Dasatinib

Abstract

Imatinib is used for treatment against chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) cells and it now became standard therapy. However, some patients do not respond to imatinib therapy, and this has become clinically problematic. The cause of imatinib resistance is the development of point mutations in the BCR-ABL kinase domain. Dasatinib is a novel, oral and multi-targeted kinase inhibitor of BCR-ABL and Src family kinases. Dasatinib binds to both the inactive and active states of BCR-ABL and is 325-fold more potent than imatinib. Dasatinib has been investigated in a series of open label phase II trial (START: Src/ABL Tyrosine kinase inhibition Activity Research Trials). Dasatinib is effective therapy for BCR-ABL-positive leukemia if patients become resistant to or intolerant of imatinib. However, one of the T3151 mutations occurs most frequently and is highly resistant to imatinib as well as to the second generation AbI kinase inhibitor, dasatinib. Dasatinib is well tolerated, but it should be monitored for side effects like thrombocytopenia and pleural effusion. Altering the dasatinib regimen from 70 mg twice daily to 100 mg daily provides the most favorable overall benefit risk profile with improved tolerability and reduces the risk of side effects such as pleural effusion.