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Clinical effect of imatinib added to intensive combination chemotherapy for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia

Abstract

Clinical impact of imatinib was evaluated in 20 patients (median age, 37 years; range, 15–67 years) with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), who were administered with induction chemotherapy of daunorubicin, vincristine, prednisolone, and L-asparaginase, along with imatinib 600?mg/day during remission induction and 400?mg/day during consolidation courses. One patient died on day 14 from septic shock, while the remaining 19 achieved complete remission (CR). In total, 15 patients underwent allogeneic hematopoietic cell transplantation (HCT) during first CR. After median follow-up period of 799 days, six patients experienced recurrence; two with early recurrence within 100 days, one with leptomeningeal recurrence at 11 month, and three with post-HCT recurrence. Eight patients died. Median CR duration (821 days) and median patient survival (894 days) in the study were significantly longer by 2.9- and 2.3-fold, respectively, when compared to those of 18 historical patients treated with same regimen of combination chemotherapy without imatinib. Toxicities of the combined treatment were manageable and included grade 4 myelosuppression (n=20) and reversible grade 3 hyperbilirubinemia (n=4). Beneficial clinical effects were observed when imatinib was added to combination chemotherapy in patients with newly diagnosed Ph+ ALL. Further studies with larger number of patients are necessary.

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References

  1. Kurzrock R, Kantarjian HM, Druker BJ, Talpaz M . Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics. Ann Intern Med 2003; 138: 819–830.

    Article  CAS  PubMed  Google Scholar 

  2. Song H, Lee JH, Jeon BM, Lee JH, Seo EJ, Park CJ et al. The outcome of Philadelphia chromosome-positive adult ALL: characteristics and prognosis. Cancer Res Treat 2002; 34: 289–295.

    Article  PubMed  Google Scholar 

  3. Preti HA, O’Brien S, Giralt S, Beran M, Pierce S, Kantarjian HM . Philadelphia-chromosome-positive adult acute lymphocytic leukemia: characteristics, treatment results, and prognosis in 41 patients. Am J Med 1994; 97: 60–65.

    Article  CAS  PubMed  Google Scholar 

  4. Bloomfield CD, Peterson LC, Yunis JJ, Brunning RD . The Philadelphia chromosome (Ph1) in adults presenting with acute leukaemia: a comparison of Ph1+ and Ph1-patients. Br J Haematol 1977; 36: 347–358.

    Article  CAS  PubMed  Google Scholar 

  5. Wetzler M, Dodge RK, Mrozek K, Carroll AJ, Tantravahi R, Block AW et al. Prospective karyotype analysis in adult acute lymphoblastic leukemia: the cancer and leukemia Group B experience. Blood 1999; 93: 3983–3993.

    CAS  PubMed  Google Scholar 

  6. Linker C, Damon L, Ries C, Navarro W . Intensified and shortened cyclical chemotherapy for adult acute lymphoblastic leukemia. J Clin Oncol 2002; 20: 2464–2471.

    Article  CAS  PubMed  Google Scholar 

  7. Linker CA, Levitt LJ, O’Donnell M, Forman SJ, Ries CA . Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood 1991; 78: 2814–2822.

    CAS  PubMed  Google Scholar 

  8. Durrant IJ, Richards SM, Prentice HG, Goldstone AH . The Medical Research Council trials in adult acute lymphocytic leukemia. Hematol Oncol Clin N Am 2000; 14: 1327–1352.

    Article  CAS  Google Scholar 

  9. Kantarjian HM, O’Brien S, Smith TL, Cortes J, Giles FJ, Beran M et al. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol 2000; 18: 547–561.

    Article  CAS  PubMed  Google Scholar 

  10. Gokbuget N, Hoelzer D, Arnold R, Bohme A, Bartram CR, Freund M et al. Treatment of adult ALL according to protocols of the German Multicenter Study Group for Adult ALL (GMALL). Hematol Oncol Clin N Am 2000; 14: 1307–1325.

    Article  CAS  Google Scholar 

  11. Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood 1995; 85: 2025–2037.

    CAS  PubMed  Google Scholar 

  12. Gleissner B, Gokbuget N, Bartram CR, Janssen B, Rieder H, Janssen JW et al. Leading prognostic relevance of the BCR-ABL translocation in adult acute B-lineage lymphoblastic leukemia: a prospective study of the German Multicenter Trial Group and confirmed polymerase chain reaction analysis. Blood 2002; 99: 1536–1543.

    Article  CAS  PubMed  Google Scholar 

  13. Dombret H, Gabert J, Boiron JM, Rigal-Huguet F, Blaise D, Thomas X et al. Outcome of treatment in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia – results of the prospective multicenter LALA-94 trial. Blood 2002; 100: 2357–2366.

    Article  CAS  PubMed  Google Scholar 

  14. Stirewalt DL, Guthrie KA, Beppu L, Bryant EM, Doney K, Gooley T et al. Predictors of relapse and overall survival in Philadelphia chromosome-positive acute lymphoblastic leukemia after transplantation. Biol Blood Marrow Transplant 2003; 9: 206–212.

    Article  PubMed  Google Scholar 

  15. Avivi I, Goldstone AH . Bone marrow transplant in Ph+ ALL patients. Bone Marrow Transplant 2003; 31: 623–632.

    Article  CAS  PubMed  Google Scholar 

  16. Snyder DS, Nademanee AP, O’Donnell MR, Parker PM, Stein AS, Margolin K et al. Long-term follow-up of 23 patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with allogeneic bone marrow transplant in first complete remission. Leukemia 1999; 13: 2053–2058.

    Article  CAS  PubMed  Google Scholar 

  17. Stockschlader M, Hegewisch-Becker S, Kruger W, tom Dieck A, Mross K, Hoffknecht M et al. Bone marrow transplantation for Philadelphia-chromosome-positive acute lymphoblastic leukemia. Bone Marrow Transplant 1995; 16: 663–667.

    CAS  PubMed  Google Scholar 

  18. Barrett AJ, Horowitz MM, Ash RC, Atkinson K, Gale RP, Goldman JM et al. Bone marrow transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 1992; 79: 3067–3070.

    CAS  PubMed  Google Scholar 

  19. Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002; 346: 645–652.

    Article  CAS  PubMed  Google Scholar 

  20. O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 348: 994–1004.

    Article  PubMed  Google Scholar 

  21. Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001; 344: 1038–1042.

    Article  CAS  PubMed  Google Scholar 

  22. Hoelzer D, Gokbuget N, Ottmann OG . Targeted therapies in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. Semin Hematol 2002; 39: 32–37.

    Article  CAS  PubMed  Google Scholar 

  23. Ottmann OG, Druker BJ, Sawyers CL, Goldman JM, Reiffers J, Silver RT et al. A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 2002; 100: 1965–1971.

    Article  CAS  PubMed  Google Scholar 

  24. Thomas DA, Faderl S, Cortes J, O’Brien S, Giles FJ, Kornblau SM et al. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood 2004; 103: 4396–4407.

    Article  CAS  PubMed  Google Scholar 

  25. Towatari M, Yanada M, Usui N, Takeuchi J, Sugiura I, Takeuchi M et al. Combination of intensive chemotherapy and imatinib can rapidly induce high-quality complete remission for a majority of patients with newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia. Blood 2004; 104: 3507–3512.

    Article  CAS  PubMed  Google Scholar 

  26. Lee S, Kim YJ, Min CK, Kim HJ, Eom KS, Kim DW et al. The effect of first-line imatinib interim therapy on the outcome of allogeneic stem cell transplantation in adults with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 2005; 105: 3449–3457.

    Article  CAS  PubMed  Google Scholar 

  27. Devaraj PE, Foroni L, Kitra-Roussos V, Secker-Walker LM . Detection of BCR-ABL and E2A-PBX1 fusion genes by RT-PCR in acute lymphoblastic leukaemia with failed or normal cytogenetics. Br J Haematol 1995; 89: 349–355.

    Article  CAS  PubMed  Google Scholar 

  28. Kreuzer KA, Lass U, Bohn A, Landt O, Schmidt CA . LightCycler technology for the quantitation of bcr/abl fusion transcripts. Cancer Res 1999; 59: 3171–3174.

    CAS  PubMed  Google Scholar 

  29. Mitterbauer G, Nemeth P, Wacha S, Cross NC, Schwarzinger I, Jaeger U et al. Quantification of minimal residual disease in patients with BCR-ABL-positive acute lymphoblastic leukaemia using quantitative competitive polymerase chain reaction. Br J Haematol 1999; 106: 634–643.

    Article  CAS  PubMed  Google Scholar 

  30. Kantarjian H, Talpaz M, O’Brien S, Garcia-Manero G, Verstovsek S, Giles F et al. High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia. Blood 2004; 103: 2873–2878.

    Article  CAS  PubMed  Google Scholar 

  31. Leis JF, Stepan DE, Curtin PT, Ford JM, Peng B, Schubach S et al. Central nervous system failure in patients with chronic myelogenous leukemia lymphoid blast crisis and Philadelphia chromosome positive acute lymphoblastic leukemia treated with imatinib (STI-571). Leuk Lymphoma 2004; 45: 695–698.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported in part by a grant (R04-2001-40) from the Korea Science and Engineering Foundation. Part of the data was presented at the 45th Annual Meeting of the American Society of Hematology, San Diego, California.

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Correspondence to H-S Chi.

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Lee, KH., Lee, JH., Choi, SJ. et al. Clinical effect of imatinib added to intensive combination chemotherapy for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Leukemia 19, 1509–1516 (2005). https://doi.org/10.1038/sj.leu.2403886

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