Mechanisms of primary and secondary resistance to imatinib in chronic myeloid leukemia.

BACKGROUND Although the vast majority of patients with chronic myeloid leukemia (CML) respond to the tyrosine kinase inhibitor (TKI) imatinib mesylate, resistance might occur de novo or during treatment. METHODS The authors reviewed the known mechanisms of primary and secondary resistance to imatinib and other TKIs used in the management of CML. RESULTS Mutations within the kinase domain of BCR-ABLI account for 30% to 40% of cases of imatinib resistance. Other mechanisms include BCR-ABLI amplification, overexpression of the SRC family of kinases, and pharmacokinetic and pharmacodynamic factors. CONCLUSIONS Although not all resistance mechanisms have been identified and understood, several agents based on the known mechanisms have already been designed and developed and are beginning clinical trials.

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