Optimizing treatment with Bcr-Abl tyrosine kinase inhibitors in Philadelphia chromosome-positive chronic myeloid leukemia: focus on dosing schedules.

Chronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia chromosome (Ph), a genetic aberration that codes for bcrabl, which plays a key role in disease pathophysiology. The first oral inhibitor of Brc-Abl was imatinib, which also targets KIT and platelet-derived growth factor receptor kinase and has demonstrated improved outcomes when compared with interferon, the previous standard of care. Imatinib resistance and intolerance have been an issue for patients, and as a result, new therapeutic approaches have been evaluated. Dose-escalated imatinib (800 mg daily) has shown some limited activity in patients with imatinib-resistant CML, but the development of second-generation tyrosine kinase inhibitors has broadened the treatment options. Dasatinib is also an oral kinase inhibitor, but it has increased potency for Brc-Abl compared with imatinib. Dasatinib has demonstrated activity in all phases of CML and Ph+ acute lymphocytic leukemia and is approved for the treatment of adults in this setting. Recent phase III data have demonstrated that, in patients with chronic-phase CML, dasatinib 100 mg once daily is equally effective, with improved tolerability, compared with the previously approved 70-mg twice-daily dose. Nilotinib, which has been recently approved, has increased potency for Brc-Abl compared with imatinib and has demonstrated activity in patients with imatinib-resistant and -intolerant chronic- and accelerated-phase CML. As experience with these agents continues to mature, we might optimize the treatment efficacy and safety profiles by altering dose regimens.