Hematologic Malignancies by yaosaigeng

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									     Hematologic Malignancies

WFUBMC Pediatric Residency Noon Conference
        Pamela Bensimhon, MD
                4/28/08
Pediatric Cancer Distribution

                                Leukemia (31%)
                                Lymphoma (14%)
                                CNS
                                NBL
                                Retinoblastoma
                                Wilms/ Ren al
                                Hepatic
                                Bone
                                RMS/ NRSTS
                                Germ cell
                                other
The preceeding stats reflect all of childhood, but the
incidence actually varies with age
                                                Hematologic Cancer

Leukemia   (~70%)                                           Lymphoma (~30%)

                     Acute (~99%)                                                 Hodgkins

  Lymphoblastic   (80%)           Myelogenous    (20%)               Classical             Nodular Lcyte Pred
      2500 cases/yr                 800-900 cases/yr


           Pre-B    (80%)                   AML                 Nodular Sclerosing

           T cell   (20%)                APL    (10%)                             NHL    (45%)


            Mature B
                                                                     Mature                       Precurser
                    Chronic (~1%)

                                                                         T Cell                  Lymphoblastic
                            CML

                                                                       Anaplastic

                                                                         B Cell

                                                                              Burkitts

                                                                       Diffuse Large B cell
                              Leukemogenesis
• First hit can occur in utero
    – Translocations can be found on guthrie cards
    – Time to development variable                                           DNA Damage
                                                                                    First Hit
         • Requires second hit                                       Congenital or accumulated over years
• Predisposing factors
    – Down syndrome                                              Differentiation or Maturation Block
                                                                                  Second Hit
    – Chromosome fragility syndromes                                      Time to second hit variable
         • Bloom Syndrome/ Fanconi Anemia/ AT
    – Twins/ siblings                                                 Proliferation and Survival
         • Monozygotic twin of <5yo with Leuk has 20% risk                    Changes
         • Sibings have 4-fold increased risk from general pop
    – Ionizing radiation/ Drugs                                     Clinical Evolution of Disease
    – Syndromes:
         • Li-Fraumeni, Klinefelter, Schwachman-Diamond, Kostman,
           Diamond-Blackfan, Ataxia-Telangiectasia, NF, etc
      Acute Leukemia: Classic Presentations
• 3 yo lethargic, pale, refusing to walk, with fevers and
  some bruising. WBC 4.5, Hb 9.5, plts 50K
• 16yo boy with cough, decreasing stamina on the
  soccer field, has large medistinal mass and high WBC
• 13yo with fatigue, fever and menorrhagia, has
  gingival hyperplasia, an orbital mass and a WBC of
  110K, plt ct 40K
      Acute Leukemia: Classic Presentations
• 3 yo lethargic, pale, refusing to walk, with fevers and some
  bruising. WBC 4.5, Hb 9.5, plts 50K
   – Pre B-cell ALL
• 16yo boy with cough, decreasing stamina on the soccer
  field, has large medistinal mass and high WBC
   – T-cell ALL
• 13yo with fatigue, fever and menorrhagia, has gingival
  hyperplasia, a WBC of 110K, plt ct 40K, and an orbital
  mass.
   – AML
      Acute Leukemia: Clinical Presentation
• Most common                       • Other common signs and sx
   – Lethargy                          – Bruising/ bleeding
   – Fever                             – Pallor
                                       – HSM, LAD
• “Classic”
                                    • Less common considerations:
   – Limp or refusal to walk            –   CNS
       • From periosteal or joint       –   Chloromas
         infiltration                   –   Testicular disease
   – Medistinal mass                    –   SVA syndrome from LAD
       • Thymus in T-cell disease       –   Skin, renal, GI, etc
                           Leukemic Lines




Lucent metaphyseal band. When seen in children over two years of age, if bilateral,
                       are usually indicative of leukemia.
                      Leukemia: Work-Up
• CBC can look like almost anything
    – WBC can be normal, low, or high (>50K in ~ 20%)
        • May be neutropenic regardless of WBC
    – Hb usually <11 (80%)
• Platelets are the most reliable
    – 92% have low platelet counts
    – 75% <100K
• +/- Blasts
    – Sometimes misread as atypical lymphocytes
                    Leukemia: Work-Up
• LDH/ Uric acid
   – Usually increased with higher WBC or more extrameduallry dz
• Coag profile
   – Factors V, IX, X and fibrinogen can be decreased in AML
What were this patient’s presenting symptoms?
What were this patient’s presenting symptoms?

Nonproductive cough x 2 weeks not responsive
to OTC cough medicine. No limitation of normal
     activity or noted shortness of breath.
                        Leukemia: Workup
• CXR
   – Mediastinal mass must be r/o before patient is sedated for bone
     marrow
        • Can be surprisingly asymptomatic
        • Compression of airway by >50% or orthopnea portend poor tolerance of
          anesthesia
• Bone Marrow/ Flow cytometry
   – >5% blasts suggests malignant process
   – >25% blasts defines leukemia
        • This is the differentiating factor between ALL and lymphoblastic lymphoma
• CSF
    BM/ Flow Results: A Fork in the Road
                                              Bone Marrow

                                             >25% blasts      <25% blasts and RE dz

                                                  Leukemia   Lymphoblastic Lymphoma

            Lymphoblastic                                          Myelogenous


Mature B             T cell                   Pre-B          AML                 APL


Burkitt's                   Risk Stratification
                   ALL Risk Stratification
• Initial risk grouping:                • Subsequent risk assessment:
    – Standard vs High                     – Based on
    – High risk features                       • Response to induction
        • WBC  50K                            • Cytogenetics
        • Age <1 or  10 yrs                   • CNS disease
        • T cell disease
                                           – Determines further therapy
    – Determines 3 vs 4 drug
      induction therapy
    – Infants go on separate protocol
                    Subsequent Risk Assessment:
                         Prognostic Factors
           Positive                    Poor                         Bad
  Triple trisomy 4, 10, 17      MLL rearrangement        Philadelphia chrom (9;22)
  TEL-AML translocation        Slow Early Responder      Hypodiploidy (<44 chrom)
 Hyperdiploid (>50 chrom)     Minimal Residual Disease        Induction failure
  Rapid Early Responder            CNS disease
No Minimal Residual Disease
      No CNS disease
                                                          Portends VERY high risk
                                                                 stratification
What happened in the 1960s?
       What happened to Improve Outcome?
• 1950s
   – Multidrug therapy to avoid drug resistance
        • First remission achieved, but not durable
• 1960s
   – CNS therapy regardless of CNS disease status
        • Increased long term survival by ~ 50%
• 1970-1990s
   – Improvements in supportive care
   – Chemotherapy adjustments
                              ALL Therapy
• Induction to achieve remission
     – 3 vs 4 drugs
• CNS prophylaxis or therapy
     – IT chemotherapy
     – +/- XRT
•   Consolidation
•   Intermittent intensification of therapy
•   Long maintenance phase
•   Total therapy
     – 2.5 yrs for girls
     – 3.5 yrs for boys
                           ALL Outcomes
•   Low risk:     90-95%
•   Standard risk    80%
•   High risk       70%
•   Very high risk 35%

• Relapsed disease:
    – Outcome dependent on time to and site of relapse
        • Extramedullary relapse >2.5 yrs from initial dx: 77% EFS @ 5 yrs
        • Bone marrow relapse <2 years from initial dx: 7% EFS @5 yrs
                           ALL Late Effects
• Neuropsychologic issues
    – Intrathecal therapy, cranial XRT
• AVN (esp in adolescent males)
    – Steroids
• Cardiomyopathy
    – Anthracylcines (esp preteen girls)
• Infertility
    – Cyclophosphamide, testicular XRT
• Secondary AML, brain tumors
    – Etoposide, cranial XRT
• Endocrine abnormalities (obesity, precocious puberty, short stature)
    – Cranial XRT
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             Back to the Fork in the Road
                                              Bone Marrow

                                             >20% blasts      <20% blasts and RE dz

                                                  Leukemia   Lymphoblastic Lymphoma

            Lymphoblastic                                          Myelogenous


Mature B             T cell                   Pre-B          AML                 APL


Burkitt's                   Risk Stratification
                                AML
• Subtypes less important than they used to be
   – Treated the same
       • except M3 (APL)
   – Can give limited prognostic information
       • M0, M6, M7 worse
       • M3 better
   – Some have associated translocations
                 AML: Prognostic Factors
• Good                       • Poor
                                –   WBC >100K
   –   Down Syndrome <4 yo      –   Infant AML
   –   Rapid remission          –   AA race
   –   t(8;21)                  –   Induction failure/ MRD present after
                                    induction
   –   t(15;17) (APL)           –   Relapsed or Secondary AML
   –   Inv 16 (M4e)             –   Monosomy 5 or 7
   –   FLT 3 ITD                –   Del 5q
                                –   Abn 3q
                                –   Complex karyotype
                                –   MLL rearrangement
                              AML: Therapy
• Highly intensive therapy required for cure
    – CNS prophylaxis included
• Matched sibling BMT after induction if available
• Treatment related mortality rate: 20-30%
    – Reaching the ceiling of intensification
• BMT considered without matched sibling if:
    –   Infant AML
    –   Monosomy 5 or 7
    –   Induction failure
    –   Relapse
                          AML: Outcomes
• Overall survival ~60-70%
• As low as 30% survival with the poorest prognostic factors

• Relapse:
   – Overall survival of relapsed/ refractory disease
       • 5-10% if relapse <1 year after therapy
       • ~35% if relapse > 1 year after therapy
       • quality of remission at transplant is an important factor
                                AML Late Effects
• Neuropsychologic issues
     – Intrathecal therapy, cranial XRT, BMT
• Cardiomyopathy
     – Anthracylcines (esp preteen girls)
• Infertility
     – Cyclophosphamide, testicular XRT, BMT
• Secondary cancers
     – Etoposide, cranial XRT
• Endocrine abnormalities (obesity, precocious puberty, short stature)
     – Cranial XRT, BMT
• Restrictive lung disease
     – BMT
• CGVHD
     – BMT
                                      APL
• Acute Promyelocytic Leukemia (M3)
   – Increased frequency of associated coagulopathy/ hemorrhage
   – t(15;17) PML-RAR
       • ATRA sensitive
           – Induces maturation and apoptosis
   – Often better prognosis
               Down Syndrome and Leukemia
•   First 3 yrs AML>ALL
•   AML is frequently preceeded by myelodysplastic syndrome
•   For AML, better outcome with less intensive therapy (incl. no BMT)
•   Can be difficult to distinguish from Transient Meyloproliferative Disease
•   Rare types more common
     – Erythroblastic (M6)
     – Megakaryocytic (M7)                                        QuickTime™ an d a
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     – Prognosis for M6/7 not as poor as usual in DS
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                 Leukemia Supportive Care
• Tumor Lysis Syndrome
   –   In rapidly growing or extensive disease
   –   Aggressive alkalinized hydration
   –   Allopurinol/ Rasburicase
   –   Close monitoring of labs for
        • Uric acid , phos , K , BUN/ Cr 
        • Ca
   – Can lead to renal failure, pulmonary edema, arrythmias
• Fever and neutropenia
   – Highest risk with very intensive chemo or prolonged neutropenia
   – Treat all fevers with broad spectrums antibiotics
          Leukemia Therapy Supportive Care
• Bactrim
   – PCP prophylaxis x 6 months after therapy
• Immunizations
   –   No live vaccines
   –   No OPV to close contacts (per CDC Varicella is recommended)
   –   Response to killed or inactivated vaccines may be suboptimal
   –   Exposure to varicella w/o previous immunity
        • Continuous household contact, >1 hr indoor play, or hospital contact
        • VZIG in 72-96 hours of exposure
        • IV Acyclovir if sx develop
   – Live vaccination can restart when off therapy for at least 3 months per the CDC.
                                                  Hematopathology

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                                              Hematologic Cancer

Leukemia   (~70%)                                 Lymphoma (~30%)
                                              10% of cancer in kids <14yo
                                              25% of cancer in kids >15yo

                         Hodgkins                                                    NHL (45%)
                    ~600 cases/year in kids                          6% of cancer in kids <14yo, 9% in >15 yo
      4% of cancer in kids <14yo, 16% in >15yo
                         M>F

            Classical             Nodular Lcyte Pred               Mature                                Precurser

      Nodular Sclerosing                        T Cell                             B Cell              Lymphoblastic
      ~70-80% in teens                                                                                    T or B cell



                                              Anaplastic               Burkitts         Diffuse Large B cell
      Hodgkin’s Disease: Clinical Presentation
• Lymphadenopathy
    – Enlarged, usually nontender, often discreet, rubbery, elastic
    – Always be leary of the supraclavicular node
• Common locations
    – Neck (75%)
    – Mediastinum (>60%)
    – Spleen, Axilla, Inguinal, Lung, bone marrow, pericardium, liver, etc.
• Involved nodal groups usually contiguous
• Clinical presentation reflects location of LAD
• +/- Systemic symptoms
    Hodgkin’s Disease: Clinical Presentation
• Systemic symptoms:
   – Portends poorer prognosis
      • B symptoms (30%)
          – Fever >101
          – Drenching night sweats
          – Weight loss  10%
   – Not prognostic
      • Puritis (15-25%)
      • Alcohol-induced pain in areas of nodal involvement (5%)
                     HD: Work-Up
• Labs:
  – CBC
     • May have mild anemia
     • Eosinophilia in 15%, neutrophilia in 50%
  – ESR/ CRP
     • May have prognostic value, certainly useful for
       surveillance
  – CMP
                    HD: Work-Up

• Radiology               • Procedures:
  – CXR                     – LN biopsy
                                  • Preferably not FNA
  – CT/MRI
  – PET scan                –Bilateral BMBx
  – +/- Bone scan           – CSF not required
                HD: Staging and Risk Assessement
• Stage I-IV based on:
    – Number of nodal groups involved
    – Whether one vs both sides of diaphragm are involved
    – Number of extranodal regions involved
• Risk group based on:
    –   Stage
    –   Presence of B symptoms (A/B)
    –   Presence of bulky mediastinal disease (X)
    –   Splenic or other extralymphatic involvement (S or E)
                               HD: Therapy
• 2-8 short, pulsed cycles of chemotherapy
    – Number of cycles depends on risk group and response
• Involved field radiation
    – Except in some low risk cases with very good response
    – Mimized when possible in females
• Relapsed or refractory disease
    – Chemotherapy
    – Radiation if not already given
    – Auto-transplant
                     HD: Prognostic Factors
• Good                           • Poor
   – Female gender                  – Bulky or extranodal disease
   – Low stage                      – B symptoms
                                    – Higher stage
                                    – Anemia at diagnosis
                                    – Hypoalbuminemia at diagnosis
                                    – Leukocytosis or lymphopenia at
                                      diagnosis
                                    – Persistently high ESR
                              HD: Outcomes
• Low/ intermediate risk: 90-95% overall survival
    – Given high survival rate, studies are currently aimed at minimizing treatment
      toxicity/ long term effects
• High risk patients: 85% overall survival
• Relapsed disease:
    – Systemic, extranodal recurrence <1 year from therapy end:
         • 40-50% OS
    – Asymptomatic nodal recurrence >1 year from therapy end:
         • 60-70% OS
                          HD: Late Effects
• Cardiomyopathy, arrythmias        • Pneumonitis, abn PFTs
    – Anthracylcines (esp preteen      – Bleomycin, XRT
      girls), XRT
                                    • Peripheral neuropathy
• Infertility                          – vincristine
    – Cyclophosphamide
                                    • Avascular Necrosis
• Secondary cancers, especially
  breast cancer in girls               – prednisone
    – XRT, etoposide                • Hypothyroidism
                                       – XRT
                             NHL (45%)
             6% of cancer in kids <14yo, 9% in >15 yo

                  Mature                                  Precurser

  T Cell                            B Cell              Lymphoblastic
                                                           T or B cell


Anaplastic              Burkitts         Diffuse Large B cell
                            NHL: Mature
• T-Cell
   – Anaplastic NHL
       • 10% of childhood NHL
       • Presents similarly to advanced HD, with extranodal dz and B symptoms
       • May have waxing and waning (or persistent) cutaneous disease
                               NHL: Mature
• B-Cell
   – Burkitt’s Lymphoma (= small noncleaved)
       • 40-50% of childhood NHL
       • Most common sites/ presentations (in USA):
            – Abdominal
                » classic presentation: intussusception
                » Abdominal obstruction, “appendicitis”
            – Head and neck, CNS, BM often involved
       • Very rapidly growing
            – High risk of tumor lysis syndrome, even before diagnosis
       • If >25% marrow involvement, mature B cell leukemia
       • “Starry Sky” histology due to histiocytes
   – Diffuse Large B -cell Lymphoma
                             NHL: Mature
• B-Cell
   – Burkitt’s Lymphoma
   – Diffuse Large B cell Lymphoma
      • 10% of childhood NHL
      • Can be difficult to distinguish from HD, but more aggressive
           – Often with HSM
           – Can have Reed-Sternberg cells
                            NHL: Precurser
• Lymphoblastic Lymphoma
   – T >> B cell
       • T cell commonly presents with mediastinal mass
            – Most stage III/IV
       • B cell often skin only
            – Most stage I/II
   – Treated like ALL
   – Tdt + (because precurser disease) unlike mature lymphomas
                      NHL: Work-Up
• Labs:                     • Procedures:
   – CBC                       – Biopsy of most
   – LDH/ Uric acid              accessible disease
   – CMP                          • Flow, pathology,
                                    cytogenetics
• Radiology                    – Bilateral BMBx
   – CXR                       – LP for CSF exam
   – CT head CAP                  • Unlike for HD
   – PET scan
           Lymphoma and Immunodeficiency
• T-cell deficiency patients
    – HIV, inherited immunodeficiency, post-transplant, etc
    – 10-100x increased risk of lymphoma
    – Not increased with B cell def, neutropenia, etc.
• Primary CNS lymphoma almost unheard of without underlying
  immunodeficiency
• Most often DLBCL
                                 NHL: Staging
• Disease is not contiguous like in HD, so staging is different
• “B”-like symptoms non-prognostic
• Ann Arbor staging system used for adults is not appropriate for kids with
  NHL due to differences in Lymphoma types and behavior
    – Ann Arbor is used in Hodgkins disease
• Use Murphy Staging system
• Stages I-IV based on:
    – Number and proximity of nodal and extranodal regions involved
    – Location of involvement
         • Other > GI > primary thoracic or paraspinal > CNS or BM
    – Extent of resection
                        NHL: Therapy
• Lymphoblastic
   – Treated like ALL
• All others
   – 3-52 weeks of short, pulsed therapy
   – CNS prophylaxis included
   – Radiation not generally employed
                              NHL: Prognosis
• Localized Disease (Stg I/II)
    – >95% EFS
• Stage III/IV disease
    – Mature B cell
         • 90% EFS without poor prognostic factors
         • Mediastinal primary, CNS/ BM involvement: 65-70% EFS
    – Lymphoblastic Lymphoma
         • 85-90% EFS
    – Anaplastic Large Cell
         • 75% EFS
         • Late recurrences more common
• Refractory/ Recurrent Dz
    – Very poor, even with BMT
                Emergent Presentations
                of Leukemia/ Lymphoma
• Superior vena cava/Superior mediastinal syndrome
   – Facial/neck/UE swelling and cyanosis
   – Collateral vein engorgement
   – Cough, hoarseness, orthopnea, wheezing
• Spinal cord compression
• Hyperleukocytosis
• Tumor Lysis Syndrome
                                  Sources
• ASPHO: Pediatric Hematology/Oncology Review Course, 2006.
• Lanzkowsky P: Manuel of Pediatric Hematology and Oncology. Elseiver Academic
  Press, New York; 2005.

								
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