Leukemia Research
Volume 34, Issue 10 , Pages 1255-1268 , October 2010

BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: A review

  • Xin An

      Affiliations

    • Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, 8000 Utopia Parkway, Jamaica, NY 11439, USA
    • Department of Medical Oncology, Cancer Center, Sun Yat-Sen University, Guangzhou, China
    • State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou, China
    • These authors contributed equally to this work.
  • ,
  • Amit K. Tiwari

      Affiliations

    • Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, 8000 Utopia Parkway, Jamaica, NY 11439, USA
    • These authors contributed equally to this work.
  • ,
  • Yibo Sun

      Affiliations

    • Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, 8000 Utopia Parkway, Jamaica, NY 11439, USA
    • These authors contributed equally to this work.
  • ,
  • Pei-Rong Ding

      Affiliations

    • Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, 8000 Utopia Parkway, Jamaica, NY 11439, USA
    • Department of Medical Oncology, Cancer Center, Sun Yat-Sen University, Guangzhou, China
    • State Key Laboratory of Oncology in South China, Sun Yat-Sen University, Guangzhou, China
    • These authors contributed equally to this work.
  • ,
  • Charles R. Ashby Jr.

      Affiliations

    • Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, 8000 Utopia Parkway, Jamaica, NY 11439, USA
  • ,
  • Zhe-Sheng Chen

      Affiliations

    • Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, 8000 Utopia Parkway, Jamaica, NY 11439, USA
    • Corresponding Author InformationCorresponding author. Tel.: +1 718 990 1432; fax: +1 718 990 1877.

Received 21 January 2010 ,Revised 25 April 2010 ,Accepted 25 April 2010.

References 

  1. Cortes J. Natural history and staging of chronic myelogenous leukemia. Hematol Oncol Clin North Am. 2004;18:569–584viii
  2. Faderl S, Talpaz M, Estrov Z, Kantarjian HM. Chronic myelogenous leukemia: biology and therapy. Ann Intern Med. 1999;131:207–219
  3. Bennett JH. Case of hypertrophy of the spleen and liver in which death took place from suppuration of the blood. Edinb Med Surg J. 1845;64:413–423
  4. Virchow RWB. Frorieps Notizen. 1845;p. 36
  5. Nowell PCHD. A minute chromosome in human chronic granulocytic leukemia. Science. 1960;132:1497
  6. Erikson J, Griffin CA, ar-Rushdi A, Valtieri M, Hoxie J, Finan J, et al. Heterogeneity of chromosome 22 breakpoint in Philadelphia-positive (Ph+) acute lymphocytic leukemia. Proc Natl Acad Sci USA. 1986;83:1807–1811
  7. Rowley JD. Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973;243:290–293
  8. Deininger MW, Goldman JM, Melo JV. The molecular biology of chronic myeloid leukemia. Blood. 2000;96:3343–3356
  9. Kantarjian HM, Talpaz M, Giles F, O’Brien S, Cortes J. New insights into the pathophysiology of chronic myeloid leukemia and imatinib resistance. Ann Intern Med. 2006;145:913–923
  10. Sawyers CL. Chronic myeloid leukemia. N Engl J Med. 1999;340(April (17)):1330–1340
  11. Kantarjian HM, Giles F, Quintas-Cardama A, Cortes J. Important therapeutic targets in chronic myelogenous leukemia. Clin Cancer Res. 2007;13(February (4)):1089–1097
  12. Sawyers CL. Signal transduction pathways involved in BCR-ABL transformation. Baillieres Clin Haematol. 1997;10:223–231
  13. Calabretta B, Perrotti D. The biology of CML blast crisis. Blood. 2004;103:4010–4022
  14. Bolin RW, Robinson WA, Sutherland J, Hamman RF. Busulfan versus hydroxyurea in long-term therapy of chronic myelogenous leukemia. Cancer. 1982;50:1683–1686
  15. Interferon alfa versus chemotherapy for chronic myeloid leukemia: a meta-analysis of seven randomized trials: Chronic Myeloid Leukemia Trialists’ Collaborative Group. J Natl Cancer Inst. 1997;89:1616–1620
  16. Bonifazi F, de Vivo A, Rosti G, Guilhot F, Guilhot J, Trabacchi E, et al. Chronic myeloid leukemia and interferon-alpha: a study of complete cytogenetic responders. Blood. 2001;98:3074–3081
  17. Ohnishi K, Ohno R, Tomonaga M, Kamada N, Onozawa K, Kuramoto A, et al. A randomized trial comparing interferon-alpha with busulfan for newly diagnosed chronic myelogenous leukemia in chronic phase. Blood. 1995;86:906–916
  18. Silver RT, Woolf SH, Hehlmann R, Appelbaum FR, Anderson J, Bennett C, et al. An evidence-based analysis of the effect of busulfan, hydroxyurea, interferon, and allogeneic bone marrow transplantation in treating the chronic phase of chronic myeloid leukemia: developed for the American Society of Hematology. Blood. 1999;94:1517–1536
  19. Baccarani M, Saglio G, Goldman J, Hochhaus A, Simonsson B, Appelbaum F, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108:1809–1820
  20. Savage DG, Antman KH. Imatinib mesylate—a new oral targeted therapy. N Engl J Med. 2002;346:683–693
  21. Sawyers CL, Hochhaus A, Feldman E, Goldman JM, Miller CB, Ottmann OG, et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood. 2002;99:3530–3539
  22. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001;293:876–880
  23. 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;7:129–141
  24. 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
  25. Golas JM, Arndt K, Etienne C, Lucas J, Nardin D, Gibbons J, et al. SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice. Cancer Res. 2003;63:375–381
  26. Kantarjian HM, Giles F, Quintas-Cardama A, Cortes J. Important therapeutic targets in chronic myelogenous leukemia. Clin Cancer Res. 2007;13:1089–1097
  27. Holtz MS, Slovak ML, Zhang F, Sawyers CL, Forman SJ, Bhatia R. Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation. Blood. 2002;99:3792–3800
  28. 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;2:561–566
  29. Legros L, Bourcier C, Jacquel A, Mahon FX, Cassuto JP, Auberger P, et al. Imatinib mesylate (STI571) decreases the vascular endothelial growth factor plasma concentration in patients with chronic myeloid leukemia. Blood. 2004;104:495–501
  30. Kvasnicka HM, Thiele J, Staib P, Schmitt-Graeff A, Griesshammer M, Klose J, et al. Reversal of bone marrow angiogenesis in chronic myeloid leukemia following imatinib mesylate (STI571) therapy. Blood. 2004;103:3549–3551
  31. Appel S, Boehmler AM, Grunebach F, Muller MR, Rupf A, Weck MM, et al. Imatinib mesylate affects the development and function of dendritic cells generated from CD34+ peripheral blood progenitor cells. Blood. 2004;103(January (2)):538–544
  32. Taieb J, Maruyama K, Borg C, Terme M, Zitvogel L. Imatinib mesylate impairs Flt3L-mediated dendritic cell expansion and antitumor effects in vivo. Blood. 2004;103(March (5)):1966–1967[author reply 1967]
  33. Appel S, Rupf A, Weck MM, Schoor O, Brummendorf TH, Weinschenk T, et al. Effects of imatinib on monocyte-derived dendritic cells are mediated by inhibition of nuclear factor-kappaB and Akt signaling pathways. Clin Cancer Res. 2005;11(March (5)):1928–1940
  34. Wang H, Cheng F, Cuenca A, Horna P, Zheng Z, Bhalla K, et al. Imatinib mesylate (STI-571) enhances antigen-presenting cell function and overcomes tumor-induced CD4+ T-cell tolerance. Blood. 2005;105(February (3)):1135–1143
  35. Wehner R, Wendisch M, Schakel K, Bornhauser M, Platzbecker U, Mohr B, et al. Imatinib mesylate does not impair the immunogenicity of human myeloid blood dendritic cells. Leukemia. 2006;20(September (9)):1629–1632
  36. 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
  37. Goldman JM, Melo JV. Chronic myeloid leukemia—advances in biology and new approaches to treatment. N Engl J Med. 2003;349:1451–1464
  38. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1031–1037
  39. 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
  40. 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;106:3948–3954
  41. Manley PW, Cowan-Jacob SW, Mestan J. Advances in the structural biology, design and clinical development of Bcr-Abl kinase inhibitors for the treatment of chronic myeloid leukaemia. Biochim Biophys Acta. 2005;1754:3–13
  42. Weisberg E, Manley P, Mestan J, Cowan-Jacob S, Ray A, Griffin JD. AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL. Br J Cancer. 2006;94:1765–1769
  43. 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;65:4500–4505
  44. Quintas-Cardama A, Kantarjian H, Cortes J. Flying under the radar: the new wave of BCR-ABL inhibitors. Nat Rev Drug Discov. 2007;6:834–848
  45. O’Hare T, Pollock R, Stoffregen EP, Keats JA, Abdullah OM, Moseson EM, et al. Inhibition of wild-type and mutant Bcr-Abl by AP23464, a potent ATP-based oncogenic protein kinase inhibitor: implications for CML. Blood. 2004;104:2532–2539
  46. Wisniewski D, Lambek CL, Liu C, Strife A, Veach DR, Nagar B, et al. Characterization of potent inhibitors of the Bcr-Abl and the c-kit receptor tyrosine kinases. Cancer Res. 2002;62:4244–4255
  47. Gumireddy K, Baker SJ, Cosenza SC, John P, Kang AD, Robell KA, et al. A non-ATP-competitive inhibitor of BCR-ABL overrides imatinib resistance. Proc Natl Acad Sci USA. 2005;102:1992–1997
  48. 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;109:500–502
  49. O’Brien S. NCCN clinical practice guidelines in oncology: chronic myelogenous leukemia, version 2.2010. http://www.nccn.org/professionals/physician_gls/PDF/cml.pdf [accessed July 2009].
  50. Baccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, Apperley J, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European Leukemia Net. J Clin Oncol. 2009;27:6041–6051
  51. Hughes TP, Kaeda J, Branford S, Rudzki Z, Hochhaus A, Hensley ML, et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med. 2003;349(October (15)):1423–1432
  52. Hughes T, Branford S. Molecular monitoring of BCR-ABL as a guide to clinical management in chronic myeloid leukaemia. Blood Rev. 2006;20:29–41
  53. Branford S, Cross NC, Hochhaus A, Radich J, Saglio G, Kaeda J, et al. Rationale for the recommendations for harmonizing current methodology for detecting BCR-ABL transcripts in patients with chronic myeloid leukaemia. Leukemia. 2006;20(November (11)):1925–1930
  54. 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;355:2408–2417
  55. Press RD, Galderisi C, Yang R, Rempfer C, Willis SG, Mauro MJ, et al. A half-log increase in BCR-ABL RNA predicts a higher risk of relapse in patients with chronic myeloid leukemia with an imatinib-induced complete cytogenetic response. Clin Cancer Res. 2007;13:6136–6143
  56. Khorashad JS, de Lavallade H, Apperley JF, Milojkovic D, Reid AG, Bua M, et al. Finding of kinase domain mutations in patients with chronic phase chronic myeloid leukemia responding to imatinib may identify those at high risk of disease progression. J Clin Oncol. 2008;26:4806–4813
  57. Hughes T, Saglio G, Branford S, Soverini S, Kim DW, Muller MC, et al. Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase. J Clin Oncol. 2009;27:4204–4210
  58. Barnes DJ, Palaiologou D, Panousopoulou E, Schultheis B, Yong AS, Wong A, et al. Bcr-Abl expression levels determine the rate of development of resistance to imatinib mesylate in chronic myeloid leukemia. Cancer Res. 2005;65:8912–8919
  59. Polakova KM, Polivkova V, Rulcova J, Klamova H, Jurcek T, Dvorakova D, et al. Constant BCR-ABL transcript level >or =0.1% (IS) in patients with CML responding to imatinib with complete cytogenetic remission may indicate mutation analysis. Exp Hematol. 2010;38(January (1)):20–26
  60. Wang L, Knight K, Lucas C, Clark RE. The role of serial BCR-ABL transcript monitoring in predicting the emergence of BCR-ABL kinase mutations in imatinib-treated patients with chronic myeloid leukemia. Haematologica. 2006;91:235–239
  61. Press RD, Willis SG, Laudadio J, Mauro MJ, Deininger MW. Determining the rise in BCR-ABL RNA that optimally predicts a kinase domain mutation in patients with chronic myeloid leukemia on imatinib. Blood. 2009;114(September (13)):2598–2605
  62. Talpaz M, Silver RT, Druker BJ, Goldman JM, Gambacorti-Passerini C, Guilhot F, et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood. 2002;99:1928–1937
  63. 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
  64. Hochhaus A, O’Brien SG, Guilhot F, Druker BJ, Branford S, Foroni L, et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia. 2009;23:1054–1061
  65. Cortes J, Giles F, O’Brien S, Thomas D, Garcia-Manero G, Rios MB, et al. Result of high-dose imatinib mesylate in patients with Philadelphia chromosome-positive chronic myeloid leukemia after failure of interferon-alpha. Blood. 2003;102:83–86
  66. 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
  67. Cortes J, Baccarani M, Guilhot F. A phase III, randomized, open-label study of 400mg versus 800mg of imatinib mesylate (IM) in patients (pts) with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase (CML-CP) using molecular endpoints: 1-year results of TOPS (tyrosine kinase inhibitor optimization and selectivity) study. In: ASH Annual Meeting Abstracts, vol. 112. 2008;p. 335
  68. Baranska M, Lewandowski K, Gniot M, Iwola M, Lewandowska M, Komarnicki M. Dasatinib treatment can overcome imatinib and nilotinib resistance in CML patient carrying F359I mutation of BCR-ABL oncogene. J Appl Genet. 2008;49:201–203
  69. 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;354:2531–2541
  70. Hochhaus A, Kantarjian HM, Baccarani M, Lipton JH, Apperley JF, Druker BJ, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood. 2007;109:2303–2309
  71. Hochhaus A, Baccarani M, Deininger M, Apperley JF, Lipton JH, Goldberg SL, et al. Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia. 2008;22:1200–1206
  72. Kantarjian H, Pasquini R, Hamerschlak N, Rousselot P, Holowiecki J, Jootar S, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood. 2007;109:5143–5150
  73. Kantarjian H, Pasquini R, Levy V, Jootar S, Holowiecki J, Hamerschlak N, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily: two-year follow-up of a randomized phase 2 study (START-R). Cancer. 2009;115:4136–4147
  74. Guilhot F, Apperley J, Kim DW, Bullorsky EO, Baccarani M, Roboz GJ, et al. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood. 2007;109:4143–4150
  75. Apperley JF, Cortes JE, Kim DW, Roy L, Roboz GJ, Rosti G, et al. Dasatinib in the treatment of chronic myeloid leukemia in accelerated phase after imatinib failure: the START a trial. J Clin Oncol. 2009;27:3472–3479
  76. Cortes J, Rousselot P, Kim DW, Ritchie E, Hamerschlak N, Coutre S, et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood. 2007;109:3207–3213
  77. Cortes J, Kim DW, Raffoux E, Martinelli G, Ritchie E, Roy L, et al. Efficacy and safety of dasatinib in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blast phase. Leukemia. 2008;22:2176–2183
  78. Shah NP, Kantarjian HM, Kim DW, Rea D, Dorlhiac-Llacer PE, Milone JH, et al. Intermittent target inhibition with dasatinib 100mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol. 2008;26:3204–3212
  79. Stone RM, Kim DW, Kantarjian HM, Rousselot Aea P. Dasatinib dose-optimization study in chronic phase chronic myeloid leukemia (CML-CP): three-year follow-up with dasatinib 100mg once daily and landmark analysis of cytogenetic response and progression-free survival (PFS). J Clin Oncol. 2009;27:7007;(Meeting Abstracts)
  80. Kantarjian H, Cortes J, Kim DW, Dorlhiac-Llacer P, Pasquini R, DiPersio J, et al. Phase 3 study of dasatinib 140mg once daily versus 70mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up. Blood. 2009;113:6322–6329
  81. Borthakur G, Kantarjian HM. SMOBe, efficacy of dasatinib in patients (pts) with previously untreated chronic myelogenous leukemia (CML) in early chronic phase (CML-CP). J Clin Oncol. 2008;26:7013;[abstracts]
  82. 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;354:2542–2551
  83. Kantarjian HM, Giles F, Gattermann N, Bhalla K, Alimena G, Palandri F, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007;110:3540–3546
  84. Kantarjian H, Giles F, Bhalla K. Nilotinib in chronic myeloid leukemia patients in chronic phase (CML-CP) with imatinib (IM) resistance or intolerance: longer follow-up results of a phase II study. J Clin Oncol. 2009;27:7029;[meeting abstract]
  85. Le Coutre PD, Giles F, Hochhaus A, et al. Nilotinib in chronic myeloid leukemia patients in accelerated phase (CML-AP) with imatinib (IM) resistance or intolerance: longer follow-up results of a phase II study. J Clin Oncol. 2009;27:7057;[meeting abstracts]
  86. Giles FJ, Larson RA, Kantarjian HM. Nilotinib in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in blast crisis (CML-BC) who are resistant or intolerant to imatinib. J Clin Oncol. 2008;7017;(ASCO Meeting Abstracts)
  87. Martinelli G, Castagnetti F, Poerio A, et al. Molecular responses with nilotinib 800mg daily as first-line treatment of chronic myeloid leukemia in chronic phase: results of a phase II trial of the GIMEMA CML WP. J Clin Oncol. 2009;27:7074;[meeting abstracts]
  88. Litzow MR. Imatinib resistance: obstacles and opportunities. Arch Pathol Lab Med. 2006;130:669–679
  89. Shah NP. Medical management of CML. Hematol Am Soc Hematol Educ Prog. 2007;371–375
  90. Lowenberg B. Minimal residual disease in chronic myeloid leukemia. N Engl J Med. 2003;349:1399–1401
  91. Azam M, Latek RR, Daley GQ. Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL. Cell. 2003;112:831–843
  92. Hochhaus A, La Rosee P. Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance. Leukemia. 2004;18:1321–1331
  93. Shah NP, Nicoll JM, Nagar B, Gorre ME, Paquette RL, Kuriyan J, et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell. 2002;2:117–125
  94. 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;102:276–283
  95. Cortes J, Jabbour E, Kantarjian H, Yin CC, Shan J, O’Brien S, et al. Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors. Blood. 2007;110:4005–4011
  96. Hochhaus A, Kreil S, Corbin AS, La Rosee P, Muller MC, Lahaye T, et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia. 2002;16:2190–2196
  97. Jabbour E, Kantarjian H, Jones D, Talpaz M, Bekele N, O’Brien S, et al. Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate. Leukemia. 2006;20:1767–1773
  98. Soverini S, Colarossi S, Gnani A, Rosti G, Castagnetti F, Poerio A, et al. Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA Working Party on Chronic Myeloid Leukemia. Clin Cancer Res. 2006;12:7374–7379
  99. 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;23:4100–4109
  100. le Coutre P, Kreuzer KA, Pursche S, Bonin M, Leopold T, Baskaynak G, et al. Pharmacokinetics and cellular uptake of imatinib and its main metabolite CGP74588. Cancer Chemother Pharmacol. 2004;53:313–323
  101. Peng B, Hayes M, Resta D, Racine-Poon A, Druker BJ, Talpaz M, et al. Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients. J Clin Oncol. 2004;22:935–942
  102. Picard S, Titier K, Etienne G, Teilhet E, Ducint D, Bernard MA, et al. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood. 2007;109:3496–3499
  103. Larson RA, Druker BJ, Guilhot F, O’Brien SG, Riviere GJ, Krahnke T, et al. Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood. 2008;111:4022–4028
  104. Forrest DL, Trainor S, Brinkman RR, Barnett MJ, Hogge DE, Nevill TJ, et al. Cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia are correlated with Sokal risk scores and duration of therapy but not trough imatinib plasma levels. Leuk Res. 2009;33:271–275
  105. Darkow T, Henk HJ, Thomas SK, Feng W, Baladi JF, Goldberg GA, et al. Treatment interruptions and non-adherence with imatinib and associated healthcare costs: a retrospective analysis among managed care patients with chronic myelogenous leukaemia. Pharmacoeconomics. 2007;25:481–496
  106. Halpern R, Barghout V, Mody-Patel N, Williams D. Relationship between compliance, costs, hospitalizations for CML and GIST patients using imatinib mesylate [abstract]. J Clin Oncol. 2008;26:5S;[abstract 6598]
  107. Noens L, van Lierde MA, De Bock R, Verhoef G, Zachee P, Berneman Z, et al. Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: the ADAGIO study. Blood. 2009;113:5401–5411
  108. van Erp NP, Gelderblom H, Karlsson MO, Li J, Zhao M, Ouwerkerk J, et al. Influence of CYP3A4 inhibition on the steady-state pharmacokinetics of imatinib. Clin Cancer Res. 2007;13:7394–7400
  109. Gréen H, Skoglund K, Rommel F, Mirghani RA, Lotfi K. CYP3A activity influences imatinib response in patients with chronic myeloid leukemia: a pilot study on in vivo CYP3A activity. Eur J Clin Pharmacol. 2010;66:383–386
  110. Wilkinson GR. Cytochrome P4503A (CYP3A) metabolism: prediction of in vivo activity in humans. J Pharmacokinet Biopharm. 1996;24:475–490
  111. eng B, Lloyd P, Schran H. Clinical pharmacokinetics of imatinib. Clin Pharmacokinet. 2005;44:879–894
  112. Gambacorti-Passerini C, Zucchetti M, Russo D, Frapolli R, Verga M, Bungaro S, et al. Alpha1 acid glycoprotein binds to imatinib (STI571) and substantially alters its pharmacokinetics in chronic myeloid leukemia patients. Clin Cancer Res. 2003;9:625–632
  113. Jørgensen HG, Elliott MA, Allen EK, Carr CE, Holyoake TL, Smith KD. Alpha1-acid glycoprotein expressed in the plasma of chronic myeloid leukemia patients does not mediate significant in vitro resistance to STI571. Blood. 2002;5:713–715
  114. Gottesman MM. Mechanisms of cancer drug resistance. Annu Rev Med. 2002;53:615–627
  115. Mahon FX, Belloc F, Lagarde V, Chollet C, Moreau-Gaudry F, Reiffers J, et al. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood. 2003;101:2368–2373
  116. Ferrao PT, Frost MJ, Siah SP, Ashman LK. Overexpression of P-glycoprotein in K562 cells does not confer resistance to the growth inhibitory effects of imatinib (STI571) in vitro. Blood. 2003;102:4499–4503
  117. Assef Y, Rubio F, Colo G, del Monaco S, Costas MA, Kotsias BA. Imatinib resistance in multidrug-resistant K562 human leukemic cells. Leuk Res. 2009;33:710–716
  118. Galimberti S, Cervetti G, Guerrini F, Testi R, Pacini S, Fazzi R, et al. Quantitative molecular monitoring of BCR-ABL and MDR1 transcripts in patients with chronic myeloid leukemia during Imatinib treatment. Cancer Genet Cytogenet. 2005;162:57–62
  119. Hatziieremia S, Jordanides NE, Holyoake TL, Mountford JC, Jorgensen HG. Inhibition of MDR1 does not sensitize primitive chronic myeloid leukemia CD34+ cells to imatinib. Exp Hematol. 2009;37:692–700
  120. Mao Q, Unadkat JD. Role of the breast cancer resistance protein (ABCG2) in drug transport. AAPS J. 2005;7:E118–E133
  121. Brendel C, Scharenberg C, Dohse M, Robey RW, Bates SE, Shukla S, et al. Imatinib mesylate and nilotinib (AMN107) exhibit high-affinity interaction with ABCG2 on primitive hematopoietic stem cells. Leukemia. 2007;21:1267–1275
  122. Burger H, van Tol H, Boersma AW, Brok M, Wiemer EA, Stoter G, et al. Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump. Blood. 2004;104:2940–2942
  123. Shukla S, Sauna ZE, Ambudkar SV. Evidence for the interaction of imatinib at the transport-substrate site(s) of the multidrug-resistance-linked ABC drug transporters ABCB1 (P-glycoprotein) and ABCG2. Leukemia. 2008;22:445–447
  124. Mahon FX, Hayette S, Lagarde V, Belloc F, Turcq B, Nicolini F, et al. Evidence that resistance to nilotinib may be due to BCR-ABL, Pgp, or Src kinase overexpression. Cancer Res. 2008;68:9809–9816
  125. Tiwari AK, Sodani K, Wang SR, Kuang YH, Ashby CR, Chen X, et al. Nilotinib (AMN107, Tasigna) reverses multidrug resistance by inhibiting the activity of the ABCB1/Pgp and ABCG2/BCRP/MXR transporters. Biochem Pharmacol. 2009;78:153–161
  126. Chen Y, Agarwal S, Shaik NM, Chen C, Yang Z, Elmquist WF. P-glycoprotein and breast cancer resistance protein influence brain distribution of dasatinib. J Pharmacol Exp Ther. 2009;330:956–963
  127. Hiwase DK, Saunders V, Hewett D, Frede A, Zrim S, Dang P, et al. Dasatinib cellular uptake and efflux in chronic myeloid leukemia cells: therapeutic implications. Clin Cancer Res. 2008;14:3881–3888
  128. Kamath AV, Wang J, Lee FY, Marathe PH. Preclinical pharmacokinetics and in vitro metabolism of dasatinib (BMS-354825): a potent oral multi-targeted kinase inhibitor against SRC and BCR-ABL. Cancer Chemother Pharmacol. 2008;61:365–376
  129. Shen T, Kuang YH, Ashby CR, Lei Y, Chen A, Zhou Y, et al. Imatinib and nilotinib reverse multidrug resistance in cancer cells by inhibiting the efflux activity of the MRP7 (ABCC10). PLoS One. 2009;4:e7520
  130. Thomas J, Wang L, Clark RE, Pirmohamed M. Active transport of imatinib into and out of cells: implications for drug resistance. Blood. 2004;104:3739–3745
  131. White DL, Saunders VA, Dang P, Engler J, Venables A, Zrim S, et al. Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: higher doses of imatinib may overcome the negative impact of low OCT-1 activity. Blood. 2007;110:4064–4072
  132. Niwa T, Asaki T, Kimura S. NS-187 (INNO-406), a Bcr-Abl/Lyn dual tyrosine kinase inhibitor. Anal Chem Insights. 2007;2:93–106
  133. Meyn MA, Wilson MB, Abdi FA, Fahey N, Schiavone AP, Wu J, et al. Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. J Biol Chem. 2006;281:30907–30916
  134. Donato NJ, Wu JY, Stapley J, Gallick G, Lin H, Arlinghaus R, et al. BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood. 2003;101:690–698
  135. Donato NJ, Wu JY, Stapley J, Lin H, Arlinghaus R, Aggarwal BB, et al. Imatinib mesylate resistance through BCR-ABL independence in chronic myelogenous leukemia. Cancer Res. 2004;64:672–677
  136. Dai Y, Rahmani M, Corey SJ, Dent P, Grant S. A Bcr/Abl-independent, Lyn-dependent form of imatinib mesylate (STI-571) resistance is associated with altered expression of Bcl-2. J Biol Chem. 2004;279:34227–34239
  137. Wu J, Meng F, Kong LY, Peng Z, Ying Y, Bornmann WG, et al. Association between imatinib-resistant BCR-ABL mutation-negative leukemia and persistent activation of LYN kinase. J Natl Cancer Inst. 2008;100:926–939
  138. Redaelli S, Piazza R, Rostagno R, Magistroni V, Perini P, Marega M, et al. Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. J Clin Oncol. 2009;27:469–471
  139. 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;66:11314–11322
  140. Graham SM, Jorgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L, et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood. 2002;99:319–325
  141. Burgering BM. A brief introduction to FOXOlogy. Oncogene. 2008;27(April (16)):2258–2262
  142. Komatsu N, Watanabe T, Uchida M, Mori M, Kirito K, Kikuchi S, et al. A member of Forkhead transcription factor FKHRL1 is a downstream effector of STI571-induced cell cycle arrest in BCR-ABL-expressing cells. J Biol Chem. 2003;278(February (8)):6411–6419
  143. Marin D, Goldman JM, Olavarria E, Apperley JF. Transient benefit only from increasing the imatinib dose in CML patients who do not achieve complete cytogenetic remissions on conventional doses. Blood. 2003;102:2702–2703[author reply 2703–4]
  144. Kantarjian HM, Larson RA, Guilhot F, O’Brien SG, Mone M, Rudoltz M, et al. Efficacy of imatinib dose escalation in patients with chronic myeloid leukemia in chronic phase. Cancer. 2009;115:551–560
  145. Le Coutre P, Ottmann OG, Giles F, Kim DW, Cortes J, Gattermann N, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood. 2008;111:1834–1839
  146. Weisser M, Schleuning M, Haferlach C, Schwerdtfeger R, Kolb HJ. Allogeneic stem-cell transplantation provides excellent results in advanced stage chronic myeloid leukemia with major cytogenetic response to pre-transplant imatinib therapy. Leuk Lymphoma. 2007;48:295–301
  147. Kreuzer KA, Kluhs C, Baskaynak G, Movassaghi K, Dorken B, le Coutre P. Filgrastim-induced stem cell mobilization in chronic myeloid leukaemia patients during imatinib therapy: safety, feasibility and evidence for an efficient in vivo purging. Br J Haematol. 2004;124(January (2)):195–199
  148. Rea D, Raffoux E, Cayuela JM, Maarek O, Dombret H. Sustained major molecular response in the absence of any antileukaemic therapy after dasatinib treatment and autologous peripheral blood stem cell transplantation in a patient with imatinib-resistant myeloblastic-phase chronic myeloid leukaemia. Leukemia. 2009;23(June (6)):1158–1159
  149. Mughal TI, Goldman JM. Emerging strategies for the treatment of mutant Bcr-Abl T315I myeloid leukemia. Clin Lymphoma Myeloma. 2007;7(Suppl. 2):S81–S84
  150. Zhang J, Adrian FJ, Jahnke W, Cowan-Jacob SW, Li AG, Iacob RE, et al. Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature. 2010;463(January (7280)):501–506

PII: S0145-2126(10)00236-5

doi: 10.1016/j.leukres.2010.04.016

Leukemia Research
Volume 34, Issue 10 , Pages 1255-1268 , October 2010