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Long-term results of Total Therapy studies 11, 12 and 13A for childhood acute lymphoblastic leukemia at St Jude Children's Research Hospital

Leukemia volume 14, pages 2286–2294 (2000)Cite this article

Abstract

We present the long-term results of three consecutive clinical trials (total therapy studies 11, 12 and 13a) conducted for children with newly diagnosed acute lymphoblastic leukemia (all) between 1984 and 1994. in study 11 (1984–1988), the overall event-free survival rates (±1 s.e.) were 71.8 ± 2.4% and 69.3 ± 2.4%, and the cumulative risks of isolated central nervous system (cns) relapse 5.6 ± 1.2% and 5.9 ± 1.3%, at 5 and 10 years, respectively. in study 12 (1988–1991), event-free survival rates were 67.6 ± 3.4% and 61.5± 9.0%, and isolated cns relapse rates were 10.4 ± 2.3% and 10.4 ± 2.3%, respectively. early intensive intrathecal therapy in study 13a (1991–1994) has yielded a very low 5-year isolated cns relapse rate of 1.2 ± 0.9%, boosting the 5-year event-free survival rate to 76.9 ± 3.3%. factors consistently associated with an adverse prognosis included male sex, infant or adolescent age group, leukocyte count >100 × 109/l, nonhyperdiploidy karyotype and poor early response to treatment. Risk classification based on age and leukocyte count had prognostic significance in B-lineage but not T-lineage ALL. Early therapeutic interventions or modifications for patients with specific genetic abnormalities or persistent minimal residual leukemia may further improve long-term results.

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References

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

    CAS  PubMed  Google Scholar 

  2. Rivera G, Pinkel D, Simone JV, Hancock ML, Crist WM . Treatment of acute lymphoblastic leukemia. 30 years’ experience at St Jude Children's Research Hospital New Engl J Med 1993 329: 1289–1295

    Article  CAS  PubMed  Google Scholar 

  3. Rivera GK, Raimondi SC, Hancock ML, Behm FG, Pui C-H, Abromowitch M, Mirro J Jr, Ochs JS, Look AT, Williams DL, Murphy SB, Dahl GV, Kalwinshy DK, Evans WE, Kun LE, Simone JV, Crist WM . Improved outcome in childhood acute lymphoblastic leukaemia with reinforced early treatment and rotational combination chemotherapy Lancet 1991 337: 61–66

    Article  CAS  PubMed  Google Scholar 

  4. Evans WE, Relling MV, Rodman JH, Crom WR, Boyett JM, Pui C-H . Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia New Engl J Med 1998 338: 499–505

    Article  CAS  PubMed  Google Scholar 

  5. Pui C-H, Mahmoud HH, Rivera GK, Hancock ML, Sandlund JT, Behm FG, Head DR, Relling MV, Ribeiro RC, Rubnitz JE, Kun LE, Evans WE . Early intensification of intrathecal chemotherapy virtually eliminates central nervous system relapse in children with acute lymphoblastic leukemia Blood 1998 92: 411–415

    Article  CAS  PubMed  Google Scholar 

  6. Pui C-H, Ribeiro RC, Hancock ML, Rivera GK, Evans WE, Raimondi SC, Head DR, Behm FG, Mahmoud HM, Sandlund JT, Crist WM . Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia New Engl J Med 1991 325: 1682–1687

    Article  CAS  PubMed  Google Scholar 

  7. Synold TW, Relling MV, Boyett JM, Rivera GK, Sandlund JT, Mahmoud H, Crist WM, Pui C-H, Evans WE . Blast cell methotrexate-polyglutamate accumulation in vivo differs by lineage, ploidy, and methotrexate dose in acute lymphoblastic leukemia J Clin Invest 1994 94: 1996–2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Barredo JC, Synold TW, Laver J, Relling MV, Pui C-H, Priest DG, Evans WE . Differences in constitutive and post-methotrexate folylpolyglutamate synthetase activity in B-lineage and T-lineage leukemia Blood 1994 84: 564–569

    Article  CAS  PubMed  Google Scholar 

  9. Galpin AJ, Schuetz JD, Masson E, Yanishevski Y, Synold TW, Barredo JC, Pui C-H, Relling MV, Evans WE . Differences in folylpolyglutamate synthetase and dihydrofolate reductase expression in human B-lineage versus T-lineage leukemic lymphoblasts: mechanisms for lineage differences in methotrexate polyglutamylation and cytotoxicity Mol Pharmacol 1997 52: 155–163

    Article  CAS  PubMed  Google Scholar 

  10. 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

    Article  CAS  PubMed  Google Scholar 

  11. ISCN 1995 . Mitelman F (ed). An International System for Human Cytogenetic Nomeclature Karger: Basel 1995

    Google Scholar 

  12. Ribeiro RC, Broniscer A, Rivera GK, Hancock ML, Raimondi SC, Sandlund JT, Crist W, Pui C-H . Philadelphia chromosome-positive acute lymphoblastic leukemia in children: durable responses to chemotherapy associated with low initial white blood cell counts Leukemia 1997 11: 1493–1496

    Article  CAS  PubMed  Google Scholar 

  13. Mantel N . Evaluation of survival data and two new rank order statistics arising in its consideration Cancer Chemother Rep 1966 50: 163–170

    CAS  PubMed  Google Scholar 

  14. Kalbfleisch JD, Prentice RL . The Statistical Analysis of Failure Time Data John Wiley: New York 1980 pp 163–188

  15. Gray RJ . A class of K-sample tests for comparing the cumulative incidence of a competing risk Ann Stat 1988 16: 1141–1154

    Article  Google Scholar 

  16. Leung W, Hudson M, Zhu Y, Rivera GK, Ribeiro RC, Sandlund JT, Bowman LC, Evans WE, Kun L, Pui C-H . Late effects in survivors of infant leukemia Leukemia 2000 14: 1185–1190

    Article  CAS  PubMed  Google Scholar 

  17. Smith M, Arthur D, Camitta B, Carroll AJ, Crist W, Gaynon P, Gelber R, Heerema N, Korn EL, Link M, Murphy S, Pui C-H, Pullen J, Reaman 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  PubMed  Google Scholar 

  18. Silverman LB, Gelbert RD, Kimball-Dalton V, Young ML, Sallan SE . Results of the Dana-Farber Cancer Institute (DFCI) consortium protocol 91–01 for children with acute lymphoblastic leukemia (ALL) Blood 1998 92: (Suppl. 1) 483a

    Google Scholar 

  19. Nachman JB, Sather HN, Sensel MG, Trigg ME, Cherlow JM, Lukens JN, Wolff L, Uckun FM, Gaynon PS . Augmented post-induction therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy New Engl J Med 1998 338: 1663–1671

    Article  CAS  PubMed  Google Scholar 

  20. Schrappe M, Reiter A, Ludwig W-D, Harbott J, Zimmermann M, Hiddemann W, Niemeyer C, Henze G, Feldges A, Zintl F, Kornhuber B, Ritter J, Welte K, Gadner H, Riehm H . Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90 Blood 2000 95: 3310–3322

    CAS  PubMed  Google Scholar 

  21. Silverman LB, McLean TW, Gelber RD, Donnelly MJ, Gilliland DG, Tarbell NJ, Sallan SE . Intensified therapy for infants with acute lymphoblastic leukemia: results from the Dana-Farber Cancer Institute Consortium Cancer 1997 80: 2285–2295

    Article  CAS  PubMed  Google Scholar 

  22. Aricò M, Valsecchi MG, Camitta B, Schrappe M, Chessells J, Baruchel A, Gaynon P, Silverman L, Janka-Schaub G, Kamps W, Pui C-H, Masera G . Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia New Engl J Med 2000 342: 998–1006

    Article  PubMed  Google Scholar 

  23. Druker BJ, Kantarjian H, Sawyers CL, Resta D, Reese SF, Ford J, Talpaz M . Activity of an ABL specific tyrosine kinase inhibitor in patients with BCR-ABL positive acute leukemias, including chronic myelogenous leukemia in blast crisis Blood 1999 94: (Suppl. 1) 697a

    Google Scholar 

  24. Riehm H, Reiter A, Schrappe M, Berthold F, Dopfer R, Gerein H, Ludwig R, Ritter J, Stollmann B, Henze G . Die Corticosteroid-abhängige Dezimierung der Luekämiezellzahl im Blut als Prognosefaktor bei der akuten lymphoblastischen Leukämie im Kindesalter (Therpiestudie ALL-BFM 83) (The in vivo response on corticosteroid therapy as an additional prognostic factor in childhood acute lymphoblastic leukemia (therapy study ALL-BFM 83)) Klin Pädiatr 1987 199: 151–160

    Article  CAS  PubMed  Google Scholar 

  25. Gaynon PS, Desai AA, Bostrom BC, Hutchinson RJ, Lange BJ, Nachman JB, Reaman GH, Sather HN, Steinherz PG, Trigg ME, Tubergen DG, Uckun FM . Early response to therapy and outcome in childhood acute lymphoblastic leukemia. A review Cancer 1997 80: 1717–1726

    Article  CAS  PubMed  Google Scholar 

  26. Lilleyman JS, Gibson BES, Stevens RF, Will AM, Hann IM, Richards SM, Hill FGH . Clearance of marrow infiltration after 1 week of therapy for childhood lymphoblastic leukaemia: clinical importance and the effect of daunorubicin Br J Haematol 1997 97: 603–606

    Article  CAS  PubMed  Google Scholar 

  27. Gajjar A, Ribeiro R, Hancock ML, Rivera GK, Mahmoud H, Sandlund JT, Crist WM, Pui C-H . Persistence of circulating blasts after 1 week of multiagent chemotherapy confers a poor prognosis in childhood acute lymphoblastic leukemia Blood 1995 86: 1292–1295

    Article  CAS  PubMed  Google Scholar 

  28. Coustan-Smith E, Behm FG, Sanchez J, Boyett JM, Hancock ML, Raimondi SC, Rubnitz JE, Rivera GK, Sandlund JT, Pui C-H, Campana D . Immunological detection of minimal residual disease in children with acute lymphoblastic leukaemia Lancet 1998 351: 550–554

    Article  CAS  PubMed  Google Scholar 

  29. Cavé H, van der Werff ten Bosch J, Suciu S, Guidal C, Waterkeyn C, Otten J, Bakkus M, Thielemans K, Grandchamp B, Vilmer E . Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia New Engl J Med 1998 339: 591–598

    Article  PubMed  Google Scholar 

  30. Van Dongen JJM, Seriu T, Panzer-Grümayer ER, Biondi A, Pongers-Willemse MJ, Corral L, Stolz F, Schrappe M, Masera G, Kamps WA, Gadner H, van Wering ER, Ludwig W-D, Basso G, de Bruijn MAC, Cazzaniga G, Hettinger K, van der Does-van den Berg A, Hop WCJ, Riehm H, Bartram CR . Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood Lancet 1998 352: 1731–1738

    Article  CAS  PubMed  Google Scholar 

  31. Pui C-H, Campana D . New definition of remission in childhood acute lymphoblastic leukemia Leukemia 2000 14: 783–785

    Article  CAS  PubMed  Google Scholar 

  32. Coustan-Smith E, Sancho J, Hancock ML, Boyett JM, Behm FG, Raimondi SC, Sandlund JT, Rivera GK, Rubnitz JE, Ribeiro RC, Pui C-H, Campana D . Sequential monitoring of minimal residual disease in childhood acute lymphoblastic leukemia Blood (in press)

  33. Pui C-H, Evans WE . Drug therapy. Acute lymphoblastic leukemia New Engl J Med 1998 339: 605–615

    Article  CAS  PubMed  Google Scholar 

  34. Mahmoud HH, Rivera GK, Hancock ML, Krance RA, Kun LE, Behm FG, Ribeiro RC, Sandlund JT, Crist WM, Pui C-H . Low leukocyte counts with blast cells in cerebrospinal fluid of children with newly diagnosed acute lymphoblastic leukemia New Engl J Med 1993 329: 314–319

    Article  CAS  PubMed  Google Scholar 

  35. Gajjar A, Harrison PL, Sandlund JT, Rivera GK, Ribeiro R, Rubnitz J, Relling M, Evans W, Boyett JM, Pui C-H . Traumatic lumbar puncture at diagnosis adversely affects outcome in childhood acute lymphoblastic leukemia Blood (in press)

  36. Relling MV, Hancock ML, Boyett JM, Pui C-H, Evans WE . Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia Blood 1999 93: 2817–2823

    Article  CAS  PubMed  Google Scholar 

  37. Pui C-H, Relling MV . Topoisomerase II inhibitor-related acute myeloid leukemia Br J Haematol 2000 109: 13–23

    Article  CAS  PubMed  Google Scholar 

  38. Relling MV, Yanishevski Y, Nemec J, Evans WE, Boyett JM, Behm FG, Pui C-H . Etoposide and antimetabolite pharmacology in patients who develop secondary acute myeloid leukemia Leukemia 1998 12: 346–352

    Article  CAS  PubMed  Google Scholar 

  39. Relling MV, Rubnitz JE, Rivera GK, Boyett JM, Hancock ML, Felix CA, Kun LE, Walter AW, Evans WE, Pui C-H . High incidence of secondary brain tumours after radiotherapy and antimetabolites Lancet 1999 354: 34–39

    Article  CAS  PubMed  Google Scholar 

  40. Evans WE, Relling MV . Pharmacogenomics: translating functional genomics into rational therapeutics Science 1999 286: 487–491

    Article  CAS  PubMed  Google Scholar 

  41. Pui C-H, Relling MV, Behm FG, Hancock ML, Boyett JM, Raimondi SC, Krance RA, Mahmoud HH, Ribeiro RC, Sandlund JT, Head DR, Evans WE, Crist WM, Rivera GK . L-asparaginase may potentiate the leukemogenic effect of the epipodophyllotoxins Leukemia 1995 9: 1680–1684

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Ms Yinmei Zhou for statistical assistance and Ms. Doris Hurdle for typing the manuscript. This work was supported by grants CA21765, CA20180 and CA51001 from the National Cancer Institute, by a Center of Excellence grant from the State of Tennessee, and by the American Lebanese Syrian Associated Charities (ALSAC).

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Authors and Affiliations

  1. Department of Hematology-Oncology, St Jude Children's Research Hospital, Memphis, TN, USA

    C-H Pui, GK Rivera, JT Sandlund, RC Ribeiro, JE Rubnitz, A Gajjar, B Razzouk & D Campana

  2. Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA

    C-H Pui, FG Behm, SC Raimondi & D Campana

  3. University of Tennessee,College of Medicine, Memphis, TN, USA

    C-H Pui, GK Rivera, JT Sandlund, RC Ribeiro, JE Rubnitz, A Gajjar, B Razzouk & D Campana

  4. Department of Biostatistics and Epidemiology, St Jude Children's Research Hospital, Memphis, TN, USA

    JM Boyett & ML Hancock

  5. Department of Radiation Oncology, St Jude Children's Research Hospital, TN, USA

    LE Kun

  6. Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA

    MV Relling & WE Evans

  7. University of Tennessee, College of Pharmacy, Memphis, TN, USA

    MV Relling & WE Evans

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Pui, CH., Boyett, J., Rivera, G. et al. Long-term results of Total Therapy studies 11, 12 and 13A for childhood acute lymphoblastic leukemia at St Jude Children's Research Hospital. Leukemia 14, 2286–2294 (2000). https://doi.org/10.1038/sj.leu.2401938

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