Drug evaluation: Nilotinib - a novel Bcr-Abl tyrosine kinase inhibitor for the treatment of chronic myelocytic leukemia and beyond.

Chronic myelocytic leukemia (CML) is caused by the constitutively active tyrosine kinase Bcr-Abl. Inhibitors ofBcr-Abl have significantly improved the treatment of CML. Most notable is the inhibitor imatinib, which produces remissions in all phases of CML and is the current standard of care. However, imatinib resistance occurs in a significant proportion of patients, mainly through the development of mutations in the Bcr-Abl tyrosine kinase domain that impair imatinib binding. Attempts to circumvent resistance to imatinib led to the discovery of nilotinib (Tasigna; Novartis AG), a novel, potent and selective oral Bcr-Abl kinase inhibitor. Preclinical and clinical investigations have demonstrated that nilotinib effectively overcomes imatinib resistance. Efficacy has been observed in models of CML and other myeloproliferative disorders that are driven by Bcr-Abl and related kinases. In a phase II clinical trial in CML, major cytogenetic response rates were 52 and 33% for chronic- and accelerated-phase disease, respectively. Nilotinib has been filed for approval in the US and EU for use in Philadelphia-positive leukemias in patients who are resistant or intolerant to imatinib. Nilotinib is undergoing clinical trials in patients with newly diagnosed CML, acute lymphoblastic leukemia and gastrointestinal stromal tumors, among other indications.