The treatment of chronic myeloid leukemia (CML) with BCR-ABL1 tyrosine kinase inhibitors (TKIs) is highly effective in reducing disease burden and prolonging overall survival in the majority of patients. Up to one-third of patients who initiate first-line TKI therapy with imatinib, however, experience resistance to treatment, presenting as a lack or loss of response or as disease progression. Sokal or Hasford risk score at baseline and achievement of early molecular response to treatment may help identify patients at risk for resistance to first-line TKI therapy and poor prognosis. Approximately half of the patients with resistance to TKI treatment have mutations in the BCR-ABL1 kinase domain. Mutation status can be informative and should be considered alongside other factors, including patient history and drug safety profile, in second-line treatment choice. Factors present at the time of initiation of second-line TKI therapy, such as response to initial therapy, as well as achievement of molecular response within the first 6 months of second-line TKI therapy, have value in predicting response and survival outcomes. Given the expanding number of therapeutic options currently approved (FDA), an understanding of the clinical data supporting each of the options for second-line treatment would enable clinicians to develop treatment plans based on the best evidence-based information. This review estimates the incidence rate of TKI resistance that might be expected in the first-line setting, outlines practical approaches to determine TKI resistance, and discusses the factors that clinicians should consider when making a second-line treatment choice.
Keywords: Acquired resistance; BCR-ABL1; Kinase domain mutation; T315I; Tyrosine kinase inhibitor.
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