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Current Treatment of Childhood Acute Lymphoblastic Leukemia

Current Treatment of Childhood Acute Lymphoblastic Leukemia. Ahmed Naqvi The Hospital for Sick Children University of Toronto Canada. Most important risk assignment factors. At diagnosis NCI criteria CNS status Testicular disease Induction Day 7 or 14 BMA status

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Current Treatment of Childhood Acute Lymphoblastic Leukemia

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  1. Current Treatment of Childhood Acute Lymphoblastic Leukemia Ahmed Naqvi The Hospital for Sick Children University of Toronto Canada

  2. Most important risk assignment factors • At diagnosis NCI criteria CNS status Testicular disease • Induction Day 7 or 14 BMA status • End of induction Bone marrow status Cytogenetics MRD status

  3. ALL-Phases of therapy • Induction of Remission • Consolidation/CNS directed therapy • Delayed intensification • Maintenance or continuation

  4. ALL-Phases of therapy • Induction of Remission • No of drugs • Choice of corticosteroid • Definition of remission • Consolidation • CNS directed therapy • Delayed intensification • Maintenance or continuation

  5. Complete remission rates (%) • Single agents • Methotrexate (MTX) 20-40 • Mercaptopurine (MP) 25 • Prednisone (Pred) 40-60 • Vincristine (VCR) 60-80 • Daunorubicin (DNR) 5-40 • L-Asparaginase (ASP) 45-70 • Drugs combinations • VCR/Pred 85 • VCR/Pred/ASP 90-95 • Pred/VCR/MTX/MP 90 • VCR/Pred/ASP/DNR 98 Cancer Res 1969;29:2272-2280 Pediatr Clin North Am 1988;35:903-1932

  6. CCG 1922 March 1993 to 1995 • NCI low risk • 2 randomizations • Induction Pred/VCR/ASP/IT MTX VS Dex/VCR/ASP/IT MTX • Consolidation PO 6MP VS IV 6MP • N=OP 270, OD 274 • 6 year EFS ± SE • 85% ±2% for OD • 77% ±2% for OP p=.002

  7. 6 year risk of isolated CNS relapse ± SE • Dexamethasone 3.7% ± 0.8% • Prednisone 7.1% ± 1.1% p=.01 • Conclusions: • Dexamethasone significantly improves the outcome of children with standard risk ALL • Neither infectious complications nor AVN was problematic

  8. DFCI 91-01 pilot protocol • Investigational window Steroids X 3 days • Pred (40mg/m2 )VS Dex (6,18 or 150mg/m2) • Induction • Day 1 ASP, Day 4-32 VCR X 4, Dex x28 days, Days 4 & 5 DOX, Day 5 HDMTX • 16/38 (42%) septic episodes incl 4 Deaths (11%) • 87-01had 4/369 (~1%) induction deaths p=0.0035 • 91-01had 1/377 (≤1%) induction deaths p=0.0003 • Un-published COG

  9. Definition of remission • When? • ? <5% blasts in Bone Marrow Aspirate • 0.01% to 0.99 % residual blasts after 6 wks—Standard risk • ≥1% residual blasts ---- High Risk

  10. Proposed Induction Chemotherapy • NCI std risk 3 Drugs (VCR, ASP, DEX ) • NCI high risk 4 Drugs (VCR, ASP, PRED,DAUN) • BMA Day 7 • if M1, No Day 15 BMA • If M2/M3 repeat BMA on D15 • BMA on Day 15 (in case it was M2 or M3 on Day7) • If still M2 or M3 add Dauno and 3 more doses of ASP

  11. Proposed Induction Chemotherapy BMA on Day 28 • M1 and was M1 on Day 7 or 15 • NCI std risk at diagnosis continue on low risk protocol • NCI high risk at diagnosis continue on high risk protocol • M1 but D15 was M2 or M3 • Continue on high risk protocol • if still M2 or M3--- Continue 2 more weeks of induction with 4 drugs • If remission go to HR if not go to VHR

  12. ALL-Phases of therapy • Induction of Remission • Consolidation/CNS directed therapy • Methotrexate • Cranial Irradiation • Delayed intensification • Maintenance or continuation

  13. Cancer and Leukemia Group B (CALBG) 7611 • 1976-1979 • N=596 • IDM 500mg/m2 x 3 during consolidation • CRT 2400 cGy • 12 year EFS 37±3.6% and OS 49±3.5% for all patients

  14. Hem Relapse IDM 27±3% CRT43±3% p=0.0006

  15. CNS Relapse IDM 28±3% CRT 8±2% P<0.0001

  16. Test. Relapse IDM 2±1% CRT 13±3% p=0.002

  17. Conclusions: • CRT offered better CNS protection in all patients • IDM offered better systemic protection in standard risk patients and testicular in all patients • Disease free and over all survival was the same in both groups

  18. Meta-analysis of RCT of ALL therapy 1993 onwards • Six comparison groups • A XRT plus IT therapy VS Addl IT therapy 2p>0.1 • B Addition of IV MTX to long term IT therapy or XRT with IT therapy 2p=0.003 • C XRT plus short term IT therapy VS IV MTX plus short term IT therapy 2p>0.1 • D Higher doses of XRT 2>p0.1 • E XRT plus short term IT therapy VS IV MTX plus long term IT therapy 2p>0.1 • F Addition of IV MTX plus IT therapy to XRT plus IT therapy and/or IV MTX 2p>0.1

  19. Group B: Addition of IV MTX to long term IT therapy or XRT with IT therapy IV MTX Control 439/1598(27.5%) 513/1591(32.2%) OS at 10 yrs 80.1% 76.8% p=.09 EFS at 10 yrs 68.1% 61.9% • Annual rate of non-CNS relapse reduced by 17% with IV MTX p=.02 • Annual rate of CNS relapse also reduced by 19% p=.08 • Significant reduction in the overall event rate of 17% 2p=0.003 JCO;2003;21(9);1798-1809

  20. Conclusions: • Radiotherapy can be replaced by long term IT therapy without detriment to EFS or OS • IT MTX gives some additional benefit by reducing non CNS relapses • No effect on OS

  21. Comparison of intermediate-dose methotrexate with cranial irradiation for the post-induction treatment of acute lymphocytic leukemia in children NEJM 1983;308:477-481 • POG n=506 children and adolescents • ID MTX + IT therapy VS 2400cGy CRT • Standard Risk • Hematological relapse • MTX 9/117 • CRT 24/120 p<0.01 • CNS Relapse • MTX 23/117 • CRT 8/120 p=0.01 • High Risk • No difference in hematological relapse • CRT better protection to CNS p=0.03 • Standard + high risk • Testicular relapse much less in ID MTX (1 pt) vs CRT (10 pts) p=0.01

  22. N=709 • Reg A=349 • Reg B= 350 • Reg A=MTX 1gm/m2IV X12 • And MP 1gm/m2 IV X 12 • Reg B= PO MTX 30 mg/m2 • Q 6H X 6 doses and MP • 1gm/m2 IV X 12 • CCR for pts randomized to • Regimen A or B • 80.3% vs 75.9% • P=0.013

  23. N=24 <5years old T-cell ALL 1983-1999 Radiation 1800 cGy Cranial VS 8 Gm/m2 IV EFS 92±8% for MTX VS 75±13% for XRT p=0.23 OS 100% in HD MTX VS 75±13% for XRT p=0.07 Conclusion: HD MTX doses not compromise survival , while avoiding the long term effects of CRT

  24. Effects of cranial radiation in children with high risk T cell acute lymphoblastic leukemia: A pediatric Oncology group report.Laver JH et al Leukemia 2000;14:369-373 • N=222 • T-ALL • WBC >50,000 and/or CNS disease • POG studies between 1987-1995 • CRT vs TIT • 3-year CNS relapse rate in TIT group 18 VS 7%; p=0.012 • 3 year EFS was similar for both groups 65 vs 63% p=0.46

  25. Current Practice of CNS directed therapy • Cranial Irradiation is getting out of practice in favor of more intense systemic and IT therapy • St. Judes Total Therapy XV protocol----no CRT even to CNS positive patients • T-Cell ALL • 1200 cGy to children >5 years of age • HD MTX to children <5 years of age • 1800 cGy to CNS positive • B-precursor ALL • No preventive CRT for Precursor B-ALL except for some high and very high risk groups • 1800 cGy to CNS positive children

  26. ALL-Phases of therapy • Induction of Remission • Consolidation/CNS directed therapy • Delayed intensification • Maintenance or continuation

  27. CCG Dec1988-Dec 1992 • Impact of adding a single delayed Intensification • 2-9 yrs, WBC < 10,000 • N=778/Randomized 700 • Standard 351 DI 349 JCO 2003;21(9);1790-97

  28. CCR at 7 yrs SR 77% DI 83% P=0.072 NS OS at 10 yrs 90% P=0.84 Single DI augmented 7 year CCR by 6% resulting in 26% fewer AE

  29. C= Late Int only 146/364 D= Both 122/365 DFS 2p=0.10

  30. OS C= late int only 95/364 D= both 61/364 2p=0.005

  31. CCG Jan 91-Jun 95 • N=356 156 std therapy 155 augment • High risk 1-9 yrs and WBC ≥50,000 • ≥ 10 yrs of age • SER >25% blasts at Day 7 • Random allocation to std or augmented BFM • Median f/u 49 mo (2-82)

  32. Optimal duration of therapy • BFM 81 and 83 randomized pts to receive 18 or 24 months • EFS at 8 yrs 77.3% for 24 months (n=375) vs 71.2% for 18 months (n=389) p=0.025 Leukemia 2000;14;2205-2222

  33. Maintenance or continuation • Oral 6 Mercaptopurine daily • Oral Methotrexate weekly • Divided dose Methotrexate biweekly • Vincristine and Steroid pulses • Intrathecal therapy

  34. Who needs a Bone Marrow transplant in first remission ? • Hypodiploid • Philadelphia chromosome positive ALL • Failed induction • MLL gene rearrangement with SER on Day 15 marrow

  35. Late sequelae • Topoisomerase II inhibitors related Acute Myeloid Therapy • Radiation induced endocrinological toxicities and brain tumors

  36. New drugs • Targeted Therapies • Phase III 506U78 ( a prodrug of arabinosylguanine) • Phase II Campath1-H • Phase I Epratuzumab Dacluzumab Notch 1 inhibitor (gamma Secretase inhibitor)

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