Second-line therapy and beyond resistance for the treatment of patients with chronic myeloid leukemia post imatinib failure.

Chronic myeloid leukemia (CML) is characterized at the molecular level by the presence of the Philadelphia chromosome (Ph) and the resultant oncogenic signaling by the BCR-ABL fusion protein. The treatment and outlook for CML were revolutionized by the introduction of imatinib, but resistance is a substantial barrier to successful treatment in many patients. Introduction of the second-generation tyrosine kinase inhibitors (TKI) dasatinib and nilotinib has provided effective therapeutic options for many patients with resistance to front-line imatinib. However, the T315I mutation remains a significant clinical issue because it is insensitive to all currently available agents. A number of new agents are in development and many hold the promise of activity in T315I-mutated disease. Successful treatment of patients with disease harboring T315I might lie in the effective combination or sequencing of these new agents with existing TKI therapies.