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Joseph M. Wiley, MD Division of Pediatric Hematology-Oncology Chairman, Department of Pediatrics

Curing Acute Lymphoblastic Leukemia in Children Without New Agents Applying Lessons Learned in Biology, Pharmacology and Molecular Biology A Paradigm for Disease Treatment. Joseph M. Wiley, MD Division of Pediatric Hematology-Oncology Chairman, Department of Pediatrics

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Joseph M. Wiley, MD Division of Pediatric Hematology-Oncology Chairman, Department of Pediatrics

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  1. Curing Acute Lymphoblastic Leukemia in Children Without New AgentsApplying Lessons Learned in Biology, Pharmacology and Molecular BiologyA Paradigm for Disease Treatment Joseph M. Wiley, MD Division of Pediatric Hematology-Oncology Chairman, Department of Pediatrics The Herman and Walter Samuelson Children’s Hospital at Sinai, Baltimore, MD

  2. The attendees will gain an understanding of the basic Biology of ALL The attendees will learn the biologic features that predict for prognosis with therapy of ALL The attendees will learn the importance of response to therapy as a prognostic factor in ALL The attendees will gain an understanding of the importance of the role of clinical trials in childhood cancer Goals and Objectives

  3. Speaker’s Bureau Enzon Pharmaceuticals (Oncospar) Grant Funding Children’s Oncology Group- Chairman’s Grant NHLBI- Sickle Cell Network Children’s Cancer Foundation Scientific Grant Off Label Usage Almost all Pediatric chemotherapy drugs are off label Alternative funding Get a check from my mom on my birthday Conflicts of Interest

  4. Clonal Disorder of Lymphohematopoietic System Malignant event - probably as a result of a sequence of events Clonal expansion leads to marrow replacement Complex interaction of genetic, immunologic, pathologic and clinical features Acute Leukemia

  5. Incidence is ~ 1/2000- 1/2500 by age 18 Peak incidence age 4 More common in whites and boys Associated with RT exposure Increased incidence in Down’s, FA, AT, Bloom’s, etc. Acute Leukemia in Childhood

  6. Acute Lymphoblastic Leukemia (ALL) 80% of Acute Leukemia 85% B- cell Lineage 15% T- cell Lineage Acute Nonlymphoblastic Leukemia (ANLL) 20 % of Childhood Leukemia Acute Leukemia in Childhood

  7. Acute Lymphoblastic Leukemia Is the Most Common Childhood Cancer Yearly Incidence of Childhood Cancers

  8. The most common group of pediatric malignancies A paradigm for success in cancer treatment Recent discoveries lend insight to the great heterogeneity of the disease Goal is to decrease toxicity while “tailoring” therapy to risk Acute Lymphoblastic Leukemia

  9. Few, if any distinguishing features Anemia is more severe out of proportion to other abnormalities Suspicion raised when 2 or more hematopoietic lineages involved Systemic Illness that persists when other diagnostic candidates should fade Acute Lymphoblastic LeukemiaClinical Features

  10. Fever, bone pain, limp Peripheral blood cytopenias Hepatosplenomegaly, lymphadenopathy Infections, fatigue, bleeding CNS symptoms, airway compression Acute Lymphoblastic LeukemiaClinical Features

  11. Acute Lymphocytic Leukemia Peripheral Smears

  12. Acute Lymphocytic Leukemia Bone Marrow Aspirates

  13. Risk Factors for Relapse in ALL Standard Risk High Risk ____________________________________________ Age 1-9 years of age <1 yr., > 10 yrs. WBC at Diagnosis < 50,000/mm3 >50,000/mm3 Cytogenetics Many abnormal. t(9:22), t(4:11) Acute Lymphoblastic LeukemiaPrognostic Features

  14. Induction 4-6 week therapy with non myelosuppressive drugs (ex anthracyclines- high risk) Consolidation 4-10 months therapy with cyclical rounds of various drugs based in anti metabolite backbone (methotrexate, thiopurines) Maintenance 2-3 years of less intensive treatment ALL- Treatment

  15. Years of Diagnosis Number of Children 100 1995-97 1299 1993-95 1585* 1989-93 3402 80 1983-89 3711 1978-83 2984 60 1975-78 1313 1972-75 936 % Survival 40 1970-72 499 20 C C G Bleyer 1968-70 402 0 2 6 8 10 4 Total Number of Patients Treated: 16,131 Years After Study Entry *Excluding infants. Survival of Patients With Acute Lymphoblastic Leukemia, 1968-1997 CNS Prophylaxis introduced

  16. SEER 5-Year Survival RatesAge < 15 years Jemal A et al. CA Cancer J Clin. 2004;54:8-29.

  17. C C G Bleyer EFS of Young Adults Aged 16 to 21 on CCG and CALGB Trials for ALL (1988-1995) 1.0 EFS of Young Adults with ALL 0.8 CCG 0.6 Proportion 0.4 CALGB (median = 2.5 y) CALGB (median = 2.5) 0.2 0.0 0 2 4 6 8 10 Years

  18. Empiric multi-agent chemotherapy Pre-symptomatic CNS therapy Post-induction intensification Anti-metabolite therapy Re-induction/re-consolidation Risk adapted therapy Key Components of Successful Therapy

  19. Morphologic Features Immunophenotype Karyotype DNA features Response to therapy Acute Leukemia in ChildhoodBiologic Features

  20. Genetic Heterogeneity in Childhood ALL Children’s Oncology Group 14q11 Ph t(1;19) 11q23 3% 2% 4% “Normal” 4% 26% TEL-AML1 18% < 45 Chrom 1% 45 Chrom 3% > 50 Chrom Pseudodiploid 47-50 Chrom 26% 10% 6%

  21. Genotype Correlates with OutcomeChildren’s Oncology Group 100 Trisomies 4,10,17 (n = 746) TEL (n =176) 80 t(1;19) (n = 139) 60 t(4;11) (n = 44) Probability 40 t(9;22) (n=132) 4 Yr EFS (%)SE (%) Tris 4,10,17 92.1 1.1 TEL 89.0 3.1 t(1;19) 68.9 4.1 t(4;11) 49.9 11.2 t(9;22) 27.5 4.4 20 B-precursor ALL 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Years Followed 10/2001

  22. Rate of Initial Response is Strong Predictor of Event-Free-Survival <5 % Blasts in Bone Marrow Day 7= Rapid Early Response Event-Free Survival (%) Day 14 =Intermediate Early Response p=.0005 Day 28 =Slow Early Response Years Steinherz, et al: JCO 14: 389-398, 1996

  23. COG ALL Risk GroupsB-Precursor ALL • NCI Risk Groups • Trisomies 4, 10, & 17 • TEL/AML 1 • Rapidity of Response • CNS Disease • MRD - End of Induction • MLL (t(4:11)) • BCR-ABL (t(9:22)) • Chromosomes <45 Low Risk Standard Risk High Risk Very High Risk

  24. Outcome by New Risk Group Definitions B-precursor ALL Low Risk (n=544) 100 Standard Risk (n=1471) 80 High Risk (n=880) Probability 60 Very High Risk (n=78) 40 Risk Group4 Yr EFS (%)SE (%) Low 91.5% 1.6 Standard 82.1% 1.4 High 72.9% 2.1 Very High 33.6% 6.0 20 0 0 1 2 3 4 5 6 7 8 9 10/2001 Years Followed

  25. Flow Cytometry for ALL Identification

  26. Acute Lymphoblastic LeukemiaB-Precursor Standard Risk (COG AALL0331)

  27. Event-Free Survival 100 n=156 80 60 p-value = 0.00304 Probability (%) 40 n=79 MRD Negative MRD > .01% 20 0 0 1 2 3 4 5 Years Prognostic Significance of MRD POG 9906 (Higher Risk) Michael Borowitz

  28. POG 9900 DAY 29 MRD (>.01%) IS PROGNOSTIC IN ALL STUDIES 9905 SR 9904 LR 9905 IR 9906 HR

  29. Prognostic Significance of Day 8 Blood MRD Courtesy of Michael Borowitz, MD

  30. MRD and Outcome Approaches to Define a Favorable Subset Courtesy of Michael Borowitz, MD Define Unfavorable Subset Define Favorable Subset

  31. Prognostic significance of TEL and Trisomy depends on MRD status NCI HR Day 29 MRD <.01% NCI HR Day 29 MRD >.01%

  32. 981% 923% 756% 4 y EFS % S.E.

  33. Proposed 2009 Classification EFS(%) Patients (%) Low Risk – NCI SR Triple Trisomy, TEL-AML 1; Day 8 PB, Day 29 BM MRD Negative 95 13 >85 50 Standard Risk – NCI SR w/o TT, Tel; NCI HR TT, Tel; day 29 BM Negative (< 0.01%) 70–85 17 High Risk – NCI HR; SR EM; day 29 BM MRD Negative (< 0.01%) 50 20 Very High Risk – NCI SR or HR; day 29 BM MRD > 0.01%

  34. Large, Randomized Clinical Trials Combination of Biology stratification with refined use of “old” formulary Intensification of early treatment Recent improvements In ALL Results

  35. 1970’s Therapy Induction Vcr/Steroids/Dauno/Asn Continuation Cyclo/6-TG/ARA-C 6-MP/Mtx IT Mtx+/- HC/ARA-C Asn Maintenance VCR/Pred Pulses Daily 6MP/Wkly MTX Year 2005 Induction Vcr/Steroids/Dauno/PEG-Asn Continuation Cyclo/6-TG/ARA-C 6-MP/Mtx IT Mtx+/- HC/ARA-C PEG-Asn Maintenance VCR/Pred Pulses Daily 6MP/Wkly MTX Changes in Chemotherapy Strategies in ALL No new drugs- Just smarter ways to give them!!

  36. Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children’s Cancer Group Bostrom BC, et Blood. 2003;101:3809-3817

  37. C C G Bleyer Day 7 Slow Response HR Subset Chosen to Test of Augmented BFM <5% Blasts (Leukemia Cells) in Bone Marrow by Steinherz PG, JCO P < 0.001

  38. Stronger intensification More therapy in less time Vcr + Capizzi I - Mtx/asparaginase for oral 6-MP/Mtx in interim maintenance (no leukovorin) Vcr/asparaginase during 2 weeks of count suppression following Cpm/araC/thiopurine pulses Longer Intensification DI phase x 2 10 versus 4 months of postinduction intensification Augmented ‘BFM’Longer and stronger postinduction intensification

  39. C C G Bleyer Success of Longer and Stronger Postinduction Intensification (SER) Nachman JB et al. N Engl J Med. 1998;338:1663-1671. CCG-1882 P < .001

  40. CCG-1961 DFS From RER Randomization:Comparison of Stronger Versus Standard Strength Intensification for Rapid Early Responders Stronger 81% Intensified MTX/Asn Standard 70% N = 1299 RHR 0.65 P = 0.0004 Seibel, NL et al Blood 2008 111: 2548-2555

  41. Why Study Asparaginase?

  42. Asparaginase Intolerance: Inferior Outcome

  43. DFCI ALL Consortium Protocols:Objectives DFCI Prot # ASN post Ind EFS 81-01 None 74% +/- 3% 85-01 20 wks 78% +/- 3% 91-01 30 wks 83% +/- 2%

  44. Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01Silverman LB, et al, Blood. 2001;97:1211-1218)

  45. CCG 1922 (Std Risk) Dexamethasone for Prednisone CCG 1961 (High Risk) Intensified MTX/ASP BFM-90, 95 antimetabolitie (MTX, 6TG, ARA-C) dexamethasone, asparaginase DFCI 91-01 Intensified Asparaginase, HDMTX, Increased Dexamethasone Recent Advances in Pediatric ALL

  46. With Increased intensity comes (often) increased toxicity Toxicities can be supported through improved understanding of the biology and pharmacogenetics of individual patient tolerance to agents Unique genetic and pharmacodynamic features of individual agents have a major impact on the outcome, toxicity and late sequalae of cancer chemotherapy Recent Advances in Pediatric ALL

  47. Corticosteroids Methotrexate Radiation to weight-bearing bones Hormonal influences from gonadal, thyroid, and growth hormones Chronic graft-versus-host disease requiring prolonged therapy with corticosteroids Osteoporosis/Osteopenia/ Osteonecrosis in Pediatric Cancer Survivors

  48. Osteonecrosis During the Treatment of Childhood Acute Lymphoblastic Leukemia: A Prospective MRI StudyOjala AE, et al Medical and Pediatric Oncology 32:11–17 (1999) The T1-weighted coronal planes (1.0 T, SE 500/15) of the right shoulder in a 3-year-old boy with IR ALL. A: The scan after the delayed intensification phase reveals osteonecrosis in the proximal humerus. B: At the cessation of the therapy, 2.5 years later, the lesion of osteonecrosis has disappeared.

  49. Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children’s Cancer Group Bostrom BC, et Blood. 2003;101:3809-3817

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