Seminars in Hematology
Volume 46 , Pages S27-S33 , April 2009

New Directions in the Treatment of Imatinib Failure and/or Resistance

  • Francis J. Giles

      Affiliations

    • Corresponding Author InformationAddress correspondence to Francis J. Giles, MD, FRCPI, FRCPath, CTRC at the University of Texas Health Science Center at San Antonio, 7979 Wurzbach Rd, San Antonio, TX 78229

References 

  1. National Comprehensive Cancer Network. NCCN: Clinical practice guidelines in oncology (Chronic myelogenous leukemia). 2009;© 2006 National Comprehensive Cancer Network, Inc. Version 2. Jenkintown, PA
  2. 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
  3. Hochhaus A, La Rosee P. Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance. Leukemia. 2004;18:1321–1331
  4. 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
  5. Azam M, Daley GQ. Anticipating clinical resistance to target-directed agents: The BCR-ABL paradigm. Mol Diagn Ther. 2006;10:67–76
  6. 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
  7. 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
  8. Khorashad JS, Anand M, Marin D, Saunders S, Al-Jabary T, Iqbal A, et al. The presence of a BCR-ABL mutant allele in CML does not always explain clinical resistance to imatinib. Leukemia. 2006;20:658–663
  9. 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
  10. 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
  11. Copland M, Fraser AR, Harrison SJ, Holyoake TL. Targeting the silent minority: emerging immunotherapeutic strategies for eradication of malignant stem cells in chronic myeloid leukaemia. Cancer Immunol Immunother. 2005;54:297–306
  12. Huntly BJ, Gilliland DG. Leukaemia stem cells and the evolution of cancer-stem-cell research. Nat Rev Cancer. 2005;5:311–321
  13. Kantarjian HM, Talpaz M, O'Brien S, Giles F, Garcia-Manero G, Faderl S, et al. Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood. 2003;101:473–475
  14. Kantarjian HM, Druker BJ, Guilhot F, Cortes J, O'Brien SG, Krahnke T, et al. Imatinib dose escalation is effective in patients with chronic myeloid leukemia in chronic phase (CP-CML). Blood. 2007;110:317a
  15. 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
  16. Golemovic M, Verstovsek S, Giles F, Cortes J, Manshouri T, Manley PW, et al. AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, has in vitro activity against imatinib-resistant chronic myeloid leukemia. Clin Cancer Res. 2005;11:4941–4947
  17. 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
  18. 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
  19. Tokarski JS, Newitt JA, Chang CY, Cheng JD, Wittekind M, Kiefer SE, et al. The structure of dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. Cancer Res. 2006;66:5790–5797
  20. Vajpai N, Strauss A, Fendrich G, Cowan-Jacob SW, Manley PW, Grzesiek S, et al. Solution conformations and dynamics of ABL kinase-inhibitor complexes determined by NMR substantiate the different binding modes of imatinib/nilotinib and dasatinib. J Biol Chem. 2008;283:18292–18302
  21. O'Hare T, Walters DK, Deininger MW, Druker BJ. AMN107: tightening the grip of imatinib. Cancer Cell. 2005;7:117–119
  22. Kantarjian HM, Giles FJ, Hochhaus A, Bhalla KN, Ossenkoppele GJ, Gatterman N, et al. Nilotinib in patients with imatinib-resistant or –intolerant chronic myelogenous leukemia in chronic phase (CP-CML): updated phase II results [abstract 7010]. J Clin Oncol. 2008;20(Suppl):26 May
  23. Kantarjian HM, Giles FJ, Bhalla KN, Larson RA, Gatterman N, Ottmann OG, et al. Nilotinib in chronic myelogenous leukaemia in chronic phase (CP-CML) patients with imatinib resistance or –intolerance: updated phase 2 results. Hematologica. 2008;93(Suppl 1):350
  24. le Coutre P, Giles FJ, Apperley J, Ottman OG, Larson RA, Haque A, et al. Nilotinib in accelerated phase chronic myelogenous leukemia (AP-CML) patients with imatinib-resistance or –intolerance: update of a phase 2 study. J Clin Oncol. 2008;26:384s
  25. le Coutre P, Hochhaus A, Apperley J, Ossenkoppele G, Haque A, Gallagher N, et al. Nilotinib in imatinib-resistant or -intolerant patients with chronic myelogenous leukaemia in accelerated phase (AP-CML): update of a phase 2 study. Hematologica. 2008;93:47
  26. 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
  27. 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
  28. 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
  29. 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
  30. 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
  31. 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
  32. Cervantes F, Baccarani M, Lipton J, Matloub Y, Sinha R, Stone RM, et al. Dasatinib long-term efficacy in patients with chronic myeloid leukemia in chronic phase (CP-CML) with resistance or intolerance to imatinib: a two-year update of the START-C study. Haematologica. 2008;93:372
  33. Mauro MJ, Baccarani M, Cervantes F, Lipton JH, Matloub Y, Sinha R, et al. Dasatinib 2-year efficacy in patients with chronic-phase chronic myelogenous leukemia (CP-CML) with resistance or intolerance to imatinib (START-C). J Clin Oncol. 2008;26:374s
  34. Saglio G, Dombret H, Rea D, Corm S, Cortes JE, Kim DW, et al. Dasatinib efficacy in patients with imatinib-resistant/-intolerant chronic myeloid leukemia in blast phase: 24-month data from the START program. Haematologica. 2008;93:349
  35. de Lavallade H, Punnialingam S, Milojkovic D, Bua M, Khorashad JS, Gabriel IH, et al. Pleural effusions in patients with chronic myeloid leukaemia treated with dasatinib may have an immune-mediated pathogenesis. Br J Haematol. 2008;141:745–747
  36. Rousselot P, Corm S, Paquette R, Bleickardt E, Dejardin D, Kantarjian H, et al. Dasatinib compared with high-dose imatinib in patients with chronic myelogenous leukemia in chronic phase (CP-CML) after failure of standard-dose imatinib—a two-year update of the START-R study. Haematologica. 2008;93:48
  37. Rousselot P, Facon T, Paquette R, Bleickardt E, Dejardin D, Kantarjian H. Dasatinib or high-dose imatinib for patients with chronic myelogenous leukemia chronic-phase (CP-CML) resistant to standard- dose imatinib: 2-year follow-up data from START-R. J Clin Oncol. 2008;26:375s
  38. 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
  39. Kantarjian HM, Rousselot P, Pasquini R, Hamerschlak N, Holowiecki J, Dejardin D, et al. Dasatinib or high-dose imatinib for patients with chronic-phase chronic myeloid leukemia resistant to standard-dose imatinib: 2-year follow-up data from START-R (CA180-017). Blood. 2007;110:226a
  40. Abruzzese E, Alimena G, le Coutre P, Bhalla K, Ossenkoppele G, Haque A, et al Nilotinib in chronic myelogenous leukemia patients who failed prior imatinib and dasatinib therapy: updated results of an open-label phase 2 study. J Clin Oncol. 2008;26:385s
  41. Giles FJ, le Coutre P, Bhalla Kea. A phase II study of nilotinib administered to patients with imatinib resistant or intolerant chronic myelogenous leukemia (CML) in chronic phase (CP), accelerated phase (AP) or blast crisis (BC) who also failed dasatinib. J Clin Oncol. 2007;25:366s
  42. Quintas-Cardama A, Kantarjian H, Jones D, Nicaise C, O'Brien S, Giles F, et al. Dasatinib (BMS-354825) is active in Philadelphia chromosome-positive chronic myelogenous leukemia after imatinib and nilotinib (AMN107) therapy failure. Blood. 2007;109:497–499
  43. 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
  44. 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
  45. Cortes J, Bruemmendorf T, Kantarjian H, Khoury J, Rosti G, Fischer T, et al. Efficacy and safety of bosutinib (SKI-606) among patients with chronic phase Ph+ chronic myelogenous leukemia (CML). Blood. 2007;110:225a
  46. 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
  47. Deguchi Y, Kimura S, Ashihara E, Niwa T, Hodohara K, Fujiyama Y, et al. Comparison of imatinib, dasatinib, nilotinib and INNO-406 in imatinib-resistant cell lines. Leuk Res. 2008;32:980–983
  48. Kantarjian HM, Cortes J, le Coutre P, Nagler A, Pinilla J, Hochhaus A, et al. A phase I study of INNO-406 in patients with advanced Philadelphia (Ph+) chromosome-positive leukemias who are resistant or intolerant to imatinib and second generation tyrosine kinase inhibitors. Blood. 2007;110:144a
  49. 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
  50. Azam M, Nardi V, Shakespeare WC, Metcalf CA, Bohacek RS, Wang Y, et al. Activity of dual SRC-ABL inhibitors highlights the role of BCR/ABL kinase dynamics in drug resistance. Proc Natl Acad Sci U S A. 2006;103:9244–9249
  51. Warmuth M, Simon N, Mitina O, Mathes R, Fabbro D, Manley PW, et al. Dual-specific Src and Abl kinase inhibitors, PP1 and CGP76030, inhibit growth and survival of cells expressing imatinib mesylate-resistant Bcr-Abl kinases. Blood. 2003;101:664–672
  52. Carter TA, Wodicka LM, Shah NP, Velasco AM, Fabian MA, Treiber DK, et al. Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. Proc Natl Acad Sci U S A. 2005;102:11011–11016
  53. 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
  54. Gontarewicz A, Balabanov S, Keller G, Colombo R, Graziano A, Pesenti E, et al. Simultaneous targeting of aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I. Blood. 2008;111:4355–4364
  55. Kuroda J, Kimura S, Andreeff M, Ashihara E, Kamitsuji Y, Yokota A, et al. ABT-737 is a useful component of combinatory chemotherapies for chronic myeloid leukaemias with diverse drug-resistance mechanisms. Br J Haematol. 2008;140:181–190
  56. Cortes J, Kantarjian H. New targeted approaches in chronic myeloid leukemia. J Clin Oncol. 2005;23:6316–6324
  57. Tasigna (nilotinib) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2007;
  58. Sprycel (dasatinib) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2007;

 Editorial support was provided by Jeni Fagan (Health Interactions) on behalf of Novartis Oncology.

 STATEMENT OF CONFLICT OF INTEREST: Dr Giles received research support from Novartis Pharmaceuticals Corp.

PII: S0037-1963(09)00022-5

doi: 10.1053/j.seminhematol.2009.01.011

Seminars in Hematology
Volume 46 , Pages S27-S33 , April 2009