indolent disease with radiographic clinical                                                          PET alone.72, 73 In a retrospective study, PET-CT performed with
      stage III disease, an initial staging bone marrow evaluation can be                                                            low-dose non-enhanced CT was found to be more sensitive and
      deferred if observation is recommended as it will not change the                                                               specific than the routine contrast-enhanced CT in the evaluation of
      clinical recommendations. However, in the evaluation of potentially                                                            lymph node and organ involvement in patients with Hodgkin disease

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                                                                 NCCN Guidelines™ Version 3.2011                                                                                                                              NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                                 Non-Hodgkin’s Lymphomas                                                                                                                                                  Discussion


      or high-grade NHL.73 Preliminary results of another recent prospective                                                         Patients positive for HBSAg are at a greater risk for HBV reactivation
      study (47 patients; patients who had undergone prior diagnostic CT                                                             than those positive for HBCAb.74 In a prospective study of 100
      were excluded) showed a good correlation between low-dose                                                                      Chinese patients receiving chemotherapy for lymphoma, hepatitis
      unenhanced PET-CT and full-dose enhanced PET-CT in the                                                                         developed in 67% of HBSAg-positive patients and 14%
      evaluation of lymph nodes and extranodal disease in lymphomas.72                                                               HBSAg-negative patients during cytotoxic therapy.77 Other risk factors
      However, the lack of intravenous contrast and the diminished                                                                   for reactivation include young age, male gender, elevated
      resolution can make it difficult in some cases to interpret the                                                                pretreatment viral load and prolonged immunosuppression.78, 79 The
      anatomical localization and significance of FDG-avid sites. Further                                                            use of rituximab in HBCAb-positive patients has been reported to
      studies are needed to determine if PET-CT scans can replace                                                                    cause fatal HBV-related liver disease. A retrospective study of Italian
      diagnostic CT scans in the initial staging and response evaluation of                                                          HBCAb-positive patients with lymphoma found that 2.7% of patients
      lymphomas. The panel has included PET-CT scan as an optional                                                                   treated with rituximab and chemotherapy developed HBV-related liver
      work-up procedure for selected patients.                                                                                       disease compared to 0.8% of patients treated with chemotherapy
                                                                                                                                     alone. HBV-related liver disease was not seen in patients who were
      Supportive Care                                                                                                                observed or received other therapy (radiation, antibiotics, interferon).80
      Hepatitis B virus reactivation                                                                                                 Anti-viral prophylaxis has been effective in the prevention of hepatitis
      Hepatitis B virus (HBV) reactivation has been reported to occur in                                                             B reactivation during chemoimmunotherapy in HBsAg-positive
      patients treated with chemotherapy with or without anti-CD20                                                                   patients.81-83 The results of a systematic review of 14 studies involving
      monoclonal antibody; treatment with rituximab alone is also a risk for                                                         HBSAg-positive patients receiving chemotherapy showed that
      hepatitis B reactivation.74 HBV-reactivation may result in a fulminant                                                         lamivudine prophylaxis for HBSAg-positive patients undergoing
      hepatitis, hepatic failure, and death. The median time to the diagnosis                                                        chemotherapy reduced the risk for HBV reactivation by ≥79%;
      of hepatitis was approximately 4 months after the initiation of                                                                HBV-associated hepatic failure and death may also be reduced.81
      rituximab (See rituximab package insert at www.fda.gov).                                                                       None of the patients in the preventive lamivudine group developed
                                                                                                                                     HBV-related hepatic failure compared to 21 of 162 patients in the
      Testing of patients at risk for hepatitis B reactivation should include:
                                                                                                                                     control group, and only 4 deaths were attributable to HBV in the
      hepatitis B surface antigen (HBSAg) and hepatitis B core antibody
                                                                                                                                     preventive lamivudine group compared to 27 deaths in the control
      (HBCAb). In a prospective study of all patients receiving
                                                                                                                                     group. Lamivudine was well tolerated with no adverse effects. In a
      immunosuppressive (chemotherapy, antibody therapy, high dose
                                                                                                                                     small randomized study, Lau et al demonstrated that pre-emptive
      dexamethasone) therapy at MSKCC, 1% of patients were
                                                                                                                                     antiviral treatment with lamivudine was superior to deferred
      HBSAg-positive and 9% were HBCAb-positive.75 A retrospective study
                                                                                                                                     treatment.84 This study randomized 30 HBSAg-positive lymphoma
      conducted by MDACC also reported similar findings (HBSAg and
                                                                                                                                     patients to receive lamivudine before chemotherapy or to receive
      HBCAb were positive in 2% and 8% of patients respectively).76
                                                                                                                                     lamivudine for the treatment of increased viral load based on HBV
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                                                                 NCCN Guidelines™ Version 3.2011                                                                                                                              NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                                 Non-Hodgkin’s Lymphomas                                                                                                                                                  Discussion


      DNA PCR levels. HBV reactivation was observed in 53% of monitored                                                              Progressive multifocal leucoencephalopathy
      patients and none in the prophylaxis group. Interestingly, clinical                                                            Progressive multifocal leucoencephalopathy (PML) is a serious and
      cancer-related outcomes were also significantly better in the                                                                  usually fatal CNS infection caused by JC polyoma virus. In a recent
      prophylaxis group than the treatment group.                                                                                    report of 57 cases from the Research on Adverse Drug Events and
                                                                                                                                     Reports project, 52 patients with lymphoproliferative disorders
      The NCCN guidelines recommend HBSAg and HBCAb testing for all
                                                                                                                                     developed PML after treatment with rituximab and other treatments
      patients receiving rituximab. In patients where one or both of these
                                                                                                                                     which included hematopoietic stem cell transplantation or
      tests are positive, a baseline hepatitis B viral load should be
                                                                                                                                     chemotherapy with purine analogs or alkylating agents.85 Median time
      determined by quantitative PCR. However, a negative baseline PCR
                                                                                                                                     from last rituximab dose to PML diagnosis was 5.5 months. Median
      does not preclude the possibility of activation. In patients from areas
                                                                                                                                     time to death after PML diagnosis was 2.0 months. The case-fatality
      with high prevalence (Asia, Africa, Eastern Europe, and portions of
                                                                                                                                     rate was 90%.
      South America) or regions where the prevalence of HBV is not known,
      all patients receiving immunotherapy, chemotherapy, or                                                                         PML is usually diagnosed with PCR of cerebrospinal fluid (CSF) or
      chemoimmunotherapy should be tested for HBSAg and HBCAb.                                                                       sometimes brain biopsy. There is no effective treatment for PML.
      Patients receiving intravenous immunoglobulin (IVIG) may be HBCAb                                                              Patients need to be carefully monitored for the development of any
      positive as a consequence of IVIG therapy. Empiric antiviral therapy                                                           neurological symptoms. There is currently no pretreatment evaluation
      with oncologic treatment is recommended for any patient who is either                                                          that can be undertaken to predict for the subsequent development of
      HBSAg or HBCAb positive. During the treatment period, viral load                                                               PML.
      should be monitored monthly with PCR and 3 months thereafter.
      Patients receiving chemotherapy alone should receive prophylaxis if                                                            Tumor Lysis syndrome
      they have a measurable viral load independent of the viral serology. If                                                        Tumor lysis syndrome (TLS) is characterized by metabolic
      viral load is consistently undetectable, prophylaxis should be given to                                                        abnormalities caused by the abrupt release of intracellular contents
      HBSAg positive patients and may be considered in patients HBCAb                                                                into the blood resulting from cellular disintegration induced by
      positive. If viral load fails to drop, consultation with a hepatologist is                                                     chemotherapy. It is usually observed within 12 to 72 hrs after start of
      recommended. However, because of the potential emergence of                                                                    chemotherapy.86 Untreated TLS can induce profound metabolic
      resistance to lamivudine it is not the optimal drug for prophylaxis.                                                           changes resulting in cardiac arrhythmias, seizures, loss of muscle
      There are a number of appropriate agents for viral prophylaxis; good                                                           control, acute renal failure, and death.
      choice will be driven by institutional standard or recommendation from
      the consultant. The optimal duration of prophylaxis remains undefined                                                          Cairo and Bishop have recently classified TLS into laboratory TLS and
      but the panel recommended it should be maintained for at least 6                                                               clinical TLS. Laboratory TLS is defined as a 25% increase in the
      months after the completion of oncologic treatment.                                                                            levels of serum uric acid, potassium, or phosphorus or a 25%
                                                                                                                                     decrease in calcium levels.87 Clinical TLS refers to laboratory TLS
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                                                                 NCCN Guidelines™ Version 3.2011                                                                                                                              NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                                 Non-Hodgkin’s Lymphomas                                                                                                                                                  Discussion


      with clinical toxicity that requires intervention. Clinical complications                                                      Rasburicase is recombinant urate oxidase which catalyzes the
      may include renal insufficiency, cardiac arrhythmia, or seizures. The                                                          oxidation of uric acid to a highly soluble non-toxic metabolite that is
      four primary electrolyte abnormalities of TLS are hyperkalemia,                                                                readily excreted. It has been shown to be safe and highly effective in
      hyperuricemia, hyperphosphatemia, and hypocalcemia. Symptoms                                                                   the prevention and treatment of chemotherapy-induced hyperuricemia
      associated with TLS may include nausea and vomiting, diarrhea,                                                                 in both children and adults.89 The GRAAL1 (Groupe d'Etude des
      seizures, shortness of breath, or cardiac arrhythmias.                                                                         Lymphomes de l'Adulte Trial on Rasburicase Activity in Adult
                                                                                                                                     Lymphoma) study evaluated the efficacy and safety of rasburicase for
      TLS is best managed if anticipated and treatment started prior to                                                              the prevention and treatment of hyperuricemia in patients with NHL
      chemotherapy. The cornerstone of the management of TLS is                                                                      during induction chemotherapy.90 Uric acid levels decreased within 4
      hydration and the control of hyperuricemia. Allopurinol should be                                                              hours after the first injection of the drug. Creatinine levels and other
      administered prior to the initiation of chemotherapy. In cases where                                                           metabolites were also controlled with the administration of
      the uric acid level remains elevated despite treatment with allopurinol                                                        rasburicase.
      or there is renal insufficiency treatment with rasburicase is indicated.
      Electrolytes and renal function should be monitored every 6-8 hours                                                            Cortes et al recently reported the results of a prospective, randomized
      with appropriate interventions for hyperkalemia and                                                                            controlled trial which compared the efficacy of rasburicase and
      hyperphosphatemia. Careful clinical monitoring will help to preempt                                                            allopurinol in adult patients with hematological malignancies at high or
      complications and in many cases admission to ICU is appropriate.                                                               potential risk for TLS.91 The plasma uric acid response rate was 87%
      Cardiac monitoring or serial ECG may be beneficial to identify early                                                           for rasburicase, 78% for rasburicase plus allopurinol arm and 66% for
      electrolyte related cardiac abnormalities. Dialysis may be necessary in                                                        allopurinol. Rasburicase was superior to allopurinol in the overall
      cases of anuric acute renal failure.                                                                                           study population as well as in patients at high risk TLS (89% vs. 68%)
                                                                                                                                     and in patients with baseline hyperuricemia (90% vs. 53%). The time
      Allopurinol is a xanthine analog and a competitive inhibitor of xanthine                                                       to control serum uric acid in hyperuricemic patients was 4 h for
      oxidase thereby blocking conversion of purine metabolites to uric acid.                                                        rasburicase and 27 h for allopurinol. However, rasburicase can induce
      Allopurinol will decrease the formation of uric acid production and has                                                        anaphylactic reactions. Other adverse reactions include
      been shown to reduce and reduce the incidence of uric-acid                                                                     methemoglobinemia and severe hemolysis in patients with
      uropathy.88 Since the drug inhibits new uric acid formation rather than                                                        glucose-6-phosphate dehydrogenase (G6PD) deficiency.
      to reduce existing uric acid, it can take several days for elevated
      levels of uric acid to normalized after the initiation of treatment                                                            The risk factors for TLS include bone marrow involvement, bulky
      thereby delaying the start of chemotherapy. Furthermore, allopurinol                                                           tumors that are chemosensitive, rapidly proliferative or aggressive
      may lead to the accumulation of xanthine crystals in renal tubules                                                             hematologic malignancies, an elevated leukocyte count or
      leading to acute obstructive uropathy. Allopurinol will also reduce                                                            pretreatment lactate dehydrogenase (LDH), pre-existing elevated uric
      clearance of 6-mercaptopurine and high-dose methotrexate.                                                                      acid, renal disease or renal involvement of tumor. Patients diagnosed

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                                                                 NCCN Guidelines™ Version 3.2011                                                                                                                              NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                                 Non-Hodgkin’s Lymphomas                                                                                                                                                  Discussion


      with lymphoblastic lymphoma or Burkitt lymphoma are at a higher risk                                                                   AIDS-related B-cell lymphoma
      of developing TLS. Occasionally, patients with bulky presentation of                                                                   Primary Cutaneous B-cell Lymphomas
      DLBCL and patients with CLL and high white blood cell count may
      experience TLS at a moderately high frequency.                                                                                  Precursor B-cell/T-cell lymphomas
                                                                                                                                               Lymphoblastic lymphoma
      The NCCN guidelines recommend that allopurinol should be started
      2−3 days prior to chemotherapy and continued for 10−14 days.                                                                    Mature T-cell and NK-cell lymphomas
      Rasburicase is recommended for patients with any of the following
                                                                                                                                             Peripheral T-cell lymphoma (PTCL)
      risk-factors: presence of any high risk feature; bulky disease requiring
                                                                                                                                             Mycosis fungoides (MF) and Sezary syndrome(SS)
      immediate therapy; patients in whom adequate hydration is not
                                                                                                                                             Adult T-cell leukemia/lymphoma (ATLL)
      possible; allopurinol is ineffective; or acute renal failure. One dose is
                                                                                                                                             Extranodal NK/T-cell lymphomas, nasal type
      adequate in most cases; repeat dosing should be individualized.
                                                                                                                                      Post-transplant lymphoproliferative disorders (PTLD)
      NCCN Guidelines
      The National Comprehensive Cancer Network (NCCN) guidelines                                                                    Chronic Lymphocytic Leukemia (CLL)/Small
                                                                                                                                     Lymphocytic Lymphoma (SLL)
      were developed for the most common subtypes of NHL:
                                                                                                                                     CLL and SLL are different manifestations of the same disease and are
       Mature B-cell lymphomas                                                                                                      managed in much the same way.92 The major difference is that in
             Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma                                                          CLL, a significant number of the abnormal lymphocytes are also found
              (SLL)                                                                                                                  in the bone marrow and blood, while in SLL the abnormal lymphocytes
             Follicular lymphoma (FL)                                                                                               are predominantly found in the lymph nodes.
             Marginal Zone lymphomas (MZL)
                                                                                                                                     Cytogenetic abnormalities that can be detected by FISH are present
                 Extranodal MZL of mucosa associated lymphoid tissue (MALT                                                          in about 80% of patients with CLL. The most common abnormality is
                  lymphoma)                                                                                                          del(13q) (55%) followed by del(11q) (18%), trisomy 12 (16%),
                             Gastric MALT lymphoma                                                                                  del(17p) (7%), and del(6q) (7%).93 Deletion 13q is associated with a
                             Non-gastric MALT lymphoma                                                                              favorable prognosis and the longest median survival (133 months).
                 Nodal MZL                                                                                                          Deletion of 11q is associated with extensive lymphadenopathy,
                 Splenic MZL                                                                                                        disease progression and shorter median survival (79 months).93, 94
             Diffuse large B-cell lymphoma (DLBCL)                                                                                  Among patients with 11q deletion, those with a complete loss of ATM
             Mantle cell lymphoma (MCL)                                                                                             function might have impaired response to irradiation or cytotoxic
             Burkitt lymphoma (BL)                                                                                                  drugs, resulting in poor clinical outcome.95 Alkylating agent-based

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                                                                 NCCN Guidelines™ Version 3.2011                                                                                                                              NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                                 Non-Hodgkin’s Lymphomas                                                                                                                                                  Discussion


      chemoimmunotherapy regimens have significantly improved clinical                                                               have been identified.106 Higher beta-2-microglobulin was an
      outcomes by overcoming the adverse prognostic significance of                                                                  independent adverse prognostic factor in patients treated with
      del(11q) in previously untreated patients with CLL.96 Deletion 17p                                                             front-line fludarabine-based chemotherapy.107 Unmutated IGHV is
      affecting TP53 is associated with shorter treatment free intervals,                                                            associated with a poor prognosis irrespective of the stage of the
      shorter median survival (32 months), and poor response to                                                                      disease.108 The extent of mutation is also important, with the longest
      chemotherapy.93 Recent studies have identified TP53 mutations as an                                                            survivals observed in patients with >3% mutations and slightly shorter
      independent predictor of short survival and resistance to                                                                      survival seen in those with 1- 2% mutations.109 A subset of patients in
      chemotherapy.97 The resistance to chemotherapy has been attributed                                                             which the IGHV3-21 variable region is rearranged have a relatively
      to the presence of mutation in the remaining TP53 allele.98 However,                                                           more aggressive disease and short survival regardless of the mutation
      the natural history of patient with deletion 17p can be heterogeneous                                                          status.110
      with some patients having an indolent disease course.99, 100 TP53
      mutation also carries a poor prognosis regardless of the presence of                                                           Overexpression of CD38 (30% or more)111-113 and ZAP-70 (20% or
      deletion 17p when treated with fludarabine-based chemotherapy.101,                                                             more) 114-117 are also associated with a poor prognosis. However,
      102                                                                                                                            these cutoffs are based on flow cytometry and reproducibility across
                                                                                                                                     laboratories remains a problem. Recent studies have shown that the
      The impact of these prognostic factors on the clinical outcome of                                                              combined analysis of ZAP-70 and CD38 expression provides a more
      patients has been examined in large prospective randomized studies.                                                            discriminatory prediction of treatment free interval than each factor
      In the CALGB 9712 study,103 unmutated IGHV (≥98%), del(11q) and                                                                alone.118-121 Wierda et al. have developed a nomogram using age,
      del(17p) were identified as independent prognostic factors for overall                                                         2M, absolute lymphocyte count, sex, Rai stage, and number of
      and progression-free survival (PFS) whereas in other two studies                                                               involved lymph nodes that may help to stratify untreated patients with
      (E2997104 and LRF CLL4105) these features were identified as                                                                   CLL into 3 different risk groups (low, intermediate and high).122 The
      prognostic indicators for PFS. In the LRF CLL4 trial patients with                                                             estimated median survival times were not reached for low risk groups.
      5-20% of cells with del(17p) had similar response rates and survival                                                           The median survival times for intermediate and high risk groups were
      as patients without del(17p).105 In contrast, those with 20% or more of                                                        10 years and 5 years respectively. The 5-and 10-year OS rates were
      cells with del(17p) had a poor outcome with 13% response rate and a                                                            97% and 80%, 80% and 52% and 55% and 26% respectively. This
      median OS of only 11 months. The finding that del(17p) is more                                                                 prognostic model needs to be validated in prospective studies.
      frequently observed in treated patients than in untreated ones (20%
      vs. 5-10%) suggests treatment-driven clonal selection occurs during                                                            Staging
      therapy.                                                                                                                       The nearly universal involvement of the bone marrow and peripheral
                                                                                                                                     blood in CLL/SLL limits the utility of the Ann Arbor staging system.
      New prognostic markers such as beta-2-microglobulin, IGHV                                                                      Two different staging systems, Rai and Binet system are currently
      mutational status, CD38 and zeta-associated protein 70 (ZAP-70)

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                                                                 NCCN Guidelines™ Version 3.2011                                                                                                                              NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                                 Non-Hodgkin’s Lymphomas                                                                                                                                                  Discussion


      used worldwide.123, 124 The modified Rai classification is most useful                                                         Adequate immunophenotyping using flow cytometry of peripheral
      clinically and provides important prognostic information.123 Survival of                                                       blood or paraffin-section immunohistochemistry is required to confirm
      patients with low-risk disease (Rai stage 0) is essentially the same as                                                        the diagnosis of CLL/SLL. Recommended panel for
      the survival rate of age-matched controls. Patients with                                                                       immunohistochemistry include CD3, CD5, CD10, CD20, CD23 and
      intermediate-risk disease (Rai stage I-II) have a shorter survival,                                                            cyclin D1. These can be useful, particularly for diagnosing CLL/ SLL
      particularly when other adverse factors coexist, such as a lymphocyte                                                          type without circulating cells. Cell surface markers for flow cytometric
      doubling time of less than one year. Patients with high-risk disease                                                           studies include kappa/lambda, CD19, CD20, CD5, CD23 and CD10.
      (Rai stage III-IV) have a poor prognosis. Binet staging system is                                                              Additional paraffin-embedded material may be used for
      based on the number of involved areas and the level of hemoglobin                                                              immunophenotyping to determine lineage and clonality.
      and platelets and like the Rai system has a good correlation with
      clinical outcome.124                                                                                                           The typical immunophenotype includes CD5+, CD10-, CD19+, CD20,
                                                                                                                                     dim expression of surface immunoglobulin, CD23+, CD43+/-, and cyclin
      Diagnosis                                                                                                                      D1-. Distinguishing CLL/SLL from MCL is essential, as they are both
      The diagnosis of CLL requires the presence of at least 5000                                                                    CD5+ B-cell tumors. Though CD23 is often helpful, cyclin D1- is critical
      malignant B-cells/mm3. The presence of fewer B-cells in the absence                                                            in this differentiation of tumor types. FISH for the t(11;14) can help
      of lymphadenopathy or other clinical features characteristic of a                                                              distinguish MCL from CLL. Cytogenetics and/or FISH for detection of
      lymphoproliferative disorder is defined as monoclonal                                                                          del11q, del13q, trisomy 12 and del17p and molecular genetic analysis
      B-lymphocytosis (MBL). MBL is a relatively recent diagnostic category                                                          to detect IGHV mutation status can provide prognostic information and
      consisting of individuals with an abnormal B-cell population but do not                                                        guide selection of therapy. Though FISH is optional for patients with
      meet the diagnostic criteria for CLL.125 Most cases of MBL have the                                                            Rai low risk disease where observation would be recommended; it
      immunophenotype of CLL (see below). The “favorable” molecular                                                                  should be evaluated at any time therapy is considered. Cytogenetic
      lesions, mutated IGHV and del(13q), are commonly seen in patients                                                              abnormalities can evolve over time and therefore re-evaluation of FISH
      with MBL.19 The estimated rate of progression of MBL to CLL                                                                    is necessary to direct treatment options in patients with indications for
      requiring treatment was 1.1% per year. To distinguish MBL from SLL                                                             treatment. CD38 and/or ZAP-70 expression can be determined using
      evaluation with CT scan is essential. The CLL/SLL guideline now                                                                immunohistochemistry or flow cytometry. Evaluation of ZAP-70
      includes an initial stratification between CLL/SLL and MBL (absolute                                                           expression by flow cytometry can be challenging and is not
      lymphocyte count of less than 5000 B-cells/mm3, lymph nodes less                                                               recommended outside the context of clinical trials.
      than 1.5 cm, no anemia or thrombocytopenia). Observation is
                                                                                                                                     Conventional metaphase cytogenetics is difficult in CLL as a result of
      recommended for all patients diagnosed with MBL.
                                                                                                                                     the very low proliferative activity of the leukemic cells in vitro.
                                                                                                                                     Therefore, interphase cytogenetic analysis with FISH has been the
                                                                                                                                     standard method to detect the chromosomal abnormalities that have

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                                                                 NCCN Guidelines™ Version 3.2011                                                                                                                              NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                                 Non-Hodgkin’s Lymphomas                                                                                                                                                  Discussion


      important prognostic significance. However, FISH can only detect                                                               Computed tomography (CT) scans is useful to follow and monitor
      abnormalities specific to the probes utilized. Cytokine or CpG                                                                 disease progression when peripheral adenopathy is present. For
      oligonucleotide stimulation has been utilized to promote efficient                                                             anemic patients, reticulocyte counts and a direct Coombs’ test should
      metaphase analysis.126 Recent studies have demonstrated that                                                                   be performed to evaluate for the possibility of hemolysis. PET scan is
      stimulation with CpG oligonucleotide and interleukin-2 is more                                                                 generally not useful in CLL but can assist in directing nodal biopsy if
      effective than that with 12-O-tetradecanoyl-phorbol-13-acetate (TPA)                                                           Richter’s transformation is suspected.
      for the detection of chromosomal abnormalities in CLL.127, 128 A
      prospective study conducted by CLL Research Consortium confirmed                                                               Response Criteria
      that abnormal clones in CLL are more readily detected with CpG                                                                 The National Cancer Institute sponsored working group (NCI-WG) first
      oligonucleotide stimulation than with traditional B-cell mitogens and                                                          published the guidelines for the diagnosis and treatment of CLL in
      the clonal abnormalities revealed by CpG stimulated metaphase                                                                  1996.130 The recent developments in the use of prognostic markers
      cytogenetics are consistent with that detected by interphase FISH and                                                          and treatment options for CLL have led to the revision of these
      are reproducible among different cytogenetic laboratories.129 However,                                                         guidelines, particularly the response criteria.18 CR and PR are
      the use of CpG stimulation for CLL cytogenetics is not yet universally                                                         considered clinically beneficial. Relapse is defined as the disease
      available.                                                                                                                     progression after a period of 12 months or more following CR or PR.
                                                                                                                                     Refractory disease is defined as the one which does not respond to
      Workup                                                                                                                         purine analog-based therapy or which progresses within 12 months
      The workup for CLL/SLL is similar to the workup for other lymphoid                                                             after receiving such therapy.
      neoplasms. Quantitative immunoglobulins may be particularly
      informative in patients with recurrent infections. Measurement of 2M                                                          Treatment Options
      may provide useful prognostic information.107, 122 Though classically                                                          First-line Therapy
      the pattern of bone marrow involvement (diffuse versus nodular) had                                                            In earlier clinical trials the efficacy of chlorambucil plus prednisone
      prognostic significance, this is no longer a factor when one uses more                                                         was comparable to that of CVP (cyclophosphamide, vincristine and
      reliable prognostic markers such as IGHV mutation (or its surrogate                                                            prednisone) and CHOP (cyclophosphamide, doxorubicin, vincristine
      ZAP-70) and cytogenetic abnormalities determined by FISH all of                                                                and prednisone) regimens in patients with advanced CLL.131 In the
      which can be obtained by analysis of circulating lymphocytes. Thus,                                                            CALGB 9011 study, 509 patients were randomized to receive
      bone marrow biopsy is no longer considered a required part of the                                                              fludarabine, chlorambucil or the combination as first-line therapy.132
      evaluation of patients with CLL though it remains useful to evaluate                                                           The combination arm was stopped due to excessive toxicity.
      the etiology of cytopenias.                                                                                                    Complete remission (20% vs. 4% for chlorambucil), partial remission
                                                                                                                                     (43% vs. 33% for chlorambucil), median duration of remission (25
                                                                                                                                     months vs. 14 months for chlorambucil) and median PFS (20 months

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                                                                 NCCN Guidelines™ Version 3.2011                                                                                                                              NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                                 Non-Hodgkin’s Lymphomas                                                                                                                                                  Discussion


      vs. 14 months for chlorambucil) were significantly better in patients                                                          The combination of fludarabine, cyclophosphamide and rituximab
      treated with fludarabine. The study found no significant difference in                                                         (FCR) evaluated at M.D. Anderson Cancer Center as initial therapy
      OS between the two arms (66 months vs. 56 months for                                                                           produced high ORR and CR.140-142 For the 300 study patients, at a
      chlorambucil). In a phase III randomized trial conducted by the                                                                median follow up of 6 years, the ORR was 95% (72% CR).141
      GCLLSG, fludarabine was significantly better than chlorambucil in                                                              Recently, a large international randomized Phase III clinical trial
      terms of ORR (72% vs. 51% respectively) and time to treatment                                                                  (CLL8) showed that the addition of rituximab to fludarabine-based
      failure (18 months vs. 11 months respectively) in patients older than                                                          chemotherapy improved the outcome of patients with CLL with regard
      65 years (median age 70 years), but there was no survival benefit for                                                          to response rates, PFS and OS compared to those receiving
      fludarabine compared to chlorambucil (OS and PFS were 46 months                                                                fludarabine-based chemotherapy alone.143 In this trial, 817 patients
      and 19 months respectively for fludarabine; 64 months and 19 months                                                            with previously untreated CD20-positive CLL were randomized to 6
      respectively for chlorambucil).133                                                                                             courses of either FCR or FC regimen. At 3 years after randomization,
                                                                                                                                     the PFS and OS rates were 65% and 87% respectively for patients
      An European randomized study compared fludarabine with two                                                                     randomized to FCR compared to 45% and 82.5% respectively for
      alkylating agent-based combination regimens, CAP                                                                               those who received FC. FCR also induced a higher ORR (95% vs
      (cyclophosphamide, doxorubicin and prednisone) and CHOP as                                                                     88%) and more CRs (44% vs. 22%) than FC. Median PFS was 52
      first-line treatment in patients with advanced CLL.134 Fludarabine and                                                         months and 33 months for FCR and FC respectively. Based on the
      CHOP produced similar overall remission rates (71%) compared to                                                                results of this trial, the FDA approved rituximab in combination with
      CAP (58%). However, fludarabine was better tolerated than CHOP. In                                                             fludarabine and cyclophosphamide for patients with previously
      large randomized trials, the combination of fludarabine and                                                                    untreated CD20-positive CLL.
      cyclophosphamide (FC) was associated with an increase in overall
      response, CR and PFS compared to fludarabine alone.105, 135,136                                                                In a trial initiated by the CLL Research Consortium, pentostatin,
                                                                                                                                     cyclophosphamide and rituximab (PCR) demonstrated significant
      CALGB study 9712 compared the efficacy of fludarabine with                                                                     clinical activity despite poor risk-based prognoses in previously in
      concurrent or sequential administration of rituximab in untreated                                                              untreated patients.144 Responses were observed in 91% of patients
      patients with CLL.137, 138 The concurrent regimen was associated with                                                          (41% CR, 21% nodular PR and 28% PR). In a subsequent study, the
      a higher ORR (90% vs. 77% for the sequential regimen) at the                                                                   combination of higher dose pentostatin and rituximab resulted in OR
      expense of higher grade 3 or 4 toxicity. However, comparison of the                                                            of 76%, with a CR of 27%.145 However, in historical comparison, the
      outcomes of patients treated with fludarabine alone in the CALGB                                                               response rates were higher and the median treatment-free survival
      9011 trial and the pooled results from the CALGB 9712 study,                                                                   (16 months vs. 30 months for PCR) for all accrued patients was
      suggested that the addition of rituximab to fludarabine prolongs PFS                                                           notably longer in patients treated with PCR compared with PR.
      and OS.139


      Version 3.2011, 05/18/11 © National Comprehensive Cancer Network, Inc. 2011, All rights reserved. The NCCN Guidelines™ and this illustration may not be reproduced in any form without the express written permission of NCCN®.       MS-20
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                                                                 NCCN Guidelines™ Version 3.2011                                                                                                                              NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                                 Non-Hodgkin’s Lymphomas                                                                                                                                                  Discussion


      Bendamustine is an alkylating agent with a low cross-resistance with                                                           Relapsed or Refractory Disease
      other alkylating agents (chlorambucil, cyclophosphamide, ifosfamide)                                                           The FCR regimen also induced higher response rates in previously
      and fludarabine. In a pivotal phase III randomized study (n = 319),                                                            treated patients (n = 177).151 The ORR was 73% (complete remission,
      bendamustine was compared to chlorambucil in patients with                                                                     nodular partial remission, partial remissions were achieved in 25%,
      untreated CLL.146, 147 The ORR (68% vs. 31% respectively) and CR                                                               16% and 32% of patients, respectively). Recently, the REACH trial
      rate (31% vs. 2% respectively) were significantly higher for                                                                   compared six cycles FCR with six cycles of FC in 552 patients with
      bendamustine compared to chlorambucil. Median PFS (22 months vs.                                                               previously treated CLL.152 After a median follow-up time of 25 months,
      8.3 months for chlorambucil) and median duration of remission (22                                                              patients in the FCR group had significantly improved PFS (31 months)
      months vs. 8 months with chlorambucil) were also better for                                                                    compared to 21 months for those in the FC group. The ORR was also
      bendamustine. However, there were no differences in OS between the                                                             significantly higher for FCR regimen [70% including 24% CR and 46%
      two groups and the efficacy of bendamustine compared to first-line                                                             PR) vs. 58% including 13% CR and 45% PR for FC regimen). At the
      therapies other than chlorambucil has not yet been established. In a                                                           median follow up of 25 months, OS was not significantly improved for
      multicenter phase II trial (CLL2M) from the German CLL Study Group                                                             FCR. Based on the results of this trial, the FDA approved rituximab in
      (GCLLSG), bendamustine in combination with rituximab (BR) resulted                                                             combination with fludarabine and cyclophosphamide for patients with
      in an ORR was 91% (33% CR and 55% PR) for the entire study                                                                     previously treated CD20-positive CLL.
      population (n = 117) with untreated CLL.148 The GCLLSG is currently
      conducting a comparison of FCR and BR (CLL10).                                                                                 The combination of pentostatin and cyclophosphamide (PC) with or
                                                                                                                                     without rituximab (R) has shown significant activity in previously
      Alemtuzumab, a monoclonal antibody targeting CD52 has been                                                                     treated patients with relapsed or refractory disease.153, 154 In a small
      effective as a first-line treatment for patients with CLL.149, 150 In an                                                       number of previously treated patients (n = 46), the response rates
      international, multicenter randomized study (CAM307), 297 patients                                                             were similar for PC and PCR. However, based on a historical
      were randomized to receive alemtuzumab or chlorambucil as first line                                                           retrospective comparison with PC regimen, the median duration of
      treatment for patients with CLL.150 Alemtuzumab had superior PFS                                                               response for PCR (25 months) is longer than that of PC (7 months) as
      with a 42% reduction in risk of progression or death. The ORR was                                                              well as median survival (44 months for PCR and 16 months for PC).153
      significantly better for alemtuzumab (83% with 24% CR) compared to
      55% with 2% CR for chlorambucil. In patients with del(17p), the ORR                                                            In a phase I-II trial, the combination of oxaliplatin, fludarabine,
      and median PFS were 64% and 11 months respectively for                                                                         cytarabine and rituximab (OFAR) was highly active in
      alemtuzumab which were higher than that observed with chlorambucil                                                             fludarabine-refractory patients with CLL and those with Richter’s
      (20% and 2 months respectively).                                                                                               syndrome.155, 156 The ORRs were 50% in patients with Richter’s
                                                                                                                                     syndrome and 33% in those with fludarabine-refractory CLL.155
                                                                                                                                     Responses were achieved in seven (35%) of 20 patients with del(17p),
                                                                                                                                     two (29%) of seven patients with del(11q), all four patients with trisomy

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                                                                 NCCN Guidelines™ Version 3.2011                                                                                                                              NCCN Guidelines Index
                                                                                                                                                                                                                               NHL Table of Contents
                                                                 Non-Hodgkin’s Lymphomas                                                                                                                                                  Discussion


      12, and two (40%) of five patients with del(13q). The median response                                                          p53 gene mutations.162-164 Subcutaneous alemtuzumab appears as
      duration was 10 months. The ORR in patients 70 years or older (n =                                                             effective and safe as intravenous alemtuzumab in patients with
      14) was 50%.                                                                                                                   advanced stage relapsed or refractory CLL.165-168 In a recent
                                                                                                                                     retrospective analysis, favorable ORR, PFS and OS (49%, 7 and 19
      The GCLLSG conducted a trial combining bendamustine and                                                                        months, respectively) were observed with alemtuzumab in pretreated
      rituximab for patients with relapsed CLL which resulted in an ORR                                                              patients with del 17p.169 However, nodal sites of disease have
      was 77% in 62 evaluable patients with relapsed or refractory                                                                   generally not responded well with single agent alemtuzumab.
      disease.157 Complete and partial responses were seen in 14.5% and                                                              Combinations of alemtuzumab and fludarabine,170, 171 alemtuzumab
      63% of patients respectively. Stable disease was achieved in 18% of                                                            and rituximab,172, 173 cyclophosphamide, fludarabine, alemtuzumab
      patients and 5% had progressive disease.                                                                                       and rituximab (CFAR)174 have shown promising results in patients with
                                                                                                                                     relapsed or refractory disease.
      High-dose methylprednisolone (HDMP) and rituximab is well tolerated
      and an effective therapy for patients with refractory CLL including                                                            Ofatumumab, a human CD20 monoclonal antibody, was found to be
      those with unfavorable prognostic features.158-160 In a study of 28                                                            well tolerated in patients with relapsed or refractory CLL in a phase I/II
      patients with fludarabine refractory CLL, the ORR was 96% (32%                                                                 study.175 In October 2009, ofatumumab was approved by the FDA for
      CR).159 In a follow-up of 37 patients with CLL treated at Mayo Clinic                                                          the treatment of patients with CLL that is refractory to fludarabine and
      with the HDMP and rituximab, 29 (78%) patients had an objective                                                                alemtuzumab, based on the interim analysis of the pivotal
      response including five of nine patients with del(17p).158 Eight (22%)                                                         international clinical trial, which included data from 138 patients with
      patients had a complete clinical response. Three-year survival rate                                                            fludarabine- and alemtuzumab-refractory (FA-ref) CLL or patients with
      was 41%. In one study, although the combination of HDMP and                                                                    fludarabine-refractory CLL with bulky lymphadenopathy (BF-ref).176 In
      rituximab induced superior overall (93%) and complete (14%)                                                                    the interim analysis, ORR was 58% and 47% in the FA-ref and BF-ref
      response rates compared to HDMP alone (43% and 0% respectively)                                                                groups, respectively. The final results from the pivotal trial
      in hea