Seminars in Hematology
Volume 44 , Pages 15-24 , January 2007

Resistance to Targeted Therapy in Chronic Myelogenous Leukemia

References 

  1. Druker BJ. Imatinib as a paradigm of targeted therapies. Adv Cancer Res. 2004;91:1–30
  2. Hochhaus A, La Rosée P. Imatinib therapy in chronic myelogenous leukemia: Strategies to avoid and overcome resistance. Leukemia. 2004;18:1321–1331
  3. Wendel HG, deStanchina SE, Cepero E, et al. Loss of p53 impedes the antileukemic response to Bcr-Abl inhibition. Proc Natl Acad Sci U S A. 2006;103:7444–7449
  4. Burchert A, Wang Y, Cai D, et al. Compensatory PI3-kinase/Akt/mTor activation regulates imatinib resistance development. Leukemia. 2005;19:1774–1782
  5. 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
  6. Donato NJ, Wu JY, Stapley J, et al. Bcr-Abl independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood. 2003;101:690–698
  7. Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia: Recommendations from an expert panel on behalf of the European Leukemia Net. Blood. 2006;108:1809–1820
  8. Hughes TP, Kaeda J, Branford S, 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;349:1423–1432
  9. Müller MC, Gattermann N, Lahaye T, et al. Dynamics of Bcr-Abl mRNA expression in first-line therapy of chronic myelogenous leukemia patients with imatinib or interferon alpha/ara-C. Leukemia. 2003;17:2392–2400
  10. Kantarjian H, Sawyers C, Hochhaus A, et al. International STI571 CML Study Group Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002;346:645–652
  11. O’Brien SG, Guilhot F, Larson RA, et al. IRIS investigators Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994–1004
  12. 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
  13. Lahaye T, Riehm B, Berger U, et al. Response and resistance in 300 patients with Bcr-Abl-positive leukemias treated with imatinib in a single center: A 4.5-year follow-up. Cancer. 2005;103:1659–1669
  14. Talpaz M, Silver RT, Druker BJ, 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
  15. Sawyers CL, Hochhaus A, Feldman E, 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
  16. Cowan-Jacob SW, Guez V, Fendrich G, et al. Imatinib (STI571) resistance in chronic myelogenous leukemia: Molecular basis of the underlying mechanisms and potential strategies for treatment. Mini Rev Med Chem. 2004;4:285–299
  17. Gorre ME, Sawyers CL. Molecular mechanisms of resistance to STI571 in chronic myeloid leukemia. Curr Opin Hematol. 2002;9:303–307
  18. Illmer T, Schaich M, Platzbecker U, et al. P-glycoprotein–mediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylate. Leukemia. 2004;18:401–408
  19. 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
  20. Shah NP, Nicoll JM, Nagar B, 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
  21. Branford S, Rudzki Z, Parkinson I, et al. Real-time quantitative PCR analysis can be used as a primary screen to identify patients with CML treated with imatinib who have Bcr-Abl kinase domain mutations. Blood. 2004;104:2926–2932
  22. 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
  23. Khorashad JS, Anand M, Marin D, 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
  24. Roche-Lestienne C, Preudhomme C. Mutations in the ABL kinase domain pre-exist the onset of imatinib treatment. Semin Hematol. 2003;40(suppl 2):80–82
  25. Willis SG, Lange T, Demehri S, et al. High-sensitivity detection of Bcr-Abl kinase domain mutations in imatinib-naive patients: Correlation with clonal cytogenetic evolution but not response to therapy. Blood. 2005;106:2128–2137
  26. Chu S, Xu H, Shah NP, et al. Detection of Bcr-Abl kinase mutations in CD34+ cells from chronic myelogenous leukemia patients in complete cytogenetic remission on imatinib mesylate treatment. Blood. 2005;105:2093–2098
  27. Angstreich GR, Matsui W, Huff CA, et al. Effects of imatinib and interferon on primitive chronic myeloid leukaemia progenitors. Br J Haematol. 2005;130:373–381
  28. Elrick LJ, Jorgensen HG, Mountford JC, Holyoake TL. Punish the parent not the progeny. Blood. 2005;105:1862–1866
  29. Graham SM, Jörgensen HG, Allan E, 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
  30. 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
  31. Hochhaus A, Kreil S, Corbin AS, et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia. 2002;16:2190–2196
  32. Soverini S, Martinelli G, Rosti G, 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
  33. Donato NJ, Wu JY, Stapley J, et al. Imatinib mesylate resistance through Bcr-Abl independence in chronic myelogenous leukemia. Cancer Res. 2004;64:672–677
  34. Bumm T, Müller C, Al-Ali HK, et al. Emergence of clonal cytogenetic abnormalities in Ph- cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority. Blood. 2003;101:1941–1949
  35. Cortes J, O’Dwyer ME. Clonal evolution in chronic myelogenous leukemia. Hematol Oncol Clin North Am. 2004;18:671–684
  36. Gozzetti A, Tozzuoli D, Crupi R, et al. Emergence of Ph negative clones in chronic myeloid leukemia (CML) patients in complete cytogenetic remission after therapy with imatinib mesylate (STI). Eur J Haematol. 2003;71:313–314
  37. Marktel S, Marin D, Foot N, et al. Chronic myeloid leukemia in chronic phase responding to imatinib: The occurrence of additional cytogenetic abnormalities predicts disease progression. Haematologica. 2003;88:260–267
  38. Mohamed AN, Pemberton P, Zonder J, Schiffer CA. The effect of imatinib mesylate on patients with Philadelphia chromosome-positive chronic myeloid leukemia with secondary chromosomal aberrations. Clin Cancer Res. 2003;9:1333–1337
  39. O’Dwyer ME, Gatter KM, Loriaux M, et al. Demonstration of Philadelphia chromosome negative abnormal clones in patients with chronic myelogenous leukemia during major cytogenetic responses induced by imatinib mesylate. Leukemia. 2003;17:481–487
  40. O’Dwyer ME, Mauro MJ, Kurilik G, et al. The impact of clonal evolution on response to imatinib mesylate (STI571) in accelerated phase CML. Blood. 2002;100:1628–1633
  41. Schoch C, Haferlach T, Kern W, et al. Occurrence of additional chromosome aberrations in chronic myeloid leukemia patients treated with imatinib mesylate. Leukemia. 2003;17:461–463
  42. Huntly BJ, Guilhot F, Reid AG, et al. Imatinib improves but may not fully reverse the poor prognosis of patients with CML with derivative chromosome 9 deletions. Blood. 2003;102:2205–2212
  43. Quintas-Cardama A, Kantarjian H, Talpaz M, et al. Imatinib mesylate therapy may overcome the poor prognostic significance of deletions of derivative chromosome 9 in patients with chronic myelogenous leukemia. Blood. 2005;105:2281–2286
  44. Bacher U, Hochhaus A, Berger U, et al. Clonal aberrations in Philadelphia chromosome negative hematopoiesis in patients with chronic myeloid leukemia treated with imatinib or interferon alpha. Leukemia. 2005;19:460–463
  45. Gambacorti-Passerini C, Zucchetti M, Russo D, 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
  46. Gorre ME, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy caused by Bcr-Abl gene mutation or amplification. Science. 2001;293:876–880
  47. Deininger MWN, McGreevey L, Willis S, Bainbridge TM, Druker BJ, Heinrich MC. Detection of ABL kinase domain mutations with denaturing high-performance liquid chromatography. Leukemia. 2004;18:864–871
  48. Irving JA, O’Brien S, Lennard AL, Minto L, Lin F, Hall AG. Use of denaturing HPLC for detection of mutations in the Bcr-Abl kinase domain in patients resistant to imatinib. Clin Chem. 2004;50:1233–1237
  49. Soverini S, Martinelli G, Amabile M, et al. Denaturing-HPLC-based assay for detection of ABL mutations in chronic myeloid leukemia patients resistant to imatinib. Clin Chem. 2004;50:1205–1213
  50. Hochhaus A. Cytogenetic and molecular mechanisms of resistance to imatinib. Semin Hematol. 2003;40(suppl 2):69–79
  51. Hochhaus A, Kreil S, Corbin A, et al. Roots of clinical resistance to STI-571 cancer therapy. Science. 2001;293:2163–2169
  52. Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J. Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase. Science. 2000;289:1938–1942
  53. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the Bcr-Abl tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001;344:1038–1042
  54. Druker BJ, Talpaz M, Resta DJ, 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
  55. Kantarjian H, Talpaz M, O’Brien S, et al. High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome–positive chronic phase chronic myeloid leukemia. Blood. 2004;103:2873–2878
  56. Kantarjian HM, Talpaz M, O’Brien 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
  57. Müller MC, Lahaye T, Hochhaus A. [Resistance to tumor specific therapy with imatinib by clonal selection of mutated cells]. Dtsch Med Wochenschr. 2002;127:2205–2207
  58. La Rosée P, Johnson K, O’Dwyer ME, Druker BJ. In vitro studies of the combination of imatinib mesylate (Gleevec) and arsenic trioxide (Trisenox) in chronic myelogenous leukemia. Exp Hematol. 2002;30:729–737
  59. La Rosée P, O’Dwyer ME, Druker BJ. Insights from pre-clinical studies for new combination treatment regimens with the Bcr-Abl kinase inhibitor imatinib mesylate (Gleevec/Glivec) in chronic myelogenous leukemia: A translational perspective. Leukemia. 2002;16:1213–1219
  60. Berger U, Engelich G, Reiter A, Hochhaus A, Hehlmann R. Imatinib and beyond—The new CML study IV (A randomized controlled comparison of imatinib vs imatinib/interferon-alpha vs imatinib/low-dose AraC vs imatinib after interferon-alpha failure in newly diagnosed chronic phase chronic myeloid leukemia). Ann Hematol. 2004;83:258–264
  61. Burchert A, Wölfl S, Schmidt M, et al. Interferon-α, but not the ABL-kinase inhibitor imatinib (STI571), induces expression of myeloblastin and a specific T-cell response in chronic myeloid leukemia. Blood. 2003;101:259–264
  62. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia: Version 1, 2007. Jenkintown, PA: National Comprehensive Cancer Network; 2006;
  63. Jørgensen HG, Allen EK, Graham SM, et al. Lonafarnib reduces the resistance of primitive quiescent CML cells to imatinib mesylate in vitro. Leukemia. 2005;19:1184–1191
  64. Cortes J, Albitar M, Thomas D, et al. Efficacy of the farnesyl transferase inhibitor R115777 in chronic myeloid leukemia and other hematologic malignancies. Blood. 2003;101:1692–1697
  65. Cai D, Wang Y, Ottmann OG, Barth PJ, Neubauer A, Burchert A. FLT3-ITD-, but not BCR/ABL-transformed cells require concurrent Akt/mTor blockage to undergo apoptosis after histone deacetylase inhibitor treatment. Blood. 2006;107:2094–2097
  66. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006;354:2542–2551
  67. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354:2531–2541
  68. 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
  69. Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell. 2005;7:129–141
  70. Gratwohl A, Brand R, Apperley J, et al. Allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia in Europe 2006: transplant activity, long-term data and current results (An analysis by the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT)). Haematologica. 2006;91:513–521

 Supported by the Competence Network “Acute and Chronic Leukemias,” sponsored by the German Bundesministerium für Bildung und Forschung (Projektträger Gesundheitsforschung; DLR e.V.- 01 GI9980/6), and the European LeukemiaNet within the 6th European Community Framework Program for Research and Technological Development.

PII: S0037-1963(06)00255-1

doi: 10.1053/j.seminhematol.2006.12.002

Seminars in Hematology
Volume 44 , Pages 15-24 , January 2007

Article Tools