Resistance to imatinib and the possibilities of use of the dose escalation of the drug in patients with chronic myeloid leukemia

Authors: J. Mayer 1;  H. Klamová 1;  D. Žáčková 1;  M. Doubek 1;  P. Cetkovský 1;  M. Krejčí 1;  D. Dvořáková 1
Authors‘ workplace: za organizaci Česká leukemická skupina - pro život, The CzEch Leukemia Study Group – for Life, CELL ;  Interní hematoonkologická klinika FN Brno, 2Ústav hematologie a krevní transfuze, Praha 1
Published in: Transfuze Hematol. dnes,13, 2007, No. 3, p. 133-141.
Category: Comprehensive Reports, Original Papers, Case Reports


The introduction of imatinib into the treatment of chronic myeloid leukemia represents a revolutionary therapeutic approach. Together with its excellent results, the issue of imatinib resistance – the significant cause of therapeutic failure – has emerged. The authors pay attention to the relation of the mechanism of action, pharmacokinetics and pharmacodynamics to the imatinib treatment results in the scale ranging from the BCR-ABL transcript reduction to the overall survival. In addition, the most frequent mechanisms of imatinib resistance, particularly the data about the BCR-ABL kinase domain mutations are summarized and the possibilities of the management of this problem are discussed. Besides the dose escalation of imatinib the new promising agents, particularly dasatinib and nilotinib are presented and discussed.

Key words:
chronic myeloid leukemia, imatinib, resistance to imatinib, BCR-ABL, BCR-ABL kinase domain mutations, dasatinib, nilotinib


1. Nowel PC, Hungerford DA. A minute chromosome in human granulocytic leukemia. Science 1960; 132: 1497.

2. Mayer J. Chronická myeloidní leukemie jako model moderní necytostatické léčby maligních chorob. Od Virchowa po STI 571. Vnitřní lék 2002; 48: 45-49.

3. O’Dwyer ME, Druker BJ. Chronic myelogenous leukaemia – new therapeutic principles. J Int Med 2001; 250:3-9.

4. Deininger M, Buchdunger E, Druker BJ. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 2005; 105: 2640-2653.

5. Schindler T, Bornmann W, Pellicena P, et al. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 2000; 289: 1938-1942.

6. 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.

7. Peng B, Hayes M, Resta D, et al. Pharmakokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients. J Clin Oncol 2004; 22: 935-942.

8. 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.

9. Kantarjian HM, Cortes J, O’Brien S, et al. Imatinib mesylate (STI 571) therapy for Philadelphia chromosome – positive chronic myelogenous leukemia in blast phase. Blood 2002; 99: 3547-3553.

10. O’Brien S, Guilhot F, Larson RA, 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.

11. Hughes TP, Kaeda J, Branford S, et al. Frequency of major molecular response to imatinib of interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 2003; 349: 1423-1432.

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. Sokal JE, Cox EB, Baccarani M, et al. Prognostic discrimination in “good risk” chronic granulocytic leukaemia. Blood 1984; 63: 789-799.

14. Hochhaus A, La Rosée P. Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance. Leukemia 2004; 18: 1321-1313.

15. Kantarjian HM, Talpaz M, Giles F, et al. New insights into the pathophysiology of chronic myeloid leukemia and imatinib resistance. Ann Intern Med 2006; 145: 913-923.

16. Naušová J, Priwitzerová M, Jarošová M, et al. Chronická myeloidní leukemie - rezistence na imatinib mesylát (Glivec) - přehled literatury a vlastní zkušenosti. Čas Lék čes 2006; 145: 377-382.

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

18. Martinelli G, Soverini S, Rosti G, et al. New tyrosine kinase inhibitors in chronic myeloid leukemia. Haematologica 2005; 90: 534-541.

19. Martinelli G, Soverini S, Rosti G, Baccarani M. Dual tyrosine kinase inhibitors in chronic myeloid leukemia. Leukemia 2005; 19: 1872-1879.

20. Anand M, Khorashad J, Marin D, et al. Varying response to escalating dose of imatinib in patients with CML who “acquire” a BCR-ABLM244V mutant alele. Blood 2006; 108: 2881-2882.

21. McLean LA, Gathmann I, Capdeville R, et al. Pharmacogenomic analysis of cytogenetic response in chronic myeloid leukemia patients treated with imatinib. Clin Cancer Res 2004; 10: 155-165.

22. Graham SM, Jorgensen HG, Allan E, et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI 571 in vitro. Blood 2002; 99: 319-325.

23. Bhatia R, Holtz M, Niu N, et al. Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood 2003; 101: 4701-4707.

24. 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 in imatinib mesylate treatment. Blood 2005; 105: 2093-2098.

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. Rousselot P, Huguet F, Rea D, et al. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood 2007; 109: 58-60.

27. Picard S, Titier K, Etienne G, et al. Trough plasma imatinib concentrations are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 2006; 108: abstract No 2141.

28. White D, Saunders V, Dang P, et al. Molecular response to imatinib is dependent on dose in CML patients with low OCT-1 influx activity. Patients with high activity may respond equally well to standard or increased dose imatinib. Blood 2006; 108: abstract No 738.

29. Faber E, Naušová J, Jarošová M, et al. Intermitent dosage of imatinib mesylate in CML patients with a history of significant hematology toxicity after standard dosing. Leukemia lymphoma 2006; 47: 1082-1090.

30. 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 phase 2 study. Blood 2002; 99: 1928-1937.

31. 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 2000; 99: 3530-3539.

32. 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.

33. Zonder JA, Pemberton P, Brandt H, et al. The effect of dose increase of imatinib mesylate in patients with chronic of accelerated phase chronic myelogenous leukemia with inadequate hematologic or cytogenetic response to initial treatment. Clin Cancer Res 2003; 9: 2092-2097.

34. Piazza RG, Magistroni V, Andreoni F, et al. Imatinib dose increase up to 1200 mg daily can induce new complete cytogenetic remission in relapsed Ph+ chronic myeloid leukemia patients. Leukemia 2005; 19: 1985-1987.

35. Jabbour E, Cortes J, Kantarjian HM, et al. Allogeneic stem cell transplantation for patients with chronic myeloid leukemia and acute lymphoblastic leukemia after Bcr-Abl kinase mutation-related imatinib failure. Blood 2006; 108: 1421-1423.

36. Das J, Chen P, Norris D, et al. 2-aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[6-[4-(2-hydroxyphenyl)-1-piperazinyl)]-2-methyl-4-pyrimidinylamino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor. J Med Chem 2006; 49: 6819-6832.

37. Shah NP, Tran C, Lee FY, et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 2004; 305: 399-401.

38. O’Hare T, Walters DK, Stoffregen EP, et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354828 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res 2005; 65: 4500-4506.

39. Tokarski JS, Newitt JA, Chang CYJ, 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.

40. Soverini S, Martineli G, Colarossi S, et al. Mutations at residues 315 and 317 in the ABL kinase domain are the main cause of resistance to dasatinib in Ph+ leukemia patients. Blood 2006; 108: abstract No 836.

41. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 2006; 354: 2531-2541.

42. Cortes J, Kim DW, Guilhot F, et al. Dasatinib (SPRYCEL) in patients with chronic myelogenous leukemia in accelerated phase that is imatinib-resistant or intolerant: updated results of the CA 180-005 ’START-A’ phase II study. Blood 2006; 180: abstract No 2160.

43. Shah N, Pasquini R, Rousselot P, et al. Dasatinib (Sprycel) vs. escalated dose of imatinib in patients with chronic phase chronic myeloid leukemia resistant to imatinib : results of the CA180-017 START-R randomized study. Blood 2006; 108: abstract No 167.

44. Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of naive and mutant Bcr-Abl. Cancer Cell 2005; 7: 129-141.

45. O’Hare T, Walters DK, Deininger MWN, Druker BJ. AMN107: tightening the grip or imatinib. Cancer Cell 2005; 7: 117-119.

46. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 2006; 354: 2542-2541.

47. Bacarani 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.

48. Hughes T, Deininger M, Hochhaus A, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and expressing results. Blood 2006; 108: 28-37.

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