New strategies for the first-line treatment of chronic myeloid leukemia: Can resistance be avoided?

Imatinib is well established as a safe, effective therapy for patients with chronic myeloid leukemia (CML). However, point mutations in the kinase domain of Bcr-Abl can lead to imatinib resistance and reactivation of kinase activity. The second-generation Abl kinase inhibitors nilotinib and dasatinib were developed to reestablish disease control. A rising clinical challenge is using imatinib and novel Abl kinase inhibitors with the aim of completely preempting resistance. Fortunately, relapse on imatinib therapy so far has affected a minority of patients commencing treatment in the chronic phase of CIVIL, and relapse rates continue to decline with treatment duration. In contrast, nearly all patients with CML have molecularly detectable disease. Thus, even among the best responders to imatinib, disease eradication is not achieved within a timeframe of years. Herein, we review current and emerging paradigms for using AN kinase inhibitors to achieve maximal disease control and strategies to eradicate disease by targeting leukemic stem cells.