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  • Acbadem University Pediatric Hematology- Oncology Prof. Cengiz Canpolat M.D. Pediatric Hematology-Oncology
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  • Leukemias Clonal expansion and arrest at a specific stage of normal myeloid or lymphoid hematopoiesis Acute leukemia consitutes %97 of childhood leukemias ALL(%75) AML (%20) Acute undifferentiated leukemia (
  • Acute Lymphoblastic Leukemia Prognostic factors; Initial WBC count 1 y and 50 chr. good pr. (incr. apoptosis, incr. sensitivity to chemo.)
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  • Acute Lymphoblastic Leukemia Prognostic factors; Certain type of translocations in leukemic blasts Early response to chemotherapy (day 8 and 15 blast % in BM) Day 8 blast count in PB Residual leukemia during treatment (day 8 in PB and day 29 in BM)(MRD) CNS disease at diagnosis adverse prognostic factor
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  • Acute Lymphoblastic Leukemia Proposed risk classification system of pre B cell ALL Risk group Features Low (treated same as standard) age 1-9 WBC50.000 CNS 3 or testic. dis Very high Ph+ leukemia, < 45 chr., induction failure
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  • Day 29 BM Flow MRD P9904/5/6 MRD >.01% is an optimal cutoff (n=1960) 023456 0.0 0.2 0.4 0.6 0.8 1.0 Ye Event-free survival probability Day 29 Negative (n=1579) Day 29 0.01-0.1% (n=173) Day 29 >0.1% (n=208) P < 0.0001 88 1% 50% of events 68 5% 51 5% 4 y EFS 1
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  • Day 8 Blood Flow MRD P9904/5/6 (n=1933) 023456 0.0 0.2 0.4 0.6 0.8 1.0 Years Event-free survival probability 1: MRD Negative (sensitivity = 0.01%) (n=603) 2: 0.01% < MRD 0.1% (n=341) 3: 0.1% < MRD 1.0% (n=501) 4: 1.0% < MRD 10.0% (n=373) 5: MRD > 10% (n=116) P < 0.0001 92 2%, 16% of events 4 y EFS 1
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  • Significant Prognostic Factors Based on COG Studies Multivariate Analysis Day 29 MRD (0.01% cutoff): HR=3.86 NCI risk group: HR=2.1 Trisomy 4/10 status: HR=0.485 Day 8 PB MRD: HR=1.63 TEL/AML1 status: HR=0.699
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  • 2009 B-Precursor Classification (n=1687/yr) Low NCI Std Risk Trisomy 4/10 or TEL; D8 blood & D29 BM MRD < 0.01% Standard Std Risk w/o or High Risk with Trisomy 4/10,TEL; D29 MRD < 0.01% High High Risk or Std Risk w/ CNS/testes; D29 < 0.01% or D29 positive if SR T4/10, TEL Very High Std or High Risk; D29 MRD > 0.01% EFS Patients 95+% 16% 85-94% 41% 70-85% 28%
  • Acute Lymphoblastic Leukemia Most common cytogenetic abnormalities: 11q23 poor prognosis, 80% of infant ALL, 85% of 2 0 leukemia) t(4;11), 2%, MLL-AF4 fusion, CD10- B phenotype, infancy, hyperleukocytosis, dismal outcome with CT t(11;19) 5-6%, E2A-PBX1 fusion, pre B phenotype, poor prognosis, intensive therapy is necessary t(12;21), 25% of pre B cases excellent prognosis t(9;22), 3-5%, BCR-ABL fusion, B lineage, older age, hyperleukocytosis, dismal outcome with CT t(8;14), 1-2%, MYC-IGH fusion, B phenotype, boys>girls, L3 morphology, bulky extramed. disease, favorable prognosis
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  • Acute Lymphoblastic Leukemia Immunophenotype distribution 1-pre B cell 80% 2-mature B cell 1-2% 3-T cell 15-20% -older age -high initial WBC -extramedullary disease -improved prognosis on intensified protocols
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  • Acute Lymphoblastic Leukemia Prognostic significance of chr. abnormalities in ALL Chromosomal abn.5-y EFS Hyperdiploidy >50 chr. 80%(65-90%) 47-50 chr. 90%(50-98%) Near triploid, 66-73 chr.Not known, good? Near tetraploid, 82-94 chr.Not konown,
  • Acute Lymphoblastic Leukemia Testicular leukemia: Painless swelling in one or both testicles Incidence of testicular relaps is 10-23% during treatment; median time 13 months Diagnose established by testicular Bx on both sides 10% of false negativity on Bx High initial wbc (>20.000), T cell origin, mediastinal mass, significant LAP and HSM; high chance of testicular leukemia Initial screening unnecessary at the time of diagnosis unless suspected in PE
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  • Acute Lymphoblastic Leukemia Treatment: phases Remission induction CNS preventive therapy Consolidation Interim maintenance I and II Intensification I / II Maintenance
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  • Acute Lymphoblastic Leukemia Aims of therapy 1-to induce a clinical and hematologic remission 2-to maintain remission by systemic chemotherapy and prophylactic CNS therapy 3-to treat the complications of therapy and disease
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  • Acute Lymphoblastic Leukemia Completeremission No symptoms attributable to the disease (eg. fever, bone pain) No hepatosplenomegaly, lymphadenopathy, or other clinical evidence of residual leukemic tissue infiltration) Normal PB findings Less than 5% blasts in a normocellular BM No CNS or extramedullary disease Blasts fall from 10 12 to 10 9
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  • Acute Lymphoblastic Leukemia CNS preventive therapy: High increased WBC count, T cell disease, very young age, thrombocytopenia, LAP, HSM, black race increase the risk of CNS leukemia CNS, because of the blood-brain barrier, acts as a sanctuary for blasts Cranial XRT unnecessary for standard-risk pts Cranial XRT indicated only for those who have CNS leukemia and for those who are poor responders to chemo
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  • Acute Lymphoblastic Leukemia CNS preventive therapy: XRT has long term adverse CNS sequela Prophylaxis and treatment usually done with IT MTX or TIT (MTX, ARA-C, Hydrocortisone) IT MTX can cause arachnoiditis (Headaches, N/V, meningitis) but self-limited Encephalopathy, myelopathy, seizures
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  • Acute Lymphoblastic Leukemia Duration of treatment: 2.5 to 3.5 years of Rx required for ALL in most modern protocols Duration of Rx longer for boys than for girls Prognosis better if relaps occurs after Rx is finished Prognosis poor if relaps occurs during Rx In mature B cell ALL, treatment is shorter because there is rapid growth rate
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  • Acute Lymphoblastic Leukemia Bone marrow transplantation: Currently allogeneic BMT is routinely advocated for pts in 2nd remission Pts who suffer late relapses (longer than 30 mo after remission or after completing Rx) is to be treated with chemo. BMT is reserved for subsequent relapse
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  • 5-Year Survival Rates for Children (< 15 yrs) Acute Lymphoblastic Leukemia: 1960 - 2004
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  • Acute Lymphoblastic Leukemia Supportive care: R-thrombopoietin (not available everywhere) RBC and platelet transfusions Empiric use of broad spectrum of ab in F/N pts PCP prophylaxis with TMP/SMZ VZIG within 72-96 hrs of exposure to VZV Infusion of blood products Better management of tm lysis syndrome
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  • Acute Myeloid Leukemia 15-20% of all childhood leukemia Only 40-50% of newly diagnosed cases can be expected to be cured AML/ALL ratio is 1:4, except congenital leukemia cases (in the first 4 weeks of life) which is mainly AML Incidence stable from birth to age 10 exept for a peak in the neonatal period and a slight increase during adolescence Equally distributed among all ethnic groups (significantly more in hispanics) AML associated with orbital granulocytic sarcoma (OGS) in Turkish children Males=females
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  • Acute Myeloid Leukemia Predisposing factors: Acquired factors; XRT, benzene EMF contraversial Smoking and marijuana use during pregnancy, increased AML in fetus Rx with alkylating agents (Nitrogen Mustard, Cyclophosphamide, Melphalan) increased AML risk 4-5 years after Rx, deletion of chr. 5 and 7 common Long exposure to VP-16, VM-26; AML shortly after Rx, subtype M4-M5
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  • Acute Myeloid Leukemia Predisposing factors: Genetic factors; Identical twins-100% concordance Fanconis anemia->50% by 40 yrs of age Bloom syndrome DB anemia Kostmann syndrome-risk increases with age Down syndrome; most common prognostic factor -14 fold increase NF-1-activation of RAS
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  • Acute Myeloid Leukemia Secondary AML can evolve from 1-MDS and MPS 2-ionizing radiation+chemotherapy -nitrogen mustard -CTX -IFX -chlorambucil -melphalan -VP-16
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  • Acute Myeloid Leukemia Classification: M1: AML without maturation (less than 10% PMN) M2: AML with maturation (more than 10% PMN) M3: Acute promyelocytic leukemia M4: Acute myelomonocytic leukemia M5a: Acute monoblastic leukemia M5b: Acute monocytic leukemia M6: Erythroleukemia M7: Megakaryoblastic leukemia M0: Acute undifferantiated leukemia %20 or more blasts are required for the Dx of AML FAB classification is being replaced by WHO classification
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  • WHO Classification of AML 1-With recurrent genetic abnormalities t(8;21)(q22;q22), (AML1/ETO) Abnormal bone marrow eosinophilis and inv(16)(p13q22) or t(16;16)(p13;q22), (CBFMYH11) Acute promyelocytic leukemia 11q23 (MLL) abnormalities Vardinman JW, et al. Blood 2002; 100:2292-2302
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  • WHO Classification of AML 2-With multilineage dysplasia Following MDS Without MDS, but with dysplasia in at least 50% cells in >2 myeloid lineages 3-Therapy-related Alkylating agent / radiation-related type Topoisomerase II inhibitor-related type Others 4-Not otherwise categorized
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  • Potential Risk Factors Prognostic FactorHigh RiskFavorable Risk Cytogenetics Deletion 5q Monsomy 5 or 7 t(15;17) inv (16)


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