Imatinib resistance in chronic myelogenous leukemia: an emerging challenge

Aparna Khandelwal, Mallika Kawatra, Virendra Bhandari, Prashant S. Yeshwante


Resistance to imatinib is a significant clinical issue, and the underlying mechanism of this resistance is multifactorial. The efficacy of imatinib in chronic myeloid leukemia (CML) in achieving a high remission rate and improving prognosis has seriously been challenged by the development of mutants of BCR-ABL gene, which resist the action of imatinib, which is a tyrosine kinase inhibitor. We present here a case of a 35-year-old male, a known case of CML on imatinib therapy, the patient eventually landed in blast crisis and succumbed to the disease and secondary infections.


Chronic myeloid leukemia, Imatinib resistance, blast crisis

Full Text:



Faderl S, Talpaz M, Estrov Z, Kantarjian HM. Chronic myelogenous leukemia: Biology and therapy. Ann Intern Med. 1999;131(3):207-19.

Goldman JM, Melo JV. Chronic myeloid leukemia - Advances in biology and new approaches to treatment. N Engl J Med. 2003 9;349(15):1451-64.

Sattler M, Griffin JD. Molecular mechanisms of transformation by the BCR-ABL oncogene. Semin Hematol. 2003;40 2 Suppl 2:4-10.

Alimena G, Breccia M, Latagliata R, Carmosino I, Russo E, Biondo F, et al. Sudden blast crisis in patients with Philadelphia chromosome-positive chronic myeloid leukemia who achieved complete cytogenetic remission after imatinib therapy. Cancer. 2006;107(5):1008-13.

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(2):690-8.

Avery S, Nadal E, Marin D, Olavarria E, Kaeda J, Vulliamy T, et al. Lymphoid transformation in a CML patient in complete cytogenetic remission following treatment with imatinib. Leuk Res. 2004;28 Suppl 1:S75-7.

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(12):4396-407.

Bixby D, Talpaz M. Mechanisms of resistance to tyrosine kinase inhibitors in chronic myeloid leukemia and recent therapeutic strategies to overcome resistance. Hematology Am Soc Hematol Educ Program 2009:461-76.

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(6):1054-61.

Kantarjian HM, Hochhaus A, Saglio G, De Souza C, Flinn IW, Stenke L, et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol. 2011;12(9):841-51.

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(23):2408-17.

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 Leukemia Net. Blood. 2006;108(6):1809-20.

Hochhaus A, Erben P, Ernst T, Mueller MC. Resistance to targeted therapy in chronic myelogenous leukemia. Semin Hematol. 2007;441 Suppl 1:S15-24.

Barnes DJ, Melo JV. Primitive, quiescent and difficult to kill: The role of non-proliferating stem cells in chronic myeloid leukemia. Cell Cycle. 2006;5(24):2862-6.

Herweijer H, Sonneveld P, Baas F, Nooter K. Expression of mdr1 and mdr3 multidrug-resistance genes in human acute and chronic leukemias and association with stimulation of drug accumulation by cyclosporine. J Natl Cancer Inst. 1990;82(13):1133-40.

Illmer T, Schaich M, Platzbecker U, Freiberg-Richter J, Oelschlägel U, von Bonin M, et al. P-glycoprotein-mediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylate. Leukemia. 2004;18(3):401-8.

Thomas J, Wang L, Clark RE, Pirmohamed M. Active transport of imatinib into and out of cells: Implications for drug resistance. Blood. 2004;104(12):3739-45.

Wang L, Giannoudis A, Lane S, Williamson P, Pirmohamed M, Clark RE. Expression of the uptake drug transporter hOCT1 is an important clinical determinant of the response to imatinib in chronic myeloid leukemia. Clin Pharmacol Ther. 2008;83(2):258-64.

Takayama N, Sato N, O’Brien SG, Ikeda Y, Okamoto S, et al. Imatinibmesylate has limitedactivity against the central nervous system involvement of Philadelphia chromosome-positive acute lymphoblastic leukaemia due to poor penetrationinto cerebrospinal fluid. Br J Haematol. 2002;119(1):106-8.

Senior K. Gleevec does not cross blood-brain barrier. Lancet Oncol. 2003;4(4):198.

Dai H, Marbach P, Lemaire M, Hayes M, Elmquist WF. Distribution of STI-571 to the brain is limited by P-glycoprotein-mediated efflux. J Pharmacol Exp Ther. 2003;304(3):1085-92.

Wolff NC, Richardson JA, Egorin M, Ilaria RL Jr. The CNS is a sanctuary for leukemic cells in mice receiving imatinib mesylate for Bcr/Abl-induced leukemia. Blood. 2003;101(12):5010-3.

Breedveld P, Pluim D, Cipriani G, Wielinga P, van Tellingen O, Schinkel AH, et al. The effect of Bcrp1 (Abcg2) on the in vivo pharmacokinetics and brain penetration of imatinib mesylate (Gleevec): Implications for the use of breast cancer resistance protein and P-glycoprotein inhibitors to enable the brain penetration of imatinib in patients. Cancer Res. 2005;65(7):2577-82.

Breedveld P, Beijnen JH, Schellens JH. Use of P-glycoprotein and BCRP inhibitors to improve oral bioavailability and CNS penetration of anticancer drugs. Trends Pharmacol Sci. 2006;27(1):17-24.