The next generation of therapies for chronic myeloid leukemia.

Therapy with the tyrosine kinase inhibitor (TKI) represents the current standard first-line therapy for the management of patients with chronic myeloid leukemia (CML). Although most patients respond satisfactorily to imatinib, a subset of patients develops resistance mainly because of the acquisition of mutations within the kinase domain of BCR-ABL1 that impair the ability of TKIs to block the activity of the enzyme. Moreover, BCR-ABL1 transcripts can be detected in most patients by molecular techniques, underscoring the limitations of imatinib to eradicate minimal residual disease. Although the resistance conferred by most BCR-ABL1 mutations can be overcome with the use of second-generation TKIs such as nilotinib, dasastinib, bosutinib, or bafetinib, the T315I mutation, which represents a common resistance pathway in CML, remains unassailable to TKI therapy. We herein discuss current research efforts in 2 areas of vital importance in CML research, the management of patients with imatinib-resistant mutations, with particular emphasis on those carrying T315I, and the eradication of residual disease.