3% Chronic leukemia Chronic myelocytic leukemia Juvenile myelomonocytic leukemia Risk Factors for Childhood Acute Leukemia

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1 CHILDHOOD LEUKEMIA 97% Acute leukemia 75% Acute lymphoblastic leukemia 20% Acute myeloblastic leukemia Acute mixed lineage leukemia Acute undifferentiated leukemia 3% Chronic leukemia Chronic myelocytic leukemia Juvenile myelomonocytic leukemia Risk Factors for Childhood Acute Leukemia Genetic Down ALL, AML NF1 ALL, AML, JMML Bloom ALL, AML Schwachman ALL, AML Ataxia Telangiectasia ALL Fanconi Anemia AML Kostmann Granulocytopenia AML Environmental Ionizing Radiation ALL, AML In Utero X-ray ALL Benzene AML Pesticide AML Alkylating /Topo-II Inhib. AML In Utero Topo II Inhib. Infant Und L. DNA damaging Higher incidence among identical twins ALL- Epidemiology The most common malignancy in childhood Incidence 3-4 cases per children Peak incidence between 2-5 y Boys > Girls

2 White >Black Genetic predisposition <5% Clinical Features at Diagnosis in Children with Acute Lymphoblastic Leukemia Clinical features/ Symptoms % of patients Fever 61 Bleeding (petechiae or purpura) 48 Bone pain 23 Lymphadenopathy 50 Splenomegaly 63 Hepatosplenomegaly 68 Laboratory Features at Diagnosis in Children with Acute Lymphoblastic Leukemia Laboratory features % of patients Leukocyte count (mm3) <10, ,000-49, >50, Hemoglobin (g/dl) < > Platelet count (mm3) <20, ,000-99, >100, DIAGNOSIS Blood count and smear Bone marrow: Morphology Cytochemical stains Immunophenotype Cytogenetics

3 ALL TESTICULAR INVOLVEMENT CNS LEUKEMIA DIFFERENTIAL DIAGNOSIS IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA Nonmalignant conditions Juvenile rheumatoid arthritis Infectious mononucleosis Idiopathic thrombocytopenic purpura Pertussis; parapertussis Aplastic anemia Acute infectious lymphocytosis Malignancies Neuroblastoma Retinoblastoma Rhabdomyosarcoma Unusual presentations Hypereosinophilic syndrome phenotype ALL Incidence 15% Median age : 12y Male > Female High blood count Mediastinal mass Organomegaly CR < 90 % High relapse rate, CNS, Extra medullary RINCIPLES OF TREATMENT Risk group Combination chemotherapy: Remission induction CNS prevention Consolidation Maintenance

4 Irradiation BMT Late effect consideration AML ML subtypes CUTE MYELOCYTIC LEUKEMIA: AML Prognostic factors WBC > 100,000 Secondary Monosomy 7 (7q-)? Very young? Splenomegaly? M4 and M5? M1 w/o Auer rods AML: INDUCTION THERAPY Two cycles of cytosine arabinoside + daunorubicin +/- thioguanine and other agents gives remissions in 70-90% Timed sequential therapy (giving the second cycle at a specified time) does not the increase remission rate but does increase long-term cures when compared to waiting for

5 marrow recovery (or failure) before giving the second cycle (Blood 87:4979, 1996) AML: Post-induction Therapy Chemotherapy alone has given % cure rates. Cure is higher after timed-sequential induction therapy (42% vs. 27%). Short (4-12 months) of post-induction therapy is adequate CNS leukemia is less common than in ALL; prophylaxis may be accomplished with high dose Ara-C +/- intrathecal Ara-C AML: Bone Marrow Transplantation Bone marrow transplantation from a matched sibling donor during first remission gives better cure rates than chemotherapy (50-60 % vs %) Autologous BMT during first remission gives results similar to chemotherapy BMT from a matched sibling in second remission gives % cure rate but is limited by the difficulty in achieving second remission. AML Treatment Issues 50% incidence of serious bacterial infection: therefore use of G-CSF accepted New protocol is European-based and returns to the old highdose Ara-C, with the addition of myelotarg (anti-cd33, aka gemtuzumab).

6 Special circumstances Granulocytic sarcoma Down syndrome Increased incidence of all leukemias; ALL still > AML total, but RELATIVE increase of AML Do not use intensive timing (increased toxicity with therapy), but OK to use anthracyclines even with CHD M7 AML most often Transient Myeloproliferative Disease occurs in newborn period M3 (the 15;17 translocation). PROMYELOCYTIC LEUKEMIA: M 3 Characterized by a translocation [t(15;17)] that fuses the retinoic acid receptor and PML genes The t(15;17) transcript blocks differentiation that depends upon the normal receptor High dose all-trans retinoic acid overcomes this blockade Arsenic trioxide may cause apoptosis or may induce differentiation in PML cells. Promyelocytic Leukemia: M 3 Induction: all-trans retinoic acid +/- an anthracycline Intensification: anthracycline +/- Ara-C Continuation: intermittent all-trans retinoic acid +/- chemotherapy. CML

7 CML overview BCR-ABL fusion protein is generally P210, whereas Ph+ALL is usually P phases Chronic Some systemic sxs; peripheral and marrow blasts < 10% (NCI says 5%), thrombo- and leukocytosis Accelerated Progressive sxs including splenomegaly; blasts 10 (5?) -30%, baso s+eo s > 20% Blast Extramedullary disease symptoms; blasts > 30%, blasts that look like ALL or AML CML treatment Gleevac: aka STI571, aka imatinib mesylate tyrosine kinase inhibitor that blocks the function of the BCR- ABL fusion protein Morphologic vs cytogenetic vs molecular remission Additional chemo required if disease has progressed IFN, Ara-C, hydroxyurea Transplant still the Rx of choice for Peds. PEDIATRIC LYMPHOMAS

8 Concerns in enlarged LN Size >1-2 cm Increasing size over 2-4 weeks Matted or fixed Supraclavicular LN When to biopsy Supraclavicular node Increasing size over 2-4 weeks Constitutional symptoms Asymptomatic enlarged node-not decreasing in size over 6 weeks or not normal after 8-12 weeks. Laboratory -CBC with smear -Chem profile LHD, uric acid STAGING EVALUATION Disease specific -ESR, IL2R for HD -LP if head/neck NHL -BMA/Bx for all NHL, only IIB or higher HD Lymphoma Staging Murphy Ann Arbor I: tumor at one site (nodal or extranodal -- E ) II: two or more sites; same side of body (or resectable GI primary)

9 III: both sides of body but not IV (& unresec. GI & mediastinal for NHL) IV: CNS or marrow involvement (Murphy); lung, liver, marrow, or bone for Ann Arbor (< 25% marrow) B sxs are defined for HD, as is bulky disease Head and neck (possibility of CNS involvement) is a further consideration for NHL PET or gallium NON-HODGKIN S LYMPHOMA Malignant solid tumor of immune system Undifferentiated lymphoid cells Spread: aggressive, diffuse, unpredictable Lymphoid tissue; BM and CNS infiltration High growth fraction and doubling time Dx and Rx ASAP Rapid CTX response; tumor lysis concern. Incidence/Etiology NHL 6% childhood cancer 60% of childhood lymphomas Peak age of 5-15; M:F ratio of 2.5:1 Increased with SCIDS, HIV, EBV post t-cell depleted BMT post solid organ transplant Geographic, viral, genetic & immunologic factors. TYPES OF NHL Lymphoblastic (30-35%)

10 90 % immature T cells (very similar to T-ALL) remainder pre-b phenotype (as in ALL) 50-70% anterior mediastinum neck, supraclavicular, axillary adenopathy Classic: older child with intussusception Small non-cleaved cell (40-50%) --Mature B-cell phenotype --Burkitt's and non-burkitt's --90% abdomen --Ascites and intusussception --Endemic in Africa (Burkitt's), with EBV 97%. BURKITT FACTS 100 new cases/year in US, 2-3:1 male:female; mean age 11 years (in non-endemic form) small, noncleaved cell; mature B phenotype; intraabdominal (sporadic) or jaw (endemic) most common primary site 90% have t(8;14) (8 ~ c-myc; 14 ~ heavy chains) others are 8;2 or 8;22 (2, 22 ~ light chains) Extremely rapidly-growing; tumor lysis issues. Adult Data: Stage: EFS OS I-II 91% 78% IV 25% 25% BURKITT PROGNOSIS

11 but in patients < 40 yo 70% 60% Large-cell lymphoma (15-20%) - Anaplastic (Ki-1) lymphoma ALK fusion protein - Diffuse Large B-cell lymphoma (DLBCL) - frequent Mediastinal involvement - More like Hodgkin lymphoma than other NHLs - Peripheral T-cell lymphoma - Often involves skin, CNS, lymph nodes, lung, testes, muscles, and GI tract low grade lymphomas rare in children Follicular marginal zone/malt primary CNS (often seen with HIV infection) peripheral cutaneous (mycosis fungoides) CLINICAL PRESENTATIONS Abdomen: (35%): pain, distention, jaundice, GI problems, mass Head/neck (13%): lymphadenopathy, jaw swelling, single enlarged tonsil, nasal obstruction, rhinorrhea, cranial nerve palsies Mediastinum (26%): SVC syndrome CNS (rare): HA, V, irritability, papilledema +Fever, malaise, night sweats, wt. loss, Staging of NHL I Single tumor /node NOT in mediastinum or abdomen II 1-2 nodes same side of diaphragm or resectable GI

12 primary III 2+ nodes both sides of diaphragm; intrathoracic or extensive intra-abd IV Any of above with CNS and/or BM PROGNOSIS AFFECTED BY Incomplete remission in first 2 mos. Rx Large tumor burden (LDH >1000) Stages III and IV: CNS or BM involvement Delay in treatment Relapse **More favorable: Stage I or II, head/neck, peripheral nodes, GI tract NHL Treatment Surgery for diagnostic bx or second look Radiation Therapy: emergency airway obstruction or CNS complication may be used for local control of residual mass Chemotherapy: Combination chemo is usual, with overall cure rates %; high risk of tumor lysis and hyperuricemia Relapse: Re-induction, followed by BMT NHL chemotherapy overview Low-stage NHL s are treated with CHOP (+/- rituximab anti-cd20) Higher-stage lymphoblastic lymphomas are treated on leukemia protocols Higher-stage non-lymphoblastic NHLs require extremely aggressive chemotherapy with significant infectious risks, but still have generally good remission rates

13 High-dose chemotherapy with stem cell rescue is considered an option for relapse, though without the success rates of HD; T cell disease probably requires an allogeneic response. HODGKIN S DISEASE Immune system malignancy, involving B or T lymphocytes Reed-Sternberg cells Spread: slow, predictable, with extension to contiguous lymph nodes Infiltration to non-lymphoid organs is rare INCIDENCE AND ETIOLOGY Hodgkin s 5% of childhood cancers Bimodal peaks, at and >50; rare < 5 M:F ratio of 3:1; variation r/t geography and SES, and type Increased in immunologic disorders, HIV, EBV. TYPES OF HODGKIN S LYMPHOMA Nodular sclerosing (NS), 40-60%, lower cervical, supraclavicular, mediastinal nodes Mixed cellularity (MC), 15-30%; advanced disease with extranodal involvement Lymphocyte predominance (LP), 5-15%, presents as localized disease

14 Lymphocyte depletion (LD) (<5%); widespread disease. CLINICAL PRESENTATION Painless lymph node swelling (90%) that persists despite antibiotic therapy Palpable non-tender, firm, mobile, rubbery nodes; Mediastinal adenopathy (60%); SVC Bulky: when mass is > 1/3 thorax diameter B symptoms: Fever of >38C for 3 days, drenching night sweats, 10% weight loss. MEDIASTINAL MASSES Risk for anesthesia (esp. if tracheal compression > 50% by CT) Least invasive diagnostic procedure therefore indicated (incl. thoracentesis) Emergent steroids or RT generally acceptable prior to biopsy HD and DLBCL tend to have areas of necrosis and therefore look more bumpy than T-ALL. HODGKIN S ANN ARBOR STAGING I Single lymph node region II Two+ node regions on same side of diaphragm III Nodes on both sides of diaphragm, or localized extralymphatic spread IV Diffuse or disseminated involvement of one+ extralymphatic organs or tissues.

15 PROGNOSIS FAVORABLE: <10, F, favorable subtypes (LP and NS) and Stage I non-bulky disease UNFAVORABLE: Persistently elevated ESR; LD histopathology; bulky disease--largest dimension >10cm; B symptoms; TREATMENT AND PROGNOSIS Dependent on age, stage, and tumor burden RT alone, CTX alone RT: varies from involved field for localized disease to extended field to total nodal irradiation, inverted Y plus mantle most often multimodal therapy, with low-dose involved field RT and multi-agent CTX Combined modality 70-90% LT cure. Hodgkin Px and Rx Splenectomy generally no longer used Exact type and ratio of combined modality therapy changes due to differences in success rates for salvage therapy and concerns for late effects of therapy Second malignancy risks Sterility risks