International Journal of Hematology

, Volume 89, Issue 1, pp 3–13 | Cite as

Recent advances in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia

Review Article


The advent of imatinib, a selective inhibitor of the ABL tyrosine kinase, has revolutionized the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Combined with chemotherapy, imatinib exerts remarkable efficacy in patients with newly diagnosed disease with a complete remission (CR) rate of 95% and a survival rate of 55% at 3 years. Profound eradication of leukemia cells not only provides patients with a better chance for receiving allogeneic hematopoietic stem cell transplantation during first CR but also contributes to durable CR even without transplantation. Despite such improvement, however, relapse does occur, mainly owing to acquisition of resistance. Growing comprehension of the molecular mechanisms of resistance to imatinib has led to the development of novel BCR–ABL inhibitors that yield higher affinity for BCR–ABL and/or potent inhibitory activity against other target molecules such as SRC family kinases. The second-generation ABL kinase inhibitors, namely dasatinib and nilotinib, are already showing clinical activity in patients with imatinib-resistant Ph+ ALL, and other novel agents are undergoing preclinical and early clinical evaluation. Further improvement in treatment results will be achieved by identifying each patient’s disease profile based on information obtained before and during treatment and by optimizing subsequent treatment accordingly.


Acute lymphoblastic leukemia Philadelphia chromosome BCR–ABL Imatinib Tyrosine kinase inhibitor 


  1. 1.
    Cytogenetic abnormalities in adult acute lymphoblastic leukemia: correlations with hematologic findings outcome. A collaborative study of the Group Francais de Cytogenetique Hematologique. Blood. 1996;87:3135–42.Google Scholar
  2. 2.
    Secker-Walker LM, Prentice HG, Durrant J, Richards S, Hall E, Harrison G. Cytogenetics adds independent prognostic information in adults with acute lymphoblastic leukaemia on MRC trial UKALL XA. MRC Adult Leukaemia Working Party. Br J Haematol. 1997;96:601–10. doi:10.1046/j.1365-2141.1997.d01-2053.x.PubMedCrossRefGoogle Scholar
  3. 3.
    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;93:3983–93.PubMedGoogle Scholar
  4. 4.
    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;99:1536–43. doi:10.1182/blood.V99.5.1536.PubMedCrossRefGoogle Scholar
  5. 5.
    Moorman AV, Harrison CJ, Buck GA, Richards SM, Secker-Walker LM, Martineau M, et al. Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood. 2007;109:3189–97. doi:10.1182/blood-2006-10-051912.PubMedCrossRefGoogle Scholar
  6. 6.
    Pullarkat V, Slovak ML, Kopecky KJ, Forman SJ, Appelbaum FR. Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia: results of Southwest Oncology Group 9400 study. Blood. 2008;111:2563–72. doi:10.1182/blood-2007-10-116186.PubMedCrossRefGoogle Scholar
  7. 7.
    Hermans A, Heisterkamp N, von Linden M, van Baal S, Meijer D, van der Plas D, et al. Unique fusion of bcr and c-abl genes in Philadelphia chromosome positive acute lymphoblastic leukemia. Cell. 1987;51:33–40. doi:10.1016/0092-8674(87)90007-9.PubMedCrossRefGoogle Scholar
  8. 8.
    Chan LC, Karhi KK, Rayter SI, Heisterkamp N, Eridani S, Powles R, et al. A novel abl protein expressed in Philadelphia chromosome positive acute lymphoblastic leukaemia. Nature. 1987;325:635–7. doi:10.1038/325635a0.PubMedCrossRefGoogle Scholar
  9. 9.
    Clark SS, McLaughlin J, Timmons M, Pendergast AM, Ben-Neriah Y, Dow LW, et al. Expression of a distinctive BCR–ABL oncogene in Ph1-positive acute lymphocytic leukemia (ALL). Science. 1988;239:775–7. doi:10.1126/science.3422516.PubMedCrossRefGoogle Scholar
  10. 10.
    Burmeister T, Schwartz S, Bartram CR, Gokbuget N, Hoelzer D, Thiel E. Patients’ age and BCR–ABL frequency in adult B-precursor ALL: a retrospective analysis from the GMALL study group. Blood. 2008;112:918–9. doi:10.1182/blood-2008-04-149286.PubMedCrossRefGoogle Scholar
  11. 11.
    Lugo TG, Pendergast AM, Muller AJ, Witte ON. Tyrosine kinase activity and transformation potency of bcr–abl oncogene products. Science. 1990;247:1079–82. doi:10.1126/science.2408149.PubMedCrossRefGoogle Scholar
  12. 12.
    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;85:2025–37.PubMedGoogle Scholar
  13. 13.
    Thomas X, Danaila C, Le QH, Sebban C, Troncy J, Charrin C, et al. Long-term follow-up of patients with newly diagnosed adult acute lymphoblastic leukemia: a single institution experience of 378 consecutive patients over a 21-year period. Leukemia. 2001;15:1811–22.PubMedGoogle Scholar
  14. 14.
    Takeuchi J, Kyo T, Naito K, Sao H, Takahashi M, Miyawaki S, 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;16:1259–66. doi:10.1038/sj.leu.2402526.PubMedCrossRefGoogle Scholar
  15. 15.
    Annino L, Vegna ML, Camera A, Specchia G, Visani G, Fioritoni G, et al. Treatment of adult acute lymphoblastic leukemia (ALL): long-term follow-up of the GIMEMA ALL 0288 randomized study. Blood. 2002;99:863–71. doi:10.1182/blood.V99.3.863.PubMedCrossRefGoogle Scholar
  16. 16.
    Kantarjian H, Thomas D, O’Brien S, Cortes J, Giles F, Jeha 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;101:2788–801. doi:10.1002/cncr.20668.PubMedCrossRefGoogle Scholar
  17. 17.
    Schrappe M, Arico M, Harbott J, Biondi A, Zimmermann M, Conter V, et al. Philadelphia chromosome-positive (Ph+) childhood acute lymphoblastic leukemia: good initial steroid response allows early prediction of a favorable treatment outcome. Blood. 1998;92:2730–41.PubMedGoogle Scholar
  18. 18.
    Roy A, Bradburn M, Moorman AV, Burrett J, Love S, Kinsey SE, et al. Early response to induction is predictive of survival in childhood Philadelphia chromosome positive acute lymphoblastic leukaemia: results of the Medical Research Council ALL 97 trial. Br J Haematol. 2005;129:35–44. doi:10.1111/j.1365-2141.2005.05425.x.PubMedCrossRefGoogle Scholar
  19. 19.
    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;79:3067–70.PubMedGoogle Scholar
  20. 20.
    Chao NJ, Blume KG, Forman SJ, Snyder DS. Long-term follow-up of allogeneic bone marrow recipients for Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 1995;85:3353–4.PubMedGoogle Scholar
  21. 21.
    Cornelissen JJ, Carston M, Kollman C, King R, Dekker AW, Lowenberg B, et al. Unrelated marrow transplantation for adult patients with poor-risk acute lymphoblastic leukemia: strong graft-versus-leukemia effect and risk factors determining outcome. Blood. 2001;97:1572–7. doi:10.1182/blood.V97.6.1572.PubMedCrossRefGoogle Scholar
  22. 22.
    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;100:2357–66. doi:10.1182/blood-2002-03-0704.PubMedCrossRefGoogle Scholar
  23. 23.
    Esperou H, Boiron JM, Cayuela JM, Blanchet O, Kuentz M, Jouet JP, et al. A potential graft-versus-leukemia effect after allogeneic hematopoietic stem cell transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: results from the French Bone Marrow Transplantation Society. Bone Marrow Transplant. 2003;31:909–18. doi:10.1038/sj.bmt.1703951.PubMedCrossRefGoogle Scholar
  24. 24.
    Lee S, Kim DW, Cho B, Kim YJ, Kim YL, Hwang JY, et al. Risk factors for adults with Philadelphia-chromosome-positive acute lymphoblastic leukaemia in remission treated with allogeneic bone marrow transplantation: the potential of real-time quantitative reverse-transcription polymerase chain reaction. Br J Haematol. 2003;120:145–53. doi:10.1046/j.1365-2141.2003.03988.x.PubMedCrossRefGoogle Scholar
  25. 25.
    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;9:206–12. doi:10.1016/S1083-8791(03)70011-1.PubMedCrossRefGoogle Scholar
  26. 26.
    Yanada M, Naoe T, Iida H, Sakamaki H, Sakura T, Kanamori H, et al. Myeloablative allogeneic hematopoietic stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia in adults: significant roles of total body irradiation and chronic graft-versus-host disease. Bone Marrow Transplant. 2005;36:867–72. doi:10.1038/sj.bmt.1705148.PubMedCrossRefGoogle Scholar
  27. 27.
    Laport GG, Alvarnas JC, Palmer JM, Snyder DS, Slovak ML, Cherry AM, et al. Long-term remission of Philadelphia chromosome-positive acute lymphoblastic leukemia after allogeneic hematopoietic cell transplantation from matched sibling donors: a 20-year experience with the fractionated total body irradiation-etoposide regimen. Blood. 2008;112:903–9. doi:10.1182/blood-2008-03-143115.PubMedCrossRefGoogle Scholar
  28. 28.
    Dunlop LC, Powles R, Singhal S, Treleaven JG, Swansbury GJ, Meller S, et al. Bone marrow transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia. Bone Marrow Transplant. 1996;17:365–9.PubMedGoogle Scholar
  29. 29.
    Atta J, Fauth F, Keyser M, Petershofen E, Weber C, Lippok G, et al. Purging in BCR–ABL-positive acute lymphoblastic leukemia using immunomagnetic beads: comparison of residual leukemia and purging efficiency in bone marrow vs peripheral blood stem cells by semiquantitative polymerase chain reaction. Bone Marrow Transplant. 2000;25:97–104. doi:10.1038/sj.bmt.1702096.PubMedCrossRefGoogle Scholar
  30. 30.
    Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells. Nat Med. 1996;2:561–6. doi:10.1038/nm0596-561.PubMedCrossRefGoogle Scholar
  31. 31.
    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. doi:10.1056/NEJMoa022457.PubMedCrossRefGoogle Scholar
  32. 32.
    Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408–17. doi:10.1056/NEJMoa062867.PubMedCrossRefGoogle Scholar
  33. 33.
    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;344:1038–42. doi:10.1056/NEJM200104053441402.PubMedCrossRefGoogle Scholar
  34. 34.
    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;100:1965–71. doi:10.1182/blood-2001-12-0181.PubMedCrossRefGoogle Scholar
  35. 35.
    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;103:4396–407. doi:10.1182/blood-2003-08-2958.PubMedCrossRefGoogle Scholar
  36. 36.
    Lee KH, Lee JH, Choi SJ, Lee JH, Seol M, Lee YS, et al. Clinical effect of imatinib added to intensive combination chemotherapy for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Leukemia. 2005;19:1509–16. doi:10.1038/sj.leu.2403886.PubMedCrossRefGoogle Scholar
  37. 37.
    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;105:3449–57. doi:10.1182/blood-2004-09-3785.PubMedCrossRefGoogle Scholar
  38. 38.
    Yanada M, Takeuchi J, Sugiura I, Akiyama H, Usui N, Yagasaki F, 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;24:460–6. doi:10.1200/JCO.2005.03.2177.PubMedCrossRefGoogle Scholar
  39. 39.
    Wassmann B, Pfeifer H, Goekbuget N, Beelen DW, Beck J, Stelljes M, et al. Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood. 2006;108:1469–77. doi:10.1182/blood-2005-11-4386.PubMedCrossRefGoogle Scholar
  40. 40.
    de Labarthe A, Rousselot P, Huguet-Rigal F, Delabesse E, Witz F, Maury S, 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;109:1408–13. doi:10.1182/blood-2006-03-011908.PubMedCrossRefGoogle Scholar
  41. 41.
    Thomas DA, Kantarjian HM, Cortes J, Ravandi F, Faderl S, Jones D, et al. Outcome after frontline therapy with the hyper-CVAD and imatinib mesylate regimen for adults with de novo or minimally treated Philadelphia (Ph) positive acute lymphoblastic leukemia (ALL). Proc Am Clin Soc Oncol. 2008;26:7019a. abstract.Google Scholar
  42. 42.
    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;104:3507–12. doi:10.1182/blood-2004-04-1389.PubMedCrossRefGoogle Scholar
  43. 43.
    Wassmann B, Pfeifer H, Stadler M, Bornhauser M, Bug G, Scheuring UJ, et al. Early molecular response to posttransplantation imatinib determines outcome in MRD+ Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood. 2005;106:458–63. doi:10.1182/blood-2004-05-1746.PubMedCrossRefGoogle Scholar
  44. 44.
    Yanada M, Takeuchi J, Sugiura I, Akiyama H, Usui N, Yagasaki F, 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;93:287–90. doi:10.3324/haematol.11891.PubMedCrossRefGoogle Scholar
  45. 45.
    Brisco MJ, Condon J, Hughes E, Neoh SH, Sykes PJ, Seshadri R, et al. Outcome prediction in childhood acute lymphoblastic leukaemia by molecular quantification of residual disease at the end of induction. Lancet. 1994;343:196–200. doi:10.1016/S0140-6736(94)90988-1.PubMedCrossRefGoogle Scholar
  46. 46.
    Brisco J, Hughes E, Neoh SH, Sykes PJ, Bradstock K, Enno A, et al. Relationship between minimal residual disease and outcome in adult acute lymphoblastic leukemia. Blood. 1996;87:5251–6.PubMedGoogle Scholar
  47. 47.
    van Dongen JJ, Seriu T, Panzer-Grumayer ER, Biondi A, Pongers-Willemse MJ, Corral L, et al. Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet. 1998;352:1731–8. doi:10.1016/S0140-6736(98)04058-6.PubMedCrossRefGoogle Scholar
  48. 48.
    Cave H, van der Werff ten Bosch J, Suciu S, Guidal C, Waterkeyn C, Otten J, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia. European Organization for Research and Treatment of Cancer—Childhood Leukemia Cooperative Group. N Engl J Med. 1998;339:591–8. doi:10.1056/NEJM199808273390904.PubMedCrossRefGoogle Scholar
  49. 49.
    Coustan-Smith E, Behm FG, Sanchez J, Boyett JM, Hancock ML, Raimondi SC, et al. Immunological detection of minimal residual disease in children with acute lymphoblastic leukaemia. Lancet. 1998;351:550–4. doi:10.1016/S0140-6736(97)10295-1.PubMedCrossRefGoogle Scholar
  50. 50.
    Dworzak MN, Froschl G, Printz D, Mann G, Potschger U, Muhlegger N, et al. Prognostic significance and modalities of flow cytometric minimal residual disease detection in childhood acute lymphoblastic leukemia. Blood. 2002;99:1952–8. doi:10.1182/blood.V99.6.1952.PubMedCrossRefGoogle Scholar
  51. 51.
    Mortuza FY, Papaioannou M, Moreira IM, Coyle LA, Gameiro P, Gandini D, et al. Minimal residual disease tests provide an independent predictor of clinical outcome in adult acute lymphoblastic leukemia. J Clin Oncol. 2002;20:1094–104. doi:10.1200/JCO.20.4.1094.PubMedCrossRefGoogle Scholar
  52. 52.
    Nyvold C, Madsen HO, Ryder LP, Seyfarth J, Svejgaard A, Clausen N, et al. Precise quantification of minimal residual disease at day 29 allows identification of children with acute lymphoblastic leukemia and an excellent outcome. Blood. 2002;99:1253–8. doi:10.1182/blood.V99.4.1253.PubMedCrossRefGoogle Scholar
  53. 53.
    Vidriales MB, Perez JJ, Lopez-Berges MC, Gutierrez N, Ciudad J, Lucio P, et al. Minimal residual disease in adolescent (older than 14 years) and adult acute lymphoblastic leukemias: early immunophenotypic evaluation has high clinical value. Blood. 2003;101:4695–700. doi:10.1182/blood-2002-08-2613.PubMedCrossRefGoogle Scholar
  54. 54.
    Bruggemann M, Raff T, Flohr T, Gokbuget N, Nakao M, Droese J, et al. Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood. 2006;107:1116–23. doi:10.1182/blood-2005-07-2708.PubMedCrossRefGoogle Scholar
  55. 55.
    Raff T, Gokbuget N, Luschen S, Reutzel R, Ritgen M, Irmer S, et al. Molecular relapse in adult standard-risk ALL patients detected by prospective MRD monitoring during and after maintenance treatment: data from the GMALL 06/99 and 07/03 trials. Blood. 2007;109:910–5. doi:10.1182/blood-2006-07-037093.PubMedCrossRefGoogle Scholar
  56. 56.
    Zhou J, Goldwasser MA, Li A, Dahlberg SE, Neuberg D, Wang H, et al. Quantitative analysis of minimal residual disease predicts relapse in children with B-lineage acute lymphoblastic leukemia in DFCI ALL Consortium Protocol 95-01. Blood. 2007;110:1607–11. doi:10.1182/blood-2006-09-045369.PubMedCrossRefGoogle Scholar
  57. 57.
    Yanada M, Sugiura I, Takeuchi J, Akiyama H, Maruta A, Ueda Y, et al. Prospective monitoring of BCR–ABL transcript levels in patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia undergoing imatinib-combined chemotherapy. Br J Haematol. 2008;143:503–10. doi:10.1111/j.1365-2141.2008.07377.x.Google Scholar
  58. 58.
    Zembutsu H, Yanada M, Hishida A, Katagiri T, Tsuruo T, Sugiura I, et al. Prediction of risk of disease recurrence by genome-wide cDNA microarray analysis in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with imatinib-combined chemotherapy. Int J Oncol. 2007;31:313–22.PubMedGoogle Scholar
  59. 59.
    Delannoy A, Lheritier V, Thomas X, Castaigne S, Rigal-Huguet F, Raffoux E, et al. Treatment of Philadelphia-positive acute lymphocytic leukemia (Ph+ ALL) in the elderly with imatinib mesylate (STI571) and chemotherapy. Blood. 2005;106:abstract #146.Google Scholar
  60. 60.
    Ottmann OG, Wassmann B, Pfeifer H, Giagounidis A, Stelljes M, Duhrsen U, et al. Imatinib compared with chemotherapy as front-line treatment of elderly patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). Cancer. 2007;109:2068–76. doi:10.1002/cncr.22631.PubMedCrossRefGoogle Scholar
  61. 61.
    Vignetti M, Fazi P, Cimino G, Martinelli G, Di Raimondo F, Ferrara F, 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;109:3676–8. doi:10.1182/blood-2006-10-052746.PubMedCrossRefGoogle Scholar
  62. 62.
    Kantarjian HM, Giles F, Quintas-Cardama A, Cortes J. Important therapeutic targets in chronic myelogenous leukemia. Clin Cancer Res. 2007;13:1089–97. doi:10.1158/1078-0432.CCR-06-2147.PubMedCrossRefGoogle Scholar
  63. 63.
    Deininger MW. Optimizing therapy of chronic myeloid leukemia. Exp Hematol. 2007;35:144–54. doi:10.1016/j.exphem.2007.01.023.PubMedCrossRefGoogle Scholar
  64. 64.
    Kujawski L, Talpaz M. Strategies for overcoming imatinib resistance in chronic myeloid leukemia. Leuk Lymphoma. 2007;48:2310–22. doi:10.1080/10428190701665988.PubMedCrossRefGoogle Scholar
  65. 65.
    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;110:2242–9. doi:10.1182/blood-2007-03-066936.PubMedCrossRefGoogle Scholar
  66. 66.
    Branford S, Rudzki Z, Walsh S, Parkinson I, Grigg A, Szer J, 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;102:276–83. doi:10.1182/blood-2002-09-2896.PubMedCrossRefGoogle Scholar
  67. 67.
    Soverini S, Martinelli G, Rosti G, Bassi S, Amabile M, Poerio A, et al. ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on chronic myeloid leukemia. J Clin Oncol. 2005;23:4100–9. doi:10.1200/JCO.2005.05.531.PubMedCrossRefGoogle Scholar
  68. 68.
    O’Hare T, Walters DK, Stoffregen EP, Jia T, Manley PW, Mestan J, 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;65:4500–5. doi:10.1158/0008-5472.CAN-05-0259.PubMedCrossRefGoogle Scholar
  69. 69.
    Pfeifer H, Wassmann B, Pavlova A, Wunderle L, Oldenburg J, Binckebanck 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;110:727–34. doi:10.1182/blood-2006-11-052373.PubMedCrossRefGoogle Scholar
  70. 70.
    Hu Y, Liu Y, Pelletier S, Buchdunger E, Warmuth M, Fabbro D, 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;36:453–61. doi:10.1038/ng1343.PubMedCrossRefGoogle Scholar
  71. 71.
    Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science. 2004;305:399–401. doi:10.1126/science.1099480.PubMedCrossRefGoogle Scholar
  72. 72.
    Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354:2531–41. doi:10.1056/NEJMoa055229.PubMedCrossRefGoogle Scholar
  73. 73.
    Ottmann O, Dombret H, Martinelli G, Simonsson B, Guilhot F, Larson RA, 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;110:2309–15. doi:10.1182/blood-2007-02-073528.PubMedCrossRefGoogle Scholar
  74. 74.
    Foa R, Vignetti M, Vitale A, Meloni G, Guarini A, De Propris S, et al. Dasatinib as front-line monotherapy for the induction treatment of adult and elderly Ph+ acute lymphoblastic leukemia (ALL) patients: interim analysis of the GIMEMA prospective study LAL1205. Blood. 2007;110:7a. abstract.Google Scholar
  75. 75.
    Ravandi F, Faderl S, Thomas DA, Brown D, Garris R, Borthakur A, et al. Phase II study of combination of the hyperCVAD regimen with dasatinib in patients (pts) with newly diagnosed Philadelphia chromosome positive (Ph+) acyte lymphoblastic leukemia (ALL). Proc Am Clin Soc Oncol. 2008;26:7020a. abstract.Google Scholar
  76. 76.
    Weisberg E, Manley PW, Breitenstein W, Bruggen J, Cowan-Jacob SW, Ray A, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr–Abl. Cancer Cell. 2005;7:129–41. doi:10.1016/j.ccr.2005.01.007.PubMedCrossRefGoogle Scholar
  77. 77.
    Kantarjian H, Giles F, Wunderle L, Bhalla K, O’Brien S, Wassmann B, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006;354:2542–51. doi:10.1056/NEJMoa055104.PubMedCrossRefGoogle Scholar
  78. 78.
    Ottmann OG, Larson RA, Kantarjian HM, Le Coutre P, Baccarani M, Haque A, et al. Nilotinib in patients (pts) with relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who are resistant or intolerant to imatinib. Blood. 2007;110:2815a. doi:10.1182/blood-2007-02-073528. abstract.CrossRefGoogle Scholar
  79. 79.
    Puttini M, Coluccia AM, Boschelli F, Cleris L, Marchesi E, Donella-Deana A, et al. In vitro and in vivo activity of SKI-606, a novel Src-Abl inhibitor, against imatinib-resistant Bcr-Abl+ neoplastic cells. Cancer Res. 2006;66:11314–22. doi:10.1158/0008-5472.CAN-06-1199.PubMedCrossRefGoogle Scholar
  80. 80.
    Kimura S, Naito H, Segawa H, Kuroda J, Yuasa T, Sato K, et al. NS-187, a potent and selective dual Bcr–Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia. Blood. 2005;106:3948–54. doi:10.1182/blood-2005-06-2209.PubMedCrossRefGoogle Scholar
  81. 81.
    Harrington EA, Bebbington D, Moore J, Rasmussen RK, Ajose-Adeogun AO, Nakayama T, et al. VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nat Med. 2004;10:262–7. doi:10.1038/nm1003.PubMedCrossRefGoogle Scholar
  82. 82.
    Giles FJ, Cortes J, Jones D, Bergstrom D, Kantarjian H, Freedman SJ. MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR–ABL mutation. Blood. 2007;109:500–2. doi:10.1182/blood-2006-05-025049.PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2008

Authors and Affiliations

  1. 1.Department of Hematology and OncologyNagoya University Graduate School of MedicineNagoyaJapan
  2. 2.Aichi Cancer CenterNagoyaJapan

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