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Pediatric Hematology Oncology, Schneider Children’s Medical Center of Israel, Petal-Tikva,

לויקמיה ולימפומה בילדים דר. יצחק יניב מנהל המחלקה להמטולוגיה ואונקולוגיה ילדים מרכז שניידר לרפואת ילדים בישראל. Pediatric Hematology Oncology, Schneider Children’s Medical Center of Israel, Petal-Tikva, Sackler School of Medicine, Tel Aviv University, Israel. Childhood malignancy.

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Pediatric Hematology Oncology, Schneider Children’s Medical Center of Israel, Petal-Tikva,

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  1. לויקמיה ולימפומה בילדיםדר. יצחק יניבמנהל המחלקה להמטולוגיה ואונקולוגיה ילדיםמרכז שניידר לרפואת ילדים בישראל Pediatric Hematology Oncology, Schneider Children’s Medical Center of Israel, Petal-Tikva, Sackler School of Medicine, Tel Aviv University, Israel.

  2. Childhood malignancy

  3. Cancer Cell, 2002

  4. 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

  5. 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

  6. ALL- Epidemiology • The most common malignancy in childhood • Incidence 3-4 cases per 100000 children • Peak incidence between 2-5 y • Boys > Girls • White >Black • Genetic predisposition <5%

  7. Age distribution

  8. Clinical Features at Diagnosis in Children withAcute Lymphoblastic Leukemia Clinical features/ Symptoms % of patients Fever 61 Bleeding (petechiae or purpura) 48 Bone pain 23 Lymphadenopathy 50 Splenomegaly 63 Hepatosplenomegaly 68

  9. Laboratory Features at Diagnosis in Children withAcute Lymphoblastic Leukemia Laboratory features % of patients Leukocyte count (mm3) <10,000 53 10,000-49,000 30 >50,000 17 Hemoglobin (g/dl) <7.0 43 7.0-11.0 45 >11.0 12 Platelet count (mm3) <20,000 28 20,000-99,000 47 >100,000 25

  10. ALL testicular involvement

  11. CNS leukemia

  12. 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

  13. Diagnosis • Blood count and smear • Bone marrow: Morphology Cytochemical stains Immunophenotype Cytogenetics

  14. Haemopoiesis

  15. FAB L1

  16. FAB L2

  17. FAB L3

  18. Cytochemical stains

  19. Lymphoid differentiation

  20. T phenotype ALL • Incidence 15% (Israel – 20 %) • Median age : 12y • Male > Female • High blood count • Mediastinal mass • Organomegaly • CR < 90 % • High relapse rate, CNS, Extra medullary

  21. אחד מתוך 2000 ילדים מפתח ALL לפני גיל 15 • ברובם הארוע הראשון קורה ברחם • 1/100 נןשא טרנסלוקציה 1;212 אך רק אחוז אחד מהם יפתח לויקמיה • דרוש ארוע נוסף כדי שהלויקמיה תופיע וזה יכול להיות קשור בזיהום או בתגובה לזיהום וגם במבנה הגנטי הקיים לגבי מטבוליזם של תרופות ותיקון נזקי DNA

  22. Genetic (somatic) Abnormalities in Childhood Cancer Numerical Chromosomal changes Structural Chromosomal changes Translocation Inversion Deletion Addition / duplication Amplification

  23. Childhood ALL Hyperdiploid G-banding FISH cep4/cep10 Cep4: centromere 4 Cep10: centromere 10 • Ca-Cytogenet. -SCMCI

  24. Genetic (somatic) Abnormalities in Childhood Cancer Numerical Chromosomal changes Structural Chromosomal changes Translocation Inversion Deletion Addition / duplication Amplification

  25. Genetic Abnormalities in Childhood Cancer Protooncogen Activation Suppressor gene Inactivation Altered function of: Growth factors Growth factor receptors Kinase inhibitors Signal transducers Transcription factors Altered down stream Genes Expression

  26. Childhood ALL Philadelphia chromosome G-banding FISH bcr/abl bcr: 22q11 abl: 9q34 46,XY,t(9;22)(q34;q11) • Ca-Cytogenet. -SCMCI

  27. ALL-B lineage Chromosomal rearrangement Activation of transcriptional control Genes ALL Translocation Genes Frequency Early B t(12;21)(p12;q22) TEL-AML1 25% Pre. B t(1;19) (q23;p13) E2A-PBX1 5% Pro. B t(17;19)(q22;p13) E2A-HLF <1% t(4;11) (q21;q23) MLL-AF4 4% B cell/Burkitt t(8;14) (q24;q32) MYC (IgH) 5% t(2;8) (p12;q24) MYC (IgL) <1% t(8;22) (q24;q11) MYC (IgL) <1% B cell t(3;11) (q27;q23) BCL6 1%

  28. Ca-Cytogenet. -SCMCI Childhood ALL – t(12;21) (TEL/AML1),del(12p) G-band FISH SKY 46,XY,t(12;21)(p13;q22),der(12)t(1;12p) H.M.

  29. Expression profiles of diagnostic bone marrow ALL blasts Yeon, Cancer Cel 2002

  30. Molecular subtypes of ALL Cancer Cell, 2002

  31. Childhood ALL, Event Free Survival by Genetic Features St Jude Pui, NEJM, 1998

  32. Prognostic Risk Factors in ALL Age: 1-6, 1-10y WBC: 20.000, 50.000 Phenotype.: T, “B”, CALLA neg. Ploidy: <2n, 3n Cytogenetic: t(9;22),t(4;11) t(12;21) Gene Expression Profile ? Early response to treatment !!!!!! PB D8, BM D15, D33 Morphology, MRD Sex, Race, CNS, Testicular involvement

  33. Early response to therapy • D-8 ( PB ; BM ) • D- 14 ( BM ) • D- 33 ( BM ) • MRD Slop by BM aberrant phenotype BM clonal Ig/TCR rearrangement

  34. M R D Minimal Residual Disease • Precise definition of remission • Prognostic significance (blast <0.01% ) • Treatment modification

  35. Immunogobuline gene rearrangement van Dongen ASH 2002

  36. . therapy antileukemic Patterns of early cellular responses to Pui, 2000

  37. International BFM Study Group • Risk MRD 5 year Relapse • TP1 TP2 Rate - % • Low <10-4 <10-4 2 • Intermediate 24 • High >10-3 10-3 84

  38. 1.0 Low risk group (n=55) neg at tp 1 0.8 Intermediate risk group (n=55) < 10e-3 at tp 2 0.6 0.4 High risk group (n=19) ≥ 10e-3 at tp 2 0.2 0.0 0 1 2 3 4 5 6 7 8 9 years from time point 2 Combined Information of MRD from Time Points 1+2 Low risk group pRFS = 0.98 ± 0.02 Intermediate risk group pRFS = 0.76 ± 0.06 p<0.001 High risk group pRFS = 0.16 ± 0.08

  39. Principles of treatment • Risk group • Combination chemotherapy: Remission induction • CNS prevention • Consolidation • Maintenance • Irradiation • BMT • Late effect consideration

  40. Leukemic cell kinetics

  41. Event- Free Survival of ALL children- St. Jude Pui, 1998 NEJM

  42. Host Pharmacogenetics Affects Treatment Response excessive toxicity non-responders responders

  43. Determinants of Treatment Response in Leukemia Leukemia Tumor burden Host Therapy Growth potential Drug resistance Drug dosage Age Drug interactions Pharmacogenomics Treatment response

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