[Nilotinib as a second-line treatment for chronic myeloid leukemia]

Chronic myeloid leukemia(CML)is a clonal disease of the hematopoietic stem cells that is characterized by excessive proliferation, but retains of the capacity for differentiation duringthe chronic phase of the disease. This phase is followed after 4-6 years by rapid progression, an accelerated phase, and consequently a fatal acute leukemia a blast crisis. The hallmark abnormality of CML is the Philadelphia chromosome that generates a BCR-ABL fusion gene, resulting in the expression of a leukemia-specific oncoprotein, Bcr-Abl. Bcr-Abl is a potent tyrosine kinase and plays a central role in CML pathogenesis. Recently, the treatment of CML has been revolutionized by the introduction of imatinib mesylate(IM). With daily IM treatment, more than 80% of chronic-phase CML patients achieve a complete cytogenetic response. Nevertheless, a small percentage of CML patients are primarily refractory or acquire secondary resistance against IM. Nilotinib is a highly selective Abl kinase inhibitor that possesses greater potency and selectivity for Abl kinase than IM. In addition to being more potent than IM against wild-type BCR-ABL, nilotinib is significantly active against many IM-resistant BCR-ABL mutants. In preclinical studies, nilotinib has produced hematologic and cytogenetic responses in CML patients, with either IM resistance or IM intolerance. As second-line treatment, both nilotinib and dasatinib may be used in case of suboptimal response or failure, which is defined in the efficacy criteria of the European Leukemia Net Consensus. The choice of second-generation tyrosine kinase inhibitors may be made after the mutation analyses of the kinase domain. It is recommended that nilotinib or dasatinib whichever was shown to be active against the specific mutation, should be chosen for treatment. For patients with no mutations or patients with IM intolerance, it is recommended that either second-generation tyrosine kinase inhibitor be chosen, based on the patient's disease history.