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.