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Changing Paradigm of the Treatment of Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia

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Abstract

In the pre-imatinib era, the treatment outcome of patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) was dismal. Complete remission was generally achieved only in about 50% to 60% of patients, and allogeneic hematopoietic stem cell transplantation (allo-HSCT), when feasible in younger patients, was virtually the sole curative modality. Imatinib has changed the situation dramatically, however, in combination with conventional chemotherapy or with corticosteroid alone, producing about 95% complete remission and thus increasing the number of patients undergoing allo-HSCT. Currently, the overall survival of patients who have undergone allo-HSCT exceeds 50%, and a considerable proportion of patients for whom allo-HSCT is not feasible are predictably curable. The next question is how to prevent relapse, which is observed not only in more than half of patients for whom allo-HSCT is not feasible but also in a considerable number of patients after allo-HSCT. Thus, improvement of postremission therapy is crucial. Whether intensive chemotherapy with currently available cytotoxic drugs contributes to the prevention of relapse is questionable, because intensive chemotherapy alone in the pre-imatinib era nearly always failed to cure this disease. Promising partners to be combined with imatinib or with a second-generation tyrosine kinase inhibitor (TKI) will be corticosteroids and vincristine. New TKIs such as dasatinib should be incorporated into the early phase of postremission therapy. Recognizing the small number of patients with Ph+ ALL, intergroup or international studies are necessary to develop the best postremission therapy. In the near future, it is hoped that Ph+ ALL will become one of the leukemias for which allo-HSCT is offered only for relapsed or extremely high-risk patients.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Wetzler M, Dodge RK, Mrozek K, 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 

  2. Pui CH, Evans WE: Treatment of acute lymphoblastic leukemia. N Engl J Med 2006, 354:166–178.

    Article  CAS  PubMed  Google Scholar 

  3. Lugo TG, Pendergast AM, Muller AJ, Witte ON: Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science 1990, 247:1079–1082.

    Article  CAS  PubMed  Google Scholar 

  4. Ottmann OG, Wassmann B: Treatment of Philadelphia chromosome–positive acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program 2005:118–122.

  5. Aricò M, Valsecchi MG, Camitta B, et al.: Outcome of treatment in children with Philadelphia chromosome–positive acute lymphoblastic leukemia. N Engl J Med 2000, 342:998–1006.

    Article  PubMed  Google Scholar 

  6. Schrappe M, Aricò M, Harbott J, et al.: Philadelphia chromosome–positive (Ph+) childhood acute lymphoblastic leukemia: good initial steroid response allows early prediction of a favorable treatment outcome. Blood 1998, 92:2730–2741.

    CAS  PubMed  Google Scholar 

  7. Dombret H, Gabert J, Boiron JM, 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 

  8. Goldstone AH, Prentice HG, Durrant J, et al.: Allogeneic transplant (related or unrelated donor) is the preferred treatment for adult Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Results from the international ALL trial (MRC UKALLXII/ECOG E2993 ) [abstract]. Blood 2001, 98:856a.

    Google Scholar 

  9. Tanimoto M, Miyawaki S, Ino T, et al.: Response-oriented individualized induction therapy followed by intensive consolidation and maintenance for adult patients with acute lymphoblastic leukemia: the ALL-87 study of the Japan Adult Leukemia Study Group (JALSG). Int J Hematol 1998, 68:421–429.

    Article  CAS  PubMed  Google Scholar 

  10. Ueda T, Miyawaki S, Asou N, et al.: Response-oriented individualized induction therapy with six drugs followed by four courses of intensive consolidation, 1 year maintenance and intensification therapy: the ALL90 study of the Japan Adult Leukemia Study Group. Int J Hematol 1998, 68:279–289.

    Article  CAS  PubMed  Google Scholar 

  11. Takeuchi J, Kyo T, Naito K, et al.: Induction therapy by frequent administration of doxorubicin with four other drugs followed by intensive consolidation and maintenance therapy for adult acute lymphoblastic leukemia: the JALSG-ALL93 study. Leukemia 2002, 16:1259–1266.

    Article  CAS  PubMed  Google Scholar 

  12. Kantarjian H, Thomas D, O’Brien S, et al.: Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer 2004, 101:2788–2801.

    Article  CAS  PubMed  Google Scholar 

  13. Thomas DA: Philadelphia chromosome–positive acute lymphocytic leukemia: a new era of challenges. Hematology Am Soc Hematol Educ Program 2007:435–443.

  14. Druker BJ, Guilhot F, O’Brien SG, et al.: Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006, 355:2408–2417.

    Article  CAS  PubMed  Google Scholar 

  15. Ohno R: Treatment of chronic myeloid leukemia with imatinib mesylate. Int J Clin Oncol 2006, 11:176–183.

    Article  CAS  PubMed  Google Scholar 

  16. Ottmann OG, Druker BJ, Sawyers CL, 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 

  17. Ohno R, Japan Adult Leukemia Study Group: Treatment of Philadelphia chromosome–positive acute lymphoblastic leukemia with imatinib in combination with chemotherapy. Curr Hematol Malig Rep 2006, 1:180–187.

    Article  PubMed  Google Scholar 

  18. Ohno R: Treatment of adult patients with Philadelphia chromosome–positive acute lymphoblastic leukemia. Curr Oncol Rep 2008, 10:379–387.

    Article  CAS  PubMed  Google Scholar 

  19. Yanada M, Ohno R, Naoe T: Recent advances in the treatment of Philadelphia chromosome–positive acute lymphoblastic leukemia. Int J Hematol 2009, 89:3–13.

    Article  CAS  PubMed  Google Scholar 

  20. Towatari M, Yanada M, Usui N, 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 

  21. Yanada M, Takeuchi J, Sugiura I, et al: High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL–positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol 2006, 24:460–466.

    Article  CAS  PubMed  Google Scholar 

  22. Yanada M, Sugiura I, Takeuchi J, et al.: Prospective monitoring of BCR-ABL1 transcript levels in patients with Philadelphia chromosome–positive acute lymphoblastic leukaemia undergoing imatinib-combined chemotherapy. Br J Haematol 2008, 143:503–510.

    PubMed  Google Scholar 

  23. Thomas DA, Faderl S, Cortes J, 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 

  24. Wassmann B, Pfeifer H, Goekbuget N, et al.: Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL). Blood 2006, 108:1469–1477.

    Article  CAS  PubMed  Google Scholar 

  25. de Labarthe A, Rousselot P, Huguet-Rigal F, et al.: Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study. Blood 2007, 109:1408–1413.

    Article  PubMed  Google Scholar 

  26. Ribera JM, Oriol A, González M. Concurrent intensive chemotherapy and imatinib before and after stem cell transplantation in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Final results of the CSTIBES02 trial. Haematologica 2010, 95:87–95.

    Article  CAS  PubMed  Google Scholar 

  27. • Vignetti M, Fazi P, Cimino G, et al.: Imatinib plus steroids induces complete remissions and prolonged survival in elderly Philadelphia chromosome-positive patients with acute lymphoblastic leukemia without additional chemotherapy: results of the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) LAL0201-B protocol. Blood 2007, 109:3676–3678. This is the first report that imatinib plus steroid induced 100% CR in elderly patients with Ph + ALL.

    Article  CAS  PubMed  Google Scholar 

  28. Ottmann OG, Wassmann B, Pfeifer H, et al.: Imatinib compared with chemotherapy as front-line treatment of elderly patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph + ALL). Cancer 2007, 109:2068–2076.

    Article  CAS  PubMed  Google Scholar 

  29. Delannoy A, Delabesse E, Lhéritier V, et al.: Imatinib and methylprednisolone alternated with chemotherapy improve the outcome of elderly patients with Philadelphia-positive acute lymphoblastic leukemia: results of the GRAALL AFR09 study. Leukemia 2006, 20:1526–1532.

    Article  CAS  PubMed  Google Scholar 

  30. •• Schultz KR, Bowman WP, Aledo A: Improved early event-free survival with imatinib in Philadelphia chromosome–positive acute lymphoblastic leukemia: a Children's Oncology Group study. J Clin Oncol 2009, 27:5175–5181. This very informative report on Ph + ALL shows that, after standard induction chemotherapy, long-term imatinib plus intensive chemotherapy resulted in 88% EFS, dramatically better than historical controls, and therapy with imatinib and chemotherapy was in no way inferior to allo-HSCT.

    Article  CAS  PubMed  Google Scholar 

  31. Yanada M, Takeuchi J, Sugiura I, et al: Karyotype at diagnosis is the major prognostic factor predicting relapse-free survival for patients with Philadelphia chromosome–positive acute lymphoblastic leukemia treated with imatinib–combined chemotherapy. Haematologica 2008, 93:287–290.

    Article  PubMed  Google Scholar 

  32. Wassmann B, Pfeifer H, Stadler M, et al.: Early molecular response to posttransplantation imatinib determines outcome in MRD + Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL). Blood 2005, 106:458–463.

    Article  CAS  PubMed  Google Scholar 

  33. Lee S, Kim YJ, Chung NG et al.: The extent of minimal residual disease reduction after the first 4-week imatinib therapy determines outcome of allogeneic stem cell transplantation in adults with Philadelphia chromosome–positive acute lymphoblastic leukemia. Cancer 2009, 115:561–570.

    Article  CAS  PubMed  Google Scholar 

  34. O’Hare T, Eide CA, Deininger MW: Bcr–Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood 2007, 110:2242–2249.

    Article  PubMed  Google Scholar 

  35. Branford S, Rudzki Z, Walsh S, et al.: Detection of BCR–ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood 2003, 102:276–283.

    Article  CAS  PubMed  Google Scholar 

  36. O’Hare T, Walters DK, Stoffregen EP, et al.: In vitro activity of Bcr–Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res 2005, 65:4500–4505.

    Article  PubMed  Google Scholar 

  37. Pfeifer H, Wassmann B, Pavlova A, et al.: Kinase domain mutations of BCR–ABL frequently precede imatinib-based therapy and give rise to relapse in patients with de novo Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL). Blood 2007, 110:727–734.

    Article  CAS  PubMed  Google Scholar 

  38. Hu Y, Liu Y, Pelletier S, et al.: Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1–induced B-lymphoblastic leukemia but not chronic myeloid leukemia. Nat Genet 2004, 36:453–461.

    Article  CAS  PubMed  Google Scholar 

  39. Lindauer M, Hochhaus A: Dasatinib. Recent Results Cancer Res 2010, 184:83–102.

    Article  Google Scholar 

  40. Ottmann O, Dombret H, Martinelli G, et al.: Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome–positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood 2007, 110:2309–2315.

    Article  CAS  PubMed  Google Scholar 

  41. Porkka K, Koskenvesa P, Lundán T, et al.: Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome–positive leukemia. Blood 2008, 112:1005–1012.

    Article  CAS  PubMed  Google Scholar 

  42. Lilly MB, Ottmann OG, Shah NP, et al.: Dasatinib 140 mg once daily versus 70 mg twice daily in patients with Ph-positive acute lymphoblastic leukemia who failed imatinib: results from a phase 3 study. Am J Hematol 2010, 85:164–170.

    CAS  PubMed  Google Scholar 

  43. • Ravandi F, Kantarjian HM, Thomas DA, et al.: Phase II study of combination of the HyperCVAD regimen with dasatinib in the front line therapy of patients with Philadelphia chromosome (Ph) positive acute lymphoblastic leukemia (ALL) [abstract]. Blood (ASH Annual Meeting Abstracts) 2009, 114:Abstract 837. Dasatinib plus intensive chemotherapy induced a high CR rate in newly diagnosed adult Ph + ALL, but the severe adverse events should not be overlooked.

  44. Quintás-Cardama A, Kantarjian H, Ravandi F: Bleeding diathesis in patients with chronic myelogenous leukemia receiving dasatinib therapy. Cancer 2009, 115:2482–2490.

    Article  PubMed  Google Scholar 

  45. Quintás-Cardama A, Han X, Kantarjian H, Cortes J: Tyrosine kinase inhibitor-induced platelet dysfunction in patients with chronic myeloid leukemia. Blood 2009, 114:261–263.

    Article  PubMed  Google Scholar 

  46. • Foà R, Vitale A, Guarini A, et al.: Front-line treatment of adult Ph + acute lymphoblastic leukemia (ALL) patients. Final results of the GIMEMA LAL1205 Study [abstract 305]. Blood (ASH Annual Meeting Abstracts) 2008, 112:119a. This informative abstract reported that dasatinib plus steroid induced 100% CR in newly diagnosed adult Ph + ALL without remarkable adverse events.

  47. Ottmann OG, Larson LA, Kantarjian HM: Nilotinib in patients (pts) with relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) who are resistant or intolerant to imatinib [abstract]. Blood (ASH Annual Meeting Abstracts) 2007, 110:abstract 2815.

  48. Ohno R, Asou N, Ohnishi K: Treatment of acute promyelocytic leukemia: strategy toward further increase of cure rate. Leukemia 2003, 17:1454–1463.

    Article  CAS  PubMed  Google Scholar 

  49. Riva G, Luppi M, Barozzi P, et al.: Emergence of BCR-ABL–specific cytotoxic T cells in the bone marrow of patients with Ph + acute lymphoblastic leukemia during long-term imatinib mesylate treatment. Blood 2010, 115:1512–1518.

    Article  PubMed  Google Scholar 

  50. Kim DH, Kamel-Reid S, Chang H: Natural killer or natural killer/T cell lineage large granular lymphocytosis associated with dasatinib therapy for Philadelphia chromosome positive leukemia. Haematologica 2009, 94:135–139.

    Article  CAS  PubMed  Google Scholar 

  51. Mustjoki S, Ekblom M, Arstila TP, et al.: Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy. Leukemia 2009, 23:1398–1405.

    Article  CAS  PubMed  Google Scholar 

  52. Kano Y, Akutsu M, Tsunoda S, et al.: In vitro cytotoxic effects of a tyrosine kinase inhibitor STI571 in combination with commonly use antileukemic agents. Blood 2001, 97:1999–2007.

    Article  CAS  PubMed  Google Scholar 

  53. Thiesing JT, Ohno-Jones S, Kolibaba KS, Druker BJ: Efficacy of STI571, an abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against bcr-abl–positive cells. Blood 2000, 96:3195–3199.

    CAS  PubMed  Google Scholar 

  54. Hongo T, Okada S, Inoue N, et al.: Two groups of Philadelphia chromosome–positive childhood acute lymphoblastic leukemia classified by pretreatment multidrug sensitivity or resistance in in vitro testing. Int J Hematol 2002, 76(3):251–259.

    Article  PubMed  Google Scholar 

  55. Ramakers-van Woerden NL, Pieters R, Hoelzer D, et al.: In vitro drug resistance profile of Philadelphia positive acute lymphoblastic leukemia is heterogeneous and related to age: a report of the Dutch and German Leukemia Study Groups. Med Pediatr Oncol 2002, 38:379–386.

    Google Scholar 

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  1. Aichi Cancer Center, 1-1 Kanokoden, Chikusaku, Nagoya, 464-8681, Japan

    Ryuzo Ohno

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Ohno, R. Changing Paradigm of the Treatment of Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia. Curr Hematol Malig Rep 5, 213–221 (2010). https://doi.org/10.1007/s11899-010-0061-y

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