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Hodgkin's Disease and Non-Hodgkin's Lymphoma

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					Hodgkin’s Disease
      and
 Non-Hodgkin’s
   Lymphoma
         Harold M. Chung, MD
     Associate Professor of Medicine
   VCU Medical Center – MCV Hospitals
  Bone Marrow Transplantation Program

           November 8, 2011
Why Men Can’t Be Babysitters
                  Agenda
   Discuss Hodgkin’s Disease

   Discuss Non-Hodgkin’s Lymphoma

   Classification Systems

   Treatment Options
   2008 Estimated US Cancer Cases*
                                        Men            Women
                                       720,280         679,510

Prostate                  33%                                         31%       Breast
Lung & bronchus           13%                                         12%       Lung & bronchus
Colon & rectum            10%                                         11%       Colon & rectum
Urinary bladder             6%                                          6%      Uterine corpus
Melanoma of skin            5%                                          4%      Non-Hodgkin
                                                                                  lymphoma
Non-Hodgkin                 4%
  lymphoma                                                              4%      Melanoma of skin
Kidney                      3%                                          3%      Thyroid
Oral cavity                 3%                                          3%      Ovary
Leukemia                    3%                                          2%      Urinary bladder
Pancreas                    2%                                          2%      Pancreas
All Other Sites           18%                                         22%       All Other Sites
      *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.
      Source: American Cancer Society, 2008.
   2008 Estimated US Cancer Deaths*
                               Men           Women
                              291,270        273,560
Lung & bronchus   31%                                       26%    Lung & bronchus
Colon & rectum    10%                                       15%    Breast
Prostate           9%                                       10%    Colon & rectum
Pancreas           6%                                         6%   Pancreas
Leukemia           4%                                         6%   Ovary
Liver & intrahepatic 4%                                       4%   Leukemia
   bile duct                                                  3%   Non-Hodgkin
Esophagus          4%                                                lymphoma
Non-Hodgkin         3%                                        3%   Uterine corpus
  lymphoma                                                    2%   Multiple myeloma
Urinary bladder    3%                                         2%   Brain/ONS
Kidney             3%                                       23%    All other sites
All other sites   23%
                          ONS=Other nervous system.
                          Source: American Cancer Society, 2008.
WHO/REAL Classification of Lymphoid Neoplasms
B-Cell Neoplasms
                                                                          Mature (peripheral) T neoplasms
  Precursor B-cell neoplasm
                                                                                  T-cell chronic lymphocytic leukemia / small
       Precursor B-lymphoblastic leukemia/lymphoma                                    lymphocytic lymphoma
          (precursor B-acute lymphoblastic leukemia)                              T-cell prolymphocytic leukemia
  Mature (peripheral) B-neoplasms                                                 T-cell granular lymphocytic leukemiaII
  B-cell chronic lymphocytic leukemia / small lymphocytic                         Aggressive NK leukemia
          lymphoma                                                                Adult T-cell lymphoma/leukemia (HTLV-1+)
  B-cell prolymphocytic leukemia                                                  Extranodal NK/T-cell lymphoma, nasal type#
  Lymphoplasmacytic lymphoma‡                                                     Enteropathy-like T-cell lymphoma**
  Splenic marginal zone B-cell lymphoma
                                                                                  Hepatosplenic γδ T-cell lymphoma*
          (+ villous lymphocytes)*
                                                                                  Subcutaneous panniculitis-like T-cell lymphoma*
  Hairy cell leukemia
                                                                                  Mycosis fungoides/Sézary syndrome
  Plasma cell myeloma/plasmacytoma
  Extranodal marginal zone B-cell lymphoma of MALT type                           Anaplastic large cell lymphoma, T/null cell,
  Nodal marginal zone B-cell lymphoma                                                 primary cutaneous type
          (+ monocytoid B cells)*                                                 Peripheral T-cell lymphoma, not otherwise characterized
  Follicular lymphoma                                                             Angioimmunoblastic T-cell lymphoma
  Mantle cell lymphoma                                                            Anaplastic large cell lymphoma, T/null cell,
  Diffuse large B-cell lymphoma                                                       primary systemic type
       Mediastinal large B-cell lymphoma                                  Hodgkin’s Lymphoma (Hodgkin’s Disease)
       Primary effusion lymphoma†                                            Nodular lymphocyte predominance Hodgkin’s lymphoma
  Burkitt’s lymphoma/Burkitt cell leukemia §
                                                                             Classic Hodgkin’s lymphoma
T and NK-Cell Neoplasms
                                                                                  Nodular sclerosis Hodgkin’s lymphoma (grades 1 and 2)
  Precursor T-cell neoplasm
       Precursor T-lymphoblastic leukemia/lymphoma                                Lymphocyte-rich classic Hodgkin’s lymphoma
          (precursor T-acute lymphoblastic leukemia                               Mixed cellularity Hodgkin’s lymphoma
                                                                                  Lymphocyte depletion Hodgkin’s lymphoma
‡ Formerly known as lymphoplasmacytoid lymphoma or immunocytoma
IIEntities formally grouped under the heading large granular lymphocyte           †Not described in REAL classification
  leukemia of T- and NK-cell types
                                                                                  § Includes the so-called Burkitt-like lymphomas
* Provisional entities in the REAL classification
                                                                                  ** Formerly known as intestinal T-cell lymphoma
                                                                                  # Formerly know as angiocentric lymphoma
Hematopoietic System
                 B cell malignancies

                         Lymph node,        Lymph node,
                         lymph, blood,      lymph, blood,
Bone marrow                                                    Bone marrow
                         bone marrow        bone marrow


                     Progressive B lymphocyte maturation


Lymphoid stem cell        Maturing B cell    Mature B cell        Plasma cell
                          many stages

Pre-B acute lympho-      B cell lymphoma    Chronic lympho-   Multiple myeloma
                                            cytic leukemia
blastic leukemia
Boys Need Parents
 Hodgkin’s Disease/Lymphoma
       In the Beginning
First described in 1832 by Dr. Thomas Hodgkin

Neoplasm of B lymphocytes – large pleomorphic prominent
nucleolus in a halo - Hodgkin cells

Reed-Sternberg cell – binucleate Hodgkin cell with owl eye
appearance

Classification:
          Classical Hodgkin’s
                  Nodular sclerosis – low grade
                  Mixed cellularity
                  Lymphocyte rich classical                  1798-1866
                  Lymphocyte depleted. – high grade

        Nodular lymphocyte-rich Hodgkin’s
    Hodgkin’s Disease/Lymphoma
          In the Beginning
   Bimodal age distribution
       first peak between 2nd - 3rd decade of life
       second peak between 5th - 6th decade of life

   Male: Female 2:1 in kids, adults almost equal M:F

   Mixed cellularity (MC) Hodgkin’s Disease is more
    common at younger ages

   More common in immune deficiency patients
    Hodgkin’s Disease/Lymphoma
          In the Beginning
   Accounts for ~ 30% of all malignant lymphomas

   Composed of two different disease entities:

        Lymphocyte-predominant Hodgkin’s (LPHD), making up
              ~ 5% of cases

        Classical HD, representing ~ 95% of all HDs.

    A common factor of both HD types is that neoplastic
    cells constitute only a small minority of the cells in
    the affected tissue, often corresponding to < 2% of
    the total tumor
 Hodgkin’s Disease/Lymphoma
       In the Beginning
Fatal disease with 90% of untreated patients dying
within 2 to 3 years

With chemotherapy, >80% of patients suffering from
HD are cured.

Pathogenesis of HD is still largely unknown.

HD nearly always arises and disseminates in lymph
nodes
     Hodgkin’s Disease/Lymphoma
            Interest tidbits



   Pel-Ebstein Fevers

   Pain with alcohol consumption
    Hodgkin’s Disease/Lymphoma
        Clinical Presentation
   Nontender lymph nodes enlargement (localized)
       neck and supraclavicular area
       mediastinal adenopathy
       other (abdominal, extranodal disease)
   systemic symptoms (B symptoms)
       fever
       night sweats
       unexplained weight loss (10% per 6 months)
   other symptoms
       fatigue, weakness, pruritus
       cough , chest pain, shortness of breath, vena cava
        syndrome
       abdominal pain, bowel disturbances, ascites
       bone pain
    Hodgkin’s Disease/Lymphoma
        Clinical Presentation
SIGNS & SYMPTOMS                    % OF PATIENTS
Lymphadenopathy                           90
Mediastinal mass                          60
“B” symptoms                              30
   Fever, weight loss, night sweats
Hepatosplenomegaly                        25

   Most commonly involved lymph nodes are the
    cervical and supraclavicular in 75%
   Bone marrow is involved in 5% of patients
Reed-Sternberg Cells
CD 30 Immunostain
      Hodgkin’s Disease/Lymphoma
          Clinical Presentation
Stage Definition

  I         Involvement of a single lymph node region (I) or of a single extralymphatic organ or site (IE)

 II         Involvement of two or more lymph node regions on the same side of the diaphragm (II) or
            localized involvement of an extralymphatic organ or site and one or more lymph node
            regions on the same side of the diaphragm (IIE)

 III        Involvement of lymph node regions on both sides of the diaphragm (III) which may be
            accompanied by involvement of the spleen (IIIS) or by localized involvement of an
            extralymphatic organ or site (IIIE) or both (IIISE)

 IV         Diffuse or disseminated involvement of one or more extra lymphatic organs or tissues with
            or without associated lymph node involvement

B symptoms: fever > 38ºC for three consecutive days, drenching night sweats or unexplained loss 10% or more of
    weight the preceding 6 months
    Hodgkin’s Disease/Lymphoma
             Treatment

   Unfavorable prognostic factors:
     - Stage IIIB, IV
     - B symptoms
     - Bulky disease
     - High ESR >50
    Hodgkin’s Disease/Lymphoma
             Treatment
   Long term effects of treatment should be
    taken into consideration:
      - Treatment-related second neoplasms
              (i.e. AML, NHL and breast cancer)
      - Infertility
      - Growth consideration
      - Long-term organ dysfunction (i.e.,
              thyroid, heart, lung)
    Hodgkin’s Disease/Lymphoma
             Treatment
   Adolescent patients who have achieved
    maximum growth can be treated as adult
    patients

   Chemotherapy alone protocols for
    localized disease has been used in
    developing countries with some success


                    Lobo-Sanahuja F: Medical and Pediatric Oncology 22(6);1994
Hodgkin’s Disease/Lymphoma
         Treatment
With appropriate treatment about 85% of
 patients with Hodgkin’s disease are curable

   I A,B                Radiation Therapy
   II A                 Combination Chemo +
                         Radiotherapy
   IIB; IIIA,B; IVA,B   Combination Chemo
                         (+/- radiotherapy)
    Hodgkin’s Disease/Lymphoma
             Treatment
   Radiation therapy (35-40 Gy) 80-90% RC
       Mantle field
       Paraaortic field
       Pelvic field


   Combination chemotherapy
       ABVD                   80% RC
       BEACOPP                90% RC
Hodgkin’s Disease/Lymphoma
    Treatment Progress
                                    ABVD vs
                                    MOPP vs
                                   MOPP/ABVD
    Failure-free survival




Canellos et al,
NEJM, 2002
                            Overall survival
Hodgkin’s Disease/Lymphoma
         Treatment
    Almost no MDS/AML (at 15 years 1.0%)
     (Valagussa ’86)

    Oligospermia – 50% complete recovery

    Median FSH in normal range (Viviani ’85)

    Bleomycin-related pulmonary toxicity ~1/3
     have reduced PFT but recover in 3 months;
     ~20% omit Bleomycin.
 Cancer and Leukemia Group B 8251 and 8952:
Recurrent Hodgkin's Disease by Treatment




                      Canellos, G. P. et al. J Clin Oncol; 22:1532-1533 2004
Hodgkin’s Disease/Lymphoma – Advanced Stage
         ABVD vs MEC vs Stanford V
Hodgkin’s Disease/Lymphoma
 Actual Treatment Progress
                   100 IIIIIIIIIIIIIIII
                                   IIIIIIIII
                                      IIIII III
                                          IIIII IIIIIII
                                               IIII IIIII
                                                   IIIIII IIIIIIIIIII
                                                         IIIII          III
                                                             IIIIIII IIIIIIIIIIIIIIIII
                                                                    IIIIII                  IIIIIIIIIIIIIIIIIIIIIII
                                                                          IIIIIII                                   IIIIIIIIIIIIIIIIIIIIIIIIIIIII
                                                                                 IIIIII                                                           IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII
 PROBABILITY (%)



                                                                                       IIIIII                                                                                                IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII IIII IIII II IIII
                                                                                                                                                                                                                                                                     I                    I I          IIII III
                      80                                                                     IIIIIIIII
                                                                                                      IIIIIIIII
                                                                                                               IIIIIIII
                                                                                                                        IIIIIII
                                                                                                                               IIIIIII
                                                                                                                                      IIIIIIIII
                                                                                                                                               IIIIIIII
                                                                                                                                                       IIIIIII
                                                                                                                                                               IIIIIIII
                                                                                                                                                                      IIIIIIII
                                                                                                                                                                              IIIIIIIIII
                                                                                                                                                                                        IIIIIIIIII
                                                                                                                                                                                                  IIIIIII
                      60                                                                                                                                                                                 IIIII
                                                                                                                                                                                                             IIIIIII
                                                                                                                                                                                                                   IIIIIII
                                                                                                                                                                                                                         IIIIIIIII
                                                                                                                                                                                                                                  IIIIIIIII
                                                                                                                                                                                                                                           IIIIII
                                                                                                                                                                                                                                                 IIII
                                                                                                                                                                                                                                                    IIII
                                                                                                                                                                                                                                                      II
                                                                                                                                                                                                                                                        IIIIII
                                                                                                                                                                                                                                                             IIIIII
                                                                                                                                                                                                                                                                I II
                                                                                                                                                                                                                                                                     I
                                                                                                                                                                                                                                                                   IIIIIII
                                                                                                                                                                                                                                                                     I IIII
                      40                                                                                                                                                                                                                                                    III
                                                                                                                                                                                                                                                                            I III II
                                                                                                                                                                                                                                                                                          I
                                                                                                                                                                                                                                                                                    III IIII II
                                                                                      Expected Survival                                                                                                                                                                                       I II
                                                                                                                                                                                                                                                                                                 III
                                                                              I       HD Survival                                                                                                                                                                                                  I   IIII III

                      20                                                   I          Observed Survival


                         0
                             0                                    5                                     10                                       15                                       20                                       25                                       30                                35
                                                                                                                                                        YEARS
                                                                                                                                                                                                                                                                       Stanford, Hoppe et al
Causes of Death among 2733 Patients
 with Hodgkin’s Disease/Lymphoma

  Hodgkin lymphoma    383   41.2%
  Secondary cancers   200   21.5%
  Cardiovascular      148   15.9%
  Pulmonary           41     4.4%
  Infection           35     3.8%
  Trauma/Suicide      16     1.7%
  MDS                  11    1.2%
  Other/Unknown       96    10.3%
  Total               930   100.0%
                              Stanford, Hoppe et al
      SECOND TUMORS LONG-TERM SURVIVORS OF
           HODGKIN’S DISEASE/LYMPHOMA
        (PRIMARY RT OR COMBINED MODALITY)
                             # pts    Actuarial Incidence   Median Follow-up

   Princess Margaret        865      18% (20 years)        20 years
    Hospital, Toronto

   US Pediatric Series      1380     26.3% (30 years)      17 years
    (JCO 21:4386, 2003)

   Harvard/Joint Center     1319     35% (25 years)        12 years
    (Blood 100:1989, 2002)

   Netherlands              1253     27.7% (25 years)      14.1 years
    (JCO 18:481, 2000)

   NIH Survey of            32,591   21.9% (25 years)      10 years
    Registries and Seer
    (JCO 20:3474, 2002)
   HODGKIN’S DISEASE/LYMPHOMA
       SALVAGE REGIMENS
Regimen                        Patients             CR/PR to ASCT
DHAP                           102                  87%         60%
(dexamethasone, ara-C, cisplatin)

Mini-BEAM                      89                   77%        82%
(BCNU, etoposide, ara-C, melphalan; 2 series)

Dexa-BEAM                      225                  75%        75%
(above plus dexamethasone; 3 series)

GDP                            34                   62%        88%
(gemcitabine, dexamethasone, oxaloplatin)

ICE                            65                   84%        86%
(ifosfamide, carboplatin, etoposide)

GND                            38                   64%        --
(gemcitabine, vinorelbine, liposomal doxorubicin)
CALGB 50203 Treatment Plan

AVG:

    Doxorubicin 25mg/m2 IV d1, D15
    Vinblastine 6mg/m2 IV d1, d15
    Gemcitabine 1,000mg/m2 IV d1, d15
          800mg/m2 if gr. 4  ANC/plt ct in 2.6 pts

 Repeat every 28 days x 6 cycles
HODGKIN’S DISEASE/LYMPHOMA
Autologous Transplants as Primary Therapy
   1996 - 2002:    7 uncontrolled trials
    Event-free survival        242/337 patients     72%
    Median follow-up           42-46 months (30-86 months)

   2003:      Prospective Randomized Trial
               (JCO 21:2320, 2003)

                              163
              83 ASCT                80 (4 more cycles ABVD)
CR            89%                    92%
RFS (5 years) 88%                    94%
OS (5 years) 88%                     88%    [no difference]
   PROBABILITY OF SURVIVAL AFTER
  AUTOTRANSPLANTS FOR RELAPSED
HODGKIN’S DISEASE/LYMPHOMA, 1996-2001
                 100
                                                                  CR1 (N =
                                                                  226)
                 80
PROBABILITY, %




                                                                                  CR2+ (N =
                                                                                  733)
                 60

                                            Never in remission (N = 823)
                 40
                                                                           Relapse (N = 1,744)

                 20

                           P = 0.0001
                  0
                       0            1   2              3           4              5              6
                                                   YEARS
    ALLOTRANSPLANTATION
 HODGKIN’S DISEASE/LYMPHOMA

                      EBMTR   IBMTR   JOHNS HOPKINS
Patients                45     100          53
Median age              29      28          28
Event-free
Survival               15%     15%          26%
Median F/U (mos.)      31      36           60
Overall Survival       25%     21%          30%
Treatment Mortality    48%     61%          43%
GVH -
 Acute                 63%     35%          45%
 Chronic               55%     45%          17%
HODGKIN’S DISEASE/LYMPHOMA
  Non-Myeloablative Allotransplants
        7 series (2004-2008)

 Total Patients = 547 (1.5 – 5-year follow-up)

 Relapse                         43-64%
 PFS                             18-32%
 OS                              28-61%
 Treatment-Related Mortality     5-24%

 (The majority failed autotransplantation)
HODGKIN’S DISEASE/LYMPHOMA
 Residual Masses By PET scan
    5 series (2001-present)

  Total Patients     204          Relapses

  PET negative       144          18 (12.5%)
  after therapy

  PET positive        60          35 (58.3%)
  after therapy

           ? 40% false positive rate
                  CTN 0701

   Tandem Transplant

     Modeled after myeloma data
     High-risk Hodgkin’s Disease

     University of Nebraska – Julie Vose, MD
Monoclonal Antibodies
 MDX-060 - Anti-CD30 target
Anti-CD30 antibody
Medarex 2004 – Orphan Drug Status

Hodgkin’s Disease/Lymphoma
Anaplastic Large Cell NHL
           SGN-35 (Seattle Genetics)




A Younes et al, N Engl J Med 2010;363:1812-21.
                Good Ideas
   Cadence Pharmaceuticals
     Ofirmev
     November 2, 2010 – FDA Approval

     IV acetaminophen

     $800/IV dose
Boys Need Parents
Non-Hodgkin’s Lymphoma

      Deep Breath…

       Stand up…

        Stretch…
 Histologic Classification of
 Non-Hodgkin’s Lymphomas
1. Rappaport             -   1966
2. Lukes and Collins     -   1974
3. Kiel                  -   1974
3. Dorfman               -   1974
4. Bennet et al.,        -   1974
5. Lennert               -   1974
6. WHO                   -   1976
7. Working Formulation   -   1982
8. REAL                  -   1994
9. WHO                   -   1999
      Non-Hodgkin’s Lymphoma
       Rappaport Classification
           Nodular (follicular)   Diffuse




Indolent                                       Aggressive




                Small cell        Large cell
Non-Hodgkin’s Lymphoma
 Rappaport Classification


       Small cell, follicular
       Small cell, diffuse
       Large cell, follicular
       Large cell, diffuse
        Non-Hodgkin’s Lymphoma
          Immunophenotyping
   Immunohistochemistry
   Immunofluorescence
   Flow cytometry

   Identification of CD’s (cluster determinants)
     CD5 = T cell type
     CD20 = B cell type
Non-Hodgkin’s
 Lymphoma
   Cluster
Determinants
    Non-Hodgkin’s Lymphoma
Lukes-Collins & Kiel Classifications


   Lukes-Collins System – US
   Kiel System – Europe

   Differentiation of B-cell and T-cell lymphomas
      Non-Hodgkin’s Lymphoma
       Working Classification
   Developed in 1980’s
   NCI Investigators reviewed Rappaport, Lukes-
    Collins, and Kiel systems
   n=1175

   Goal was to clarify… now a new system!
   No consideration to B-cell or T-cell typing
   Goal was to group lymphomas according to
    aggressiveness (low, intermediate, high)
        Non-Hodgkin’s Lymphoma
         Working Classification
   Low Grade
       Small Lymphocytic
       Follicular small-cleaved cell
       Follicular mixed small-cleaved and large cell
   Intermediate Grade
       Follicular large cell
       Diffuse small cleaved cell
       Diffuse mixed small and large cell
       Diffuse large cell
   High Grade
       Large cell immunoblastic
       Lymphoblastic
       Small non-cleaved cell (Burkitt's and non-Burkitt's type)
  Hodgkin                        Non Hodgkin Lymphoma
 Lymphoma
Classical HL         Indolent           Aggressive             Highly
(NS, MC, LR,                                                 Aggressive
     LD)
                    B cell                B cell                B cell
  Nodular         Follicular             DLBCL                  Pre-B
lymphocyte         SLL/CLL            FLg3 and tFL          lymphoblastic
Predominant      Marginal zone          Mantle cell            Burkitt
  (NLPHL)          LP (WM)           Primary effusion

                   T/NK cell             T/NK cell            T/NK cell
               Mycosis fungoides           ALCL                 Pre-T
               Sezary syndrome     Angioimmunoblastic       lymphoblastic
               Primary cut ALCL    Subq panniculitis-like
                                        Blastic NK
                                     Extnanodal NK/T
                                           nasal
                                     Enteropathy-type
                                      Hepatosplenic
 Multiple
                                        PTCL nos
 Myeloma
      Non-Hodgkin’s Lymphoma
        REAL Classification
   Revised European-American Lymphoma
   Mid 1990’s – International Lymphoma
    Study Group (informal group of hematopathologists)

   Using immunophenotype, cytogenetics,
    molecular diagnostics
   Reclassified lymphomas by diagnostic
    criteria and not by risk categories
       Frequency of NHL Subtypes in Adults

                        Mantle cell (6%)

      Peripheral T-cell (6%)
                                                         Indolent (35%)
Other subtypes with a
frequency 2% (9%)




  Composite
  lymphomas (13%)




                                                  Diffuse large
Armitage et al. J Clin Oncol. 1998;16:2780–2795
                                                   B-cell (31%)
        Non-Hodgkin’s Lymphoma
           WHO Classification
   Bruce Cheson, MD and the NCI International
    Working Group reported in January 1999
   Adopted in 2001, Revised in 2008

   Discredited the Working (non-REAL) Classification
   Based on REAL (Non-working) Classification



                           Cheson et al. J Clin Oncol. 1999 Apr;17(4):1244
WHO/REAL Classification of Lymphoid Neoplasms
B-Cell Neoplasms
                                                                          Mature (peripheral) T neoplasms
  Precursor B-cell neoplasm
                                                                                  T-cell chronic lymphocytic leukemia / small
       Precursor B-lymphoblastic leukemia/lymphoma                                    lymphocytic lymphoma
          (precursor B-acute lymphoblastic leukemia)                              T-cell prolymphocytic leukemia
  Mature (peripheral) B-neoplasms                                                 T-cell granular lymphocytic leukemiaII
  B-cell chronic lymphocytic leukemia / small lymphocytic                         Aggressive NK leukemia
          lymphoma                                                                Adult T-cell lymphoma/leukemia (HTLV-1+)
  B-cell prolymphocytic leukemia                                                  Extranodal NK/T-cell lymphoma, nasal type#
  Lymphoplasmacytic lymphoma‡                                                     Enteropathy-like T-cell lymphoma**
  Splenic marginal zone B-cell lymphoma
                                                                                  Hepatosplenic γδ T-cell lymphoma*
          (+ villous lymphocytes)*
                                                                                  Subcutaneous panniculitis-like T-cell lymphoma*
  Hairy cell leukemia
                                                                                  Mycosis fungoides/Sézary syndrome
  Plasma cell myeloma/plasmacytoma
  Extranodal marginal zone B-cell lymphoma of MALT type                           Anaplastic large cell lymphoma, T/null cell,
  Nodal marginal zone B-cell lymphoma                                                 primary cutaneous type
          (+ monocytoid B cells)*                                                 Peripheral T-cell lymphoma, not otherwise characterized
  Follicular lymphoma                                                             Angioimmunoblastic T-cell lymphoma
  Mantle cell lymphoma                                                            Anaplastic large cell lymphoma, T/null cell,
  Diffuse large B-cell lymphoma                                                       primary systemic type
       Mediastinal large B-cell lymphoma                                  Hodgkin’s Lymphoma (Hodgkin’s Disease)
       Primary effusion lymphoma†                                            Nodular lymphocyte predominance Hodgkin’s lymphoma
  Burkitt’s lymphoma/Burkitt cell leukemia §
                                                                             Classic Hodgkin’s lymphoma
T and NK-Cell Neoplasms
                                                                                  Nodular sclerosis Hodgkin’s lymphoma (grades 1 and 2)
  Precursor T-cell neoplasm
       Precursor T-lymphoblastic leukemia/lymphoma                                Lymphocyte-rich classic Hodgkin’s lymphoma
          (precursor T-acute lymphoblastic leukemia                               Mixed cellularity Hodgkin’s lymphoma
                                                                                  Lymphocyte depletion Hodgkin’s lymphoma
‡ Formerly known as lymphoplasmacytoid lymphoma or immunocytoma
IIEntities formally grouped under the heading large granular lymphocyte           †Not described in REAL classification
  leukemia of T- and NK-cell types
                                                                                  § Includes the so-called Burkitt-like lymphomas
* Provisional entities in the REAL classification
                                                                                  ** Formerly known as intestinal T-cell lymphoma
                                                                                  # Formerly know as angiocentric lymphoma
Non-Hodgkin’s Lymphoma
     Specific Types


  Time For A Deep Breath…

       or an Excedrin
                     Follicular Lymphoma
                       Mbr (major breakpoint region, 150 bp)

              Bcl2                                                     Chromosome 18



                                                                 C      Chromosome 14

                          JH

                     Double strand DNA break by RAG1/2

                                 Translocation takes place in B cell precursors.


            Bcl2                                      C           t(14;18) translocation




                                                               Transformation takes place
                                                               during B cell activation in GC.


   bcl2     E            C                         C    3’E

Unregulation of Bcl2 expression by IgH enhancers
                          Bcl2 inhibits apoptosis
                          Pro-survival oncogene

          mitochondrion
                                Bax, Bad

                                                         Pro-caspase-9
                          cytochrome c
Bcl-2, Bcl-XL
                                           Apaf-1
                         dATP or ATP

                Apaf-1                                   Caspase-9




                                         Pro-caspase-3    Caspase-3



                                                          Apoptosis
 Over-expression of Bcl-2 may prevent the apoptosis
             of germinal center B cells
                                                                            Plasma cells

                           Germinal center             Germinal center

       activation



                                                         apoptosis
                                                                         Memory cells




                           Germinal center            Germinal center
IgH-Bcl2


           activation


                                                      follicular lymphoma
      Most follicular lymphoma Ig V regions contain
                                                      Apoptosis inhibited
      somatic hypermutation.
        Non-Hodgkin’s Lymphoma
          Follicular Lymphoma
   Low-grade lymphoma
     Grade 1 – Small cell
     Grade 2 – Mixed cell

     Grade 3 – Large cell



   Indolent in growth
   Chemotherapy sensitive
   Incurable
         Non-Hodgkin’s Lymphoma
    Cutaneous T-Cell (Mycosis Fungoides)
   Low-grade/Indolent lymphoma
   Radiation therapy sensitive
   Total Skin Electron Beam Therapy

   Control disease for years
   Peripheralization of lymphoma cells = Sezary Cell
   Sezary Syndrome
      Non-Hodgkin’s Lymphoma
         Diffuse Large Cell
   Very Aggressive
   Curable if chemo-sensitive upfront, not so
    if chemo-refractory or relapses within 6
    months

   Most common of all lymphomas
   Accounts for ~ 31% of all lymphomas
      Non-Hodgkin’s Lymphoma
            Mantle Cell
   Aggressive
   Accounts for ~ 6% of all lymphomas
   Incurable with standard-dose therapy
   Stem cell transplant is offered often as
    front-line consolidation treatment in
    “younger” patients
Mantle Cell Lymphoma
Morphology



                    Classical Mantle Cell

  Nodular pattern




  Diffuse pattern   Blastoid Variant
                 Mantle Cell - Treatment

   CHOP + Rituxan
       40 patients (new diagnosis)
      CR 48%, PR 48%

      Molecular CR seen in 36% of
        patients with PCR detectable
        cyclin D1/IgH translocation
      Median PFS 16.6 months, all
        patients relapsed by 36
        months
   No significant difference in PFS
    for patients having a clinical or
    molecular CR


                                        Howard, O et al., JCO, 20 (5):1288
        Non-Hodgkin’s Lymphoma
             Marginal Zone
   Indolent
   Accounts for ~10% of
    all lymphomas
   Subcategories
       MALT (H. pylori)
       Nodal
       Extra-Nodal
       Splenic
Non-Hodgkin’s Lymphoma
   Splenic Lymphoma
      Non-Hodgkin’s Lymphoma
       Primary CNS Lymphoma
   Aggressive with poor outcome
   Accounts for ~ 1-2% of all lymphomas
   Different chemotherapy treatments
   Often requires radiation to the brain:
               Brain dysfunction in younger patients
               Dementia in older patients
  Non-Hodgkin’s Lymphoma
Anaplastic Large Cell Lymphoma
   Aggressive
   Accounts for ~ 2% of all lymphomas

       ALCL ALK-1+ better prognosis, more
        common in younger patients and children

       ALCL ALK-1-negative : as bad as any other
        T-cell lymphoma
   Treatment results of aggressive advanced
   non-Hodgkin’s lymphomas using different
          chemotherapy programs

1. First-generation: CHOP
  - CR: 50-55%. Long-term survival: 35-50 %.

2. Second-generation: mBACOD, ProMACE-CytaBOM
  - CR: 70-80%. Long-term survival: 50-60%.

3. Third-generation: MACOP-B
  - CR: 84%. Long-term survival: 75%
  Non-Hodgkin’s Lymphoma
    Intergroup 0067 Study

                  3-year survival      Mortality
                  ___%________________%___

CHOP                 41                     1
mBACOD               46                     5
ProMACE-CytoBOM      46                     3
MACOP-B              41                     6


                               Southwest Oncology Group
   Non-Hodgkin’s Lymphoma
Treatment of Patients Age over 60

  Program________________5-year survival %

  CHOP                          45
  mBACOD                        39
  ProMACE-CytoBOM               41
  MACOP-B                       23
t
      Non-Hodgkin’s Lymphoma
     Peripheral T-cell Lymphoma


   Aggressive
   Accounts for ~ 7% of all lymphomas
   Very poor prognosis, often associated with
    extra-nodal presentation
   Often requiring salvage treatment and
    transplant
Burkitt’s Lymphoma
          breakpoints

 myc                                     Chromosome 8




   ***                         C        IgH Chromosome 14, 80%
  V(D)J        E        S
                                             IgChromosome 2

           Class switch recombination        Igchromosome 22

 Somatic hypermutation




                                                3’E
 myc                C                  C
          S
                                                                 t(8:14)


                                                           3’E
 myc                          C                      C
           E        S
        Non-Hodgkin’s Lymphoma
             Burkitt’s NHL
   Very Aggressive
   Curable with standard-dose therapy but
    requires very extensive chemotherapy
    protocol
   Translocation t(8,14)
   Specific Hematopathology Finding
       Starry, Starry Night
Burkitt’s Lymhoma
Starry, Starry Night
      Non-Hodgkin’s Lymphoma
         Lymphoblastic NHL

   Very aggressive
   Treatment is with acute lymphocytic
    leukemia regimen
   Often requires high-dose therapy and
    allogeneic transplantation for
    relapsed/refractory disease
      Gamma Delta-T-cell NHL
   Very, very aggressive
   Very poor outcome with standard-dose
    therapy
   High-dose therapy and allogeneic
    transplantation is standard-of-care in first
    remission
   CD57 protein positivity
          Double-Hit Lymphomas

   Multiple gene expressions
     MYC gene
     t(14,18)



   Triple-Hit
     MYC gene
     t(14,18)

     BCL-6 gene
    Non-Hodgkin’s Lymphoma
Aggressive chemotherapy regimens

   Dose-dense CHOP
   CHOP-Bleo
   CEOP-Bleo
   DexaBEAM
   HyperCVAD
BMT for Non-Hodgkin’s Lymphoma
           Indications


1. Refractory disease
2. Relapse
3. High risk in CR
4. Lymphoblastic, Burkitt’s, and gamma
  delta-t-cell lymphomas
 PROBABILITY OF SURVIVAL AFTER
AUTOTRANSPLANTS FOR FOLLICULAR
    NON-HODGKIN LYMPHOMA
                 100

                                                                CR1 (N =
                 80                                             174)
                                              CR2+ (N =
PROBABILITY, %




                                              322)
                 60
                                            Never in remission (N = 418)
                                                                  Relapse (N = 791)
                 40


                 20

                           P = 0.0009
                  0
                       0            1   2     3            4               5          6
                                            YEARS
         PROBABILITY OF SURVIVAL AFTER HLA-
          IDENTICAL SIBLING MYELOABLATIVE
                 TRANSPLANTS FOR
         FOLLICULAR NON-HODGKIN LYMPHOMA
                 100


                                    Never in remission (N =
                 80                 138)
PROBABILITY, %




                                                                      CR1-3 (N =
                                                                      79)
                 60

                                                                       Relapse (N = 193)
                 40


                 20

                           P = NS
                  0
                       0            1            2            3   4         5              6
                                                          YEARS
                   PROBABILITY OF SURVIVAL AFTER
                       AUTOTRANSPLANTS FOR
                   DIFFUSE LARGE CELL LYMPHOMA
                 100


                 80
PROBABILITY, %




                                                     CR1 (N =
                                                     438)
                 60
                                                                CR2+ (N =
                                                                651)
                 40
                                            Relapse (N = 1,443)

                 20                            Never in remission (N = 986)

                           P = 0.0001
                  0
                       0            1   2      3           4            5     6
                                            YEARS
         PROBABILITY OF SURVIVAL AFTER HLA-
          IDENTICAL SIBLING MYELOABLATIVE
                  TRANSPLANTS FOR
            DIFFUSE LARGE CELL LYMPHOMA
                 100


                 80
PROBABILITY, %




                 60


                 40                                     Relapse (N = 144)

                                                       CR1-3 (N =
                 20                                    56)
                                                    Never in remission (N = 133)
                           P = NS
                  0
                       0            1   2    3         4           5               6
                                            YEARS
Monoclonal Abs - Rituxan
Radioimmunotherapy with Y-90
         Zevalin

 Monoclonal                      Ibritumomab
  antibody                            Murine monoclonal
                                       antibody parent of
                                       Rituximab


                                 Tiuxetan
                                      Conjugated to
                                       antibody, forming strong
                                       urea-type bond
                                      Stable retention of Y-90
    Chelator
                              Beta
          Y-90 radionuclide   radiation
      New Treatment Options
   Velcade + Flavoperidol – MCC Trial
   Velcade + Darinaparsin
                Conclusion
   Discussed Hodgkin’s Disease

   Discussed Non-Hodgkin’s Lymphoma

   Discussed Classification Systems

   Discussed Treatment Options

				
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