Resistance to tyrosine kinase inhibitors in Philadelphia chromosome-positive leukemias: which mutations matter?

The advent of imatinib, a potent and selective inhibitor of the Bcr-Abl tyrosine kinase whose deregulated expression drives Philadelphia chromosome-positive leukemias, has revolutionized outcome and quality of life of patients. However, resistance can develop through a variety of mechanisms, including point mutations in the Abl kinase domain, which are capable of abrogating inhibitor binding. The problem of resistance-associated mutations has fostered intensive research over the past 5 years. Herein, we review the current knowledge on the clinical significance of Abl kinase domain mutations in various settings. We discuss the contribution of mutations to imatinib resistance, and we hypothesize how the advent of novel tyrosine kinase inhibitors could change this scenario. We also warn against a systematic screening for Abl kinase domain mutations of imatinib-naive patients and patients who exhibit and maintain a complete cytogenetic response, because the practical relevance of finding rare mutated cells in these settings still needs to be confirmed.