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.
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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 The Herman and Walter Samuelson Children’s Hospital at Sinai, Baltimore, MD Goals and Objectives 1. 2. 3. 4. 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 Conflicts of Interest • 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 Acute Leukemia • 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 in Childhood • • • • • 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 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 Lymphoblastic Leukemia Is the Most Common Childhood Cancer Annual Incidence per Million 35 30 25 20 15 10 5 0 S RB S RM L AM T HD W L NH S NB BT L AL Yearly Incidence of Childhood Cancers Acute Lymphoblastic Leukemia • 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 Clinical Features • 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 Leukemia Clinical Features • • • • • Fever, bone pain, limp Peripheral blood cytopenias Hepatosplenomegaly, lymphadenopathy Infections, fatigue, bleeding CNS symptoms, airway compression Acute Lymphocytic Leukemia Peripheral Smears Acute Lymphocytic Leukemia Bone Marrow Aspirates Acute Lymphoblastic Leukemia Prognostic Features 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) ALL- Treatment • 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 Survival of Patients With Acute Lymphoblastic Leukemia, 1968-1997 Years of Number of CCG Bleyer Diagnosis Children 100 % Survival 80 60 1995-97 1299 1993-95 1585* 1989-93 1983-89 1978-83 1975-78 1972-75 3402 3711 2984 1313 936 CNS Prophylaxis introduced 40 20 0 2 4 6 Years After Study Entry 8 1970-72 499 1968-70 402 10 Total Number of Patients Treated: 16,131 *Excluding infants. SEER 5-Year Survival Rates Age < 15 years Survival 1974-1976 Survival 1992-1999 % Increase Survival % Decrease Death Bone 55 72 31 38 Brain 55 70 27 33 Hodgkin’s 78 94 21 23 ALL 53 85 60 68 AML 14 47 236 38 Jemal A et al. CA Cancer J Clin. 2004;54:8-29. 1.0 0.6 0.4 CCG 0.2 CALGB (median CALGB (median = 2.5) = 2.5 y) 0.0 Proportion 0.8 CCG Bleyer EFS of Young Adults Aged 16 to 21 onEFSCCG and CALGB Trials of Young Adults with ALL for ALL (1988-1995) 0 2 4 6 Years 8 10 Key Components of Successful Therapy • Empiric multi-agent chemotherapy • Pre-symptomatic CNS therapy • Post-induction intensification • Anti-metabolite therapy • Re-induction/re-consolidation • Risk adapted therapy Acute Leukemia in Childhood Biologic Features • • • • • Morphologic Features Immunophenotype Karyotype DNA features Response to therapy Genetic Heterogeneity in Childhood ALL Children’s Oncology Group 11q23 4% TEL-AML1 18% 14q11 3% Ph 2% t(1;19) 4% “Normal” 26% < 45 Chrom 1% 45 Chrom 3% Pseudodiploid 10% > 50 Chrom 47-50 Chrom 6% 26% Genotype Correlates with Outcome Children’s Oncology Group 100 Probability Trisomies 4,10,17 (n = 746) TEL (n =176) 80 t(1;19) (n = 139) 60 t(4;11) (n = 44) 40 4 Yr EFS (%) Tris 4,10,17 92.1 TEL 89.0 t(1;19) 68.9 t(4;11) 49.9 t(9;22) 27.5 20 0 0 1 2 3 4 t(9;22) (n=132) SE (%) 1.1 3.1 4.1 11.2 4.4 5 6 B-precursor ALL 7 8 9 10 Years Followed 11 12 13 14 15 16 10/2001 Rate of Initial Response is Strong Predictor of Event-FreeSurvival <5 % Blasts in Bone Marrow 1 0.9 Day 7= Rapid Early Response 0.8 0.7 0.6 0.5 Day 14 =Intermediate Early Response 0.4 0.3 0.2 p=.0005 Day 28 =Slow Early Response 0.1 0 0 2 4 6 8 10 12 14 Years Steinherz, et al: JCO 14: 389-398, 1996 16 18 COG ALL Risk Groups B-Precursor ALL • NCI Risk Groups Low Risk • 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 Standard Risk High Risk Very High Risk Outcome by New Risk Group Definitions B-precursor ALL 100 Low Risk (n=544) Standard Risk (n=1471) Probability 80 High Risk (n=880) 60 40 Very High Risk (n=78) Risk Group Low Standard High Very High 20 4 Yr EFS (%) 91.5% 82.1% 72.9% 33.6% SE (%) 1.6 1.4 2.1 6.0 0 0 1 2 3 4 5 6 Years Followed 7 8 9 10/2001 Flow Cytometry for ALL Identification Acute Lymphoblastic Leukemia B-Precursor Standard Risk (COG AALL0331) MRD at Day 29 COG A A LL0331 100.0% 91.6% 90.0% MRD 80.0% # of Patients % > 1.0% 42 2.7% 0.1-0.99% 89 5.7% <0.1% 1435 91.6% Total 1566 100% % of patients 70.0% 60.0% 50.0% 40.0% 30.0% 20.0% 10.0% 2.7% 5.7% 0.0% > 1.0% 0.1-0.99% % MRD by Flow Cytometry <0.1% Prognostic Significance of MRD POG 9906 (Higher Risk) Event-Free Survival Probability (%) 100 80 n=156 60 p-value = 0.00304 40 MRD > .01% MRD Negative n=79 20 0 0 1 2 3 Years 4 5 Michael Borowitz POG 9900 DAY 29 MRD (>.01%) IS PROGNOSTIC IN ALL STUDIES 1.0 0.2 0.8 0.6 P 0.0001 Negative n 462 Positiven 119 0.0 Negative n 668 Positiven 105 0.4 P 0.0001 9905 SR 0.2 0.4 0.6 0.8 Event-free survival probability 1.0 9905 NCI Standard Risk EFS by Day 28 Marrow MRD (Cutoff=0.01%) 0.0 Event-free survival probability 9904 LR 9904 EFS by Day 28 Marrow MRD (Cutoff=0.01%) 0 1 2 3 4 5 6 0 1 2 Years 4 5 Years 1.0 0.8 0.6 0.4 P 0.0001 Negative n 156 Positiven 84 0.0 0.0 Negative n 292 Positiven 73 9906 HR 0.2 Event-free survival probability 1.0 0.8 0.6 0.4 0.2 P 0.0001 0 1 2 3 Years 4 6 EFS by Day 28 Marrow MRD (Cutoff=0.01%) EFS by Day 28 Marrow MRD (Cutoff=0.01%) Event-free survival probability 9905 IR 3 9906 9905 NCI High Risk 5 6 0 1 2 3 Years 4 5 Prognostic Significance of Day 8 Blood MRD Courtesy of Michael Borowitz, MD MRD and Outcome Approaches to Define a Favorable Subset Day 8 Blood Overall MRD negative 3 Yr EventFree Survival 74±3 Courtesy of Michael Borowitz, MD 87±5 vs 71±4 Day 29 Marrow MRD positive 58±6 vs 79±5 Define Favorable Define Unfavorable Subset Subset Prognostic significance of TEL and Trisomy depends on MRD status NCI HR Day 29NCIMRD <.01% High Risk NCI HR and 9906 Day 299905 MRD >.01% NCI High Risk 9905 and 9906 Day 28 Marrow MRD Negative (Cutoff=0.01%) 0.4 0.6 0.8 1.0 NoTEL AML1orTrisomies4and10 n 189 TEL AML1orTrisomies4and10 n 131 P 0.9304 0.2 Event-free survival probability 0.8 0.6 0.4 0.2 P 0.0006 NoTEL AML1orTrisomies4and10 n 92 TEL AML1orTrisomies4and10 n 27 0.0 0.0 Event-free survival probability 1.0 Day 28 Marrow MRD Positive (Cutoff=0.01%) 0 1 2 3 Years 4 5 6 0 1 2 3 Years 4 5 1.0 EFS by Day-8/Day29 MRD categories 0.8 981% 0.6 923% 756% 0.4 4 y EFS % S.E. 0.2 P 0.0001 Bad Day29 0.01% n 105 Go od Day8 0.01%, Day29 0.01% n 262 Other Day8 0.01% Day29 0.01% n 338 0.0 Event-free survival probability 9904 0 1 2 3 Years 4 5 6 Proposed 2009 Classification EFS(%) Patients (%) Low Risk – NCI SR Triple Trisomy, TEL-AML 1; Day 8 PB, Day 29 BM MRD Negative 95 13 Standard Risk – NCI SR w/o TT, Tel; NCI HR TT, Tel; day 29 BM Negative (< 0.01%) >85 50 High Risk – NCI HR; SR EM; day 29 BM MRD Negative (< 0.01%) 70–85 17 Very High Risk – NCI SR or HR; day 29 BM MRD > 0.01% 50 20 Recent improvements In ALL Results • Large, Randomized Clinical Trials • Combination of Biology stratification with refined use of “old” formulary • Intensification of early treatment Changes in Chemotherapy Strategies in ALL • 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 No new drugs- Just smarter ways to give them!! 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 1 0.95 PRED 0.9 (N=530) 0.85 0.8 0.75 0.7 DEX (N=530) 0.65 6 YEAR EFS (p=.003): PRED 77.3% DEX 84.8% 0.6 0.55 0.5 0 1 2 3 4 5 6 Bostrom BC, et Blood. 2003;101:3809-3817 7 8 CCG Bleyer Day 7 Slow Response HR Subset Chosen to Test of Augmented BFM Steinherz PG, JCO P < 0.001 <5% Blasts (Leukemia Cells) in Bone Marrow by Augmented ‘BFM’ Longer and stronger postinduction intensification • 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 CCG 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 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 Why Study Asparaginase? Asparaginase Intolerance: Inferior Outcome 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% Improved outcome for children with acute lymphoblastic leukemia: results of DanaFarber Consortium Protocol 91-01 Silverman LB, et al, Blood. 2001;97:1211-1218) Recent Advances in Pediatric ALL 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 Postinduction intensification Study CCG-105 Average risk CCG-1881 Lower risk CCG-1891 Average risk CCG-1882 Higher risk/SER CCG-1961 Higher risk/RER Intervention DI DI DDI Longer + stronger intensification Stronger intensification EFS 60% vs 74% @ 10 years 77% vs 83% @ 7 years 76% vs 83% @ 6 years 55% vs 75% @ 5 years 70% vs 81% @ 5 years Recent Advances in Pediatric ALL • 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 Osteoporosis/Osteopenia/ Osteonecrosis in Pediatric Cancer Survivors • • • • 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 Osteonecrosis During the Treatment of Childhood Acute Lymphoblastic Leukemia: A Prospective MRI Study Ojala 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. 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 1 0.95 PRED 0.9 (N=530) 0.85 0.8 0.75 0.7 DEX (N=530) 0.65 6 YEAR EFS (p=.003): PRED 77.3% DEX 84.8% 0.6 0.55 0.5 0 1 2 3 4 5 6 7 Bostrom BC, et Blood. 2003;101:3809-3817 8 Osteonecrosis as a Complication of Treating Acute Lymphoblastic Leukemia in Children: A Report From the Children’s Cancer Group (CCG 1882) Mattano LA, et al,. J Clin Oncol 18:3262, 2000 Osteonecrosis as a Complication of Treating Acute Lymphoblastic Leukemia in Children: A Report From the Children’s Cancer Group (CCG 1882) Mattano LA, et al,. J Clin Oncol 18:3262, 2000 Acute Leukemia Outcome Measures Hypothesis: Increased emphasis on outcomes of therapy including measures of psychological, emotional and physical well-being will optimize treatment Approach: Parallel studies to address: Burdens of care (financial, emotional) Neurotoxicity (methotrexate, dexamethasone) • • Effects of intensified therapy on stem cells • Bone mineral content and avascular necrosis Annual Incidence per Million Relapsed ALL Remains a Common Problem 35 30 25 20 15 r ALL 10 5 0 S M L M S B R R A D H LL rA T W L H N S B N LL T B A Most Patients Who Relapse Once Die! Despite high remission-induction rates and BMT CCG-1900 series trials Survival After 1st Relapse Any site (809) 3-year Survival Rate 40% Bone marrow (505) 28% Isolated CNS (185) 60% Isolated testes (52) 60% Site of relapse (n) Acute Leukemia • Progress in treatment and cure rates for leukemia in childhood has been dramatic in 40 years • Progress has been achieved through subsequent clinical research • Incorporation of biology has led to tailoring therapy and improving outcomes • There is room for new agents but biology and genetics are stronger factors in controlling outcomes • Better understanding of the “right” way to give currently available agents still shows benefits in current trial strategies Summary Your head is round so that your thinking can change direction…