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Therapy

A comparison of early intensive methotrexate/mercaptopurine with early intensive alternating combination chemotherapy for high-risk B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group phase III randomized trial

Abstract

A prospective, randomized multicenter study was performed to evaluate the relative efficacy of two different concepts for early intensive therapy in a randomized trial of children with B-precursor acute lymphoblastic leukemia (ALL) at high risk (HR) for relapse. Four hundred and ninety eligible children with HR-ALL were randomized on the Pediatric Oncology Group (POG) 9006 phase III trial between 7 January 1991 and 12 January 1994. After prednisone (PDN), vincristine (VCR), asparaginase (ASP) and daunorubicin (DNR) induction, 470 patients received either 12 intensive parenteral treatments of intermediate dose (1 g/m2 each) methotrexate (MTX) and mercaptopurine (MP) over 24 weeks (regimen A) or 12 intensive course of alternating myelosuppressive drug combinations given over 30 weeks (regimen B). These drug combinations included MTX/MP, teniposide (VM-26)/cytosine arabinoside (AC) and VCR/PDN/DNR/AC/ASP. Central nervous system (CNS) prophylaxis was age-adjusted triple intrathecal chemotherapy. Patients with CNS disease at diagnosis were treated with craniospinal irradiation after the intensive phase. Continuation was standard doses of MTX and MP for 2 years. This trial was closed early because of an apparent early difference favoring regimen B. Results show that 470 patients achieved remission (97%). Two hundred and thirty two were randomized to regimen A and 238 to regimen B. The estimated 4-year event-free survival (EFS) for patients treated with regimen A is 61.6% (s.e. = 3.3%) and with regimen B is 69.4% (s.e. = 3.1%), P = 0.091. Toxicities were more frequent on regimen B. In conclusion, for children with B-precursor ALL at high risk to relapse, early intensification with myelosuppressive combination chemotherapy was more toxic but produced no significant difference in EFS when compared to those treated with parenteral methotrexate and mercaptopurine.

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References

  1. Pullen DJ, Crist WM, Falletta JM, Vogler LB, Dowell B, Humphrey GB, Blackstock R, Eys JV, Cooper MD, Metzgar RS, Meydrech EF . Southwest Oncology Group experience with immunological phenotyping in acute lymphocytic leukemia of childhood Cancer Res 1981 41: 4802–4809

    CAS  PubMed  Google Scholar 

  2. Look AT, Roberson PK, Williams DL, Rivera G, Bowman WP, Pui CH, Ochs J, Abromowitch M, Kalwinsky D, Dahl GV, George S, Murphy SB . Prognostic importance of blast cell DNA content in childhood acute lymphocytic leukemia Blood 1985 65: 1079–1086

    CAS  PubMed  Google Scholar 

  3. Miller DR, Coccia PF, Bleyer WA, Lukens JN, Siegel SE, Sather HN, Hammond GD . Early response to induction therapy as a predictor of disease-free survival and late recurrence of childhood acute lymphoblastic leukemia: A report from the Children's Cancer Study Group J Clin Oncol 1989 7: 1807–1815

    Article  CAS  Google Scholar 

  4. Pui C-H, Crist WM, Look AT . Biology and clinical significance of cytogenetic abnormalities in childhood acute lymphoblastic leukemia Blood 1990 76: 1449–1463

    CAS  PubMed  Google Scholar 

  5. Gaynon PS, Bleyer AW, Steinherz PG, Finklestein JZ, Littman P, Miller DR, Reaman G, Sather H, Hammond GD . Day 7 marrow response and outcome for children with acute lymphoblastic leukemia and unfavorable features Med Pediatr Oncol 1990 18: 273–279

    Article  CAS  Google Scholar 

  6. Pui C-H, Behm FG, Crist WM . Clinical and biologic relevance of immunologic marker studies in childhood acute lymphoblastic leukemia Blood 1993 82: 343–362

    CAS  PubMed  Google Scholar 

  7. Camitta BM, Pullen J, Murphy S . Biology and treatment of acute lymphocytic leukemia in children Sem Oncol 1997 24: 83–91

    CAS  Google Scholar 

  8. Shuster JJ, Camitta BM, Pullen, Borowitz MJ, Carroll AJ, Look AT, Mahoney DH, Mahmoud H, Lauer SJ, Land VJ . Identification of newly diagnosed children with acute lymphocytic leukemia at high risk for relapse Cancer Res Ther and Control 1999 9: 101–107

    Google Scholar 

  9. Steinherz PG, Gaynon P, Miller DR, Reaman G, Bleyer A, Finklestein J, Evans RG, Meyers P, Steinherz LJ, Sather H, Hammond D . Improved disease-free survival of children with acute lymphoblastic leukemia at high risk for early relapse with the New York regimen – a new intensive therapy protocol: a report from the Children's Cancer Study Group J Clin Oncol 1986 4: 744–52

    Article  CAS  Google Scholar 

  10. Gaynon PS, Bleyer WA, Steinherz PG, Finklestein JZ, Littman PS, Miller DR, Reaman GH, Sather HN, Hammond GD . Modified BFM therapy for children with previously untreated acute lymphoblastic leukemia and unfavorable prognostic features; report of the Children's Cancer Study Group Study CCG-193P Am J Pediatr Hematol Oncol 1988 10: 42–50

    Article  CAS  Google Scholar 

  11. Rivera GK, Raimondi SA, Hancock ML, Behm FG, Pui CH, Abramowitch M, Mirro J Jr, Ochs JS, Look AT, Williams DL, Murphy SB, Dahl GV, Kalwinsky DK, Evans WE, Kun LE, Simone JV, Christ WM . Improved outcome in childhood acute lymphoblastic leukemia with reinforced early treatment and rotational combination chemotherapy Lancet 1991 337: 61–66

    Article  CAS  Google Scholar 

  12. Gaynon PS, Steinherz PG, Bleyer WA, Ablin AR, Albo VC, Finklestein JZ, Grossman NJ, Novak LJ, Pyesmany AF, Reaman GH, Chappell RJ, Sather HN, Hammond GD . Improved therapy for children with acute lymphoblastic leukemia and unfavorable presenting features: A follow-up report of the Children's Cancer Group Study CCG-106 J Clin Oncol 1993 11: 2234–2242

    Article  CAS  Google Scholar 

  13. Lauer SJ, Camitta BM, Leventhal BG, Mahoney D, Shuster JJ, Adair S, Casper J, Civin C, Graham M, Keifer G, Pullen J, Steuber P, Kamen B . Intensive alternating drug pairs for treatment of high-risk childhood acute lymphoblastic leukemia Cancer 1993 71: 2854–2861

    Article  CAS  Google Scholar 

  14. Reiter A, Schrappe M, Ludwig WD, Hiddemann W, Sauter S, Henze G, Zimmermann M, Lampert F, Havers W, Niethammer D, Odenwald E, Ritter J, Mann G, Welte K, Gadner H, Riehm H . Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients. Results and conclusions of the multicenter trial ALL-BFM 86 Blood 1994 84: 3122–3133

    CAS  Google Scholar 

  15. Schorin MA, Blattner S, Gelber RD, Tarbell NJ, Donnelly M, Dalton V, Cohen HJ, Sallan SE . Treatment of childhood acutelymphoblastic leukemia: Results of Dana-Farber Cancer Institute/Children's Hospital acute lymphoblastic leukemia consortium Protocol 85–01 J Clin Oncol 1994 12: 740–747

    Article  CAS  Google Scholar 

  16. Land VJ, Shuster JJ, Crist WM, Ravindranath Y, Harris MB, Krance RA, Pinkel D, Pullen DJ . Comparison of two schedules of intermediate-dose methotrexate and cytarabine consolidation therapy for childhood B-precursor cell acute lymphoblastic leukemia: A Pediatric Oncology Group Study J Clin Oncol 1994 12: 1939–1945

    Article  CAS  Google Scholar 

  17. Camitta BM, Mahoney D, Levethal BG, Lauer SJ, Shuster JJ, Adair S, Civin C, Munoz L, Steuber P, Strother D, Kamen BA . Intensive intravenous methotrexate and mercaptopurine treatment of high-risk non-T acute lymphocytic leukemia J Clin Oncol 1994 12: 1383–1389

    Article  CAS  Google Scholar 

  18. Winick N, Shuster JJ, Bowman WP, Borowitz M, Farrow A, Jacaruso D, Buchanan GR, Kamen BA . Intensive oral methotrexate protects against lymphoid marrow relapse in childhood B-precursor acute lymphoblastic leukemia J Clin Oncol 1996 14: 2803–2811

    Article  CAS  Google Scholar 

  19. Nachman J, Sather HN, Cherlow JM, Sensel MG, Gaynon PS, Lukens JN, Wolff L, Trigg ME . Response of children with high-risk acute lymphoblastic leukemia treated with and without cranial irradiation: A report from the Children's Cancer Group J Clin Oncol 1998 16: 920–930

    Article  CAS  Google Scholar 

  20. Richards S, Burrett J, Hann I, Chessells J, Hill F, Bailey C . Improved survival with early intensification: combined results from Medical Research Council Childhood ALL randomized trials, UKALL X and UKALL XI Leukemia 1998 12: 1031–1036

    Article  CAS  Google Scholar 

  21. Tubergen DG, Gilchrist, O'Brien RT, Coccia PF, Sather HN, Waskerwitz MJ, Hammond GD . Improved outcome with delayed intensification for children with acute lymphoblastic leukemia and intermediate presenting features: A Children's Cancer Group Phase III Trial J Clin Oncol 1993 11: 527–537

    Article  CAS  Google Scholar 

  22. Wheeler K . Chessells JM, Bailey CC, Richards SM. Treatment related deaths during induction and in first remission in acute lymphoblastic leukemia: MRCUKALLX Arch Dis Child 1996 74: 101–107

    Article  CAS  Google Scholar 

  23. Goldie JH, Coldman AJ, Gudauskas GA . Rationale for the use of alternating non- cross-resistant chemotherapy Cancer Treat Rep 1982 66: 439–449

    CAS  Google Scholar 

  24. Borowitz MJ, Carroll AJ, Shuster JJ, Look AT, Behm FG, Pullen DJ, Land VJ, Steuber P, Crist WM . Use of clinical and laboratory features to define prognostic subgroups in B-precursor acute lymphoblastic leukemia: experience of the Pediatric Oncology Group Rec Results Cancer Res 1993 131: 257–267

    Article  CAS  Google Scholar 

  25. Trueworthy R, Shuster J, Look T, Crist W, Borowitz M, Carroll A, Frankel L, Harris M, Wagner H, Haggard M, Mosijczuk A, Pullen J, Steuber P, Land V . Ploidy of lymphoblasts is the strongest predictor of treatment outcome in B-precursor cell acute lymphoblastic leukemia. A Pediatric Oncology Group Study J Clin Oncol 1992 10: 606–613

    Article  CAS  Google Scholar 

  26. Pullen DJ, Crist WM, Falletta JM, Boyette JM, Roper M, Dowell B, van Eys J, Humphrey GB, head D, Brock BL, Blackstock R, Metzgar RS, Cooper MD . A Pediatric Oncology Group classification protocol for acute lymphocytic leukemia (ALinC 13): Immunologic phenotypes and correlation with treatment results. In Murphy SB, Gilbert JR (eds) Leukemia Research: Advances in Cell Biology and Treatment Elsevier: Amsterdam 1994 pp 221–239

    Google Scholar 

  27. Crist WM, Carroll A, Shuster JJ, Behm FG, Whitehead M, Vietti TJ, Look AT, Mahoney D, Ragab A, Pullen DJ, Land VJ . Poor prognosis of children with pre-B acute lymphoblastic leukemia with the t (1;19) (q23;p13): A Pediatric Oncology Group Study Blood 1990 76: 117–122

    CAS  PubMed  Google Scholar 

  28. Fletcher JA, Lynch EA, Kimball VM, Donnelly M, Tantravahi R, Sallan SE . Translocation (9;22)is associated with extremely poor prognosis in intensively treated children with acute lymphoblastic leukemia Blood 1991 77: 435–439

    CAS  PubMed  Google Scholar 

  29. Shuster JJ . Handbook of Sample Size Guidelines for Clinical Trials CRC Press: Boca Raton 1992

    Google Scholar 

  30. Kaplan EL, Meier P . Nonparametric estimation from incomplete observation J Am Stat Assoc 1958 53: 457–481

    Article  Google Scholar 

  31. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, Mantel N, McPherson K, Peto J, Smith PG . Design and analysis of randomized clinical trials requiring prolonged observation of each patient: II. Analysis and examples Br J Cancer 1977 35: 1–39

    Article  CAS  Google Scholar 

  32. Cox DR . Regression models and life-tables J R Stat Soc 1972 34: 187–220

    Google Scholar 

  33. Mahoney DH, Shuster J, Nitschke R, Lauer SJ, Winick N, Steuber CP, Camitta B . Intermediate-dose intravenous methotrexate with intravenous mercaptopurine is superior to repetitive low-dose oral methotrexate with intravenous mercaptopurine for children with lower-risk B-lineage acute lymphoblastic leukemia: A Pediatric Oncology Group Phase III Trial J Clin Oncol 1998 16: 246–254

    Article  CAS  Google Scholar 

  34. Mahoney DH, Shuster JJ, Nitschke R, Lauer SJ, Steuber CP, Winick N, Camitta B . Acute neurotoxicity in children with B-precursor acute lymphoid leukemia: An association with intermediate-dose intravenous methotrexate and intrathecal triple therapy-A Pediatric Oncology Group Study J Clin Oncol 1998 16: 1712–1722

    Article  CAS  Google Scholar 

  35. Smith M, Arthur D, Camitta B, Carroll AJ, Crist W, Gaynon P, Gelber R, Heerema N, Korn EL, Link M, Murphy S, Pui CH, Pullen J, Reamon G, Sallan SE, Sather H, Shuster J, Simon R, Trigg M, Tubergen D, Uckun F, Ungerleider R . Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia J Clin Oncol 1996 14: 18–24

    Article  CAS  Google Scholar 

  36. Harris MB, JJ Shuster, Pullen J, Borowitz MJ, Carroll AJ, Behm FG, Land VJ . Consolidation therapy with antimetabolite – based therapy in standard risk acute lymphocytic leukemia of childhood: A Pediatric Oncology Group Study J Clin Oncol 1998 16: 2840–2847

    Article  CAS  Google Scholar 

  37. Chessells JM, Bailey C, Richards SM: Intensification of treatment and survival in all children with lymphoblastic Leukemia . Results of UR Medical Research Council trial UKALL X Lancet 1995 345: 143–147

    Article  CAS  Google Scholar 

  38. Pui CH, Simone JV, Hancock ML, Evans WE, Williams DL, Bowman WP, Dahl GV, Dodge RK, Ochs J, Abromowitch M, Rivera GK . Impact of three methods of treatment intensification on acute lymphoblastic leukemia in children. Long-term results of St. Jude's Total Therapy Study X Leukemia 1992 6: 150–157

    CAS  PubMed  Google Scholar 

  39. Fojo AT, Ueda K, Slamon DJ, Poplack DG, Gottesman MM, Pastan I . Expression of a multi-drug resistant gene in human tumors and tissues Proc Natl Acad Sci USA 1987 84: 265–269

    Article  CAS  Google Scholar 

  40. Bhalla K, Hindenburg A, Taub RN, Grant S . Isolation and characterization of an anthracycline-resistant human leukemia cell line Cancer Res 1985 45: 3657–6662

    CAS  PubMed  Google Scholar 

  41. Kohn W . DNA topoisomerase as targets of anticancer drug action Proc Am Assoc Cancer Res 1989 30: 669–671

    Google Scholar 

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Acknowledgements

This work was supported in part by the following grants from the National Cancer Institute, Bethesda, MD: CA 20549, CA 29139, CA 03161, CA 33625, CA 32053, CA 15989, CA 30969.

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Lauer, S., Shuster, J., Mahoney, D. et al. A comparison of early intensive methotrexate/mercaptopurine with early intensive alternating combination chemotherapy for high-risk B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group phase III randomized trial. Leukemia 15, 1038–1045 (2001). https://doi.org/10.1038/sj.leu.2402132

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