Targeted treatment of imatinib-resistant chronic myeloid leukemia: Focus on dasatinib

Abstract

The efficacy of imatinib in chronic myeloid leukemia has been remarkable, but the development of resistance and the persistence of minimal residual disease have dampened the initial enthusiasm for this much heralded 'magic bullet'. Much progress has been made in elucidating the mechanisms which underlie imatinib resistance. The most common cause of such drug resistance is the selection of leukemic clones with point mutations in the Abl kinase domain leading to amino acid substitutions which prevent the appropriate binding of the drug. Other mechanisms include genomic amplification of BCR-ABL and modulation of drug efflux or influx transporters. Dasatinib is a multi-target kinase inhibitor which has increased potency and is able to inhibit most Bcr-Abl mutant cell lines. Clinical trials of dasatinib in imatinib-resistant and -intolerant chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoid leukemia have shown that it is effective and well tolerated. In this review, we will discuss the pre-clinical development of dasatinib, the clinical trial data demonstrating its efficacy and tolerability and highlight certain aspects of its toxicity profile and mechanisms of resistance.

Keywords: Bcr-Abl; drug resistance; tyrosine kinase inhibitors.