Nilotinib

Nilotimb is an orally administered BCR-ABL tyrosine kinase inhibitor that has shown good clinical efficacy in imatinib-resistant or -intolerant, Philadelphia chromosome-positive, chronic myeloid leukaemia (CML) in a phase I/II trial. The phase I component of the trial established the dosage regimen used in the phase II part of the trial, which included several arms. Three of these arms, or phase II trials, evaluated nilotinib in each of the three phases of CML (chronic, accelerated or blast crisis). In the phase II trial in patients with chronic-phase CML, major cytogenetic response (primary endpoint) was achieved in 48% of the 280 patients who received nilotimb and had a follow-up period of >= 6 months. Major cytogenetic response rates did not differ between imatinib-resistant and -intolerant patients, and nilotinib was effective in patients with BCR-ABL mutations (except T315I). Haematologie response rate (primary endpoint) was 47% in the phase II trial with nilotinib in patients with accelerated-phase CML (n = 119). Complete haematologic response was achieved in 26% of patients and 21% had no evidence of leukaemia or returned to chronic-phase CML. Major cytogenetic response, an important secondary endpoint in the trial, occurred in 29% of patients. Data from the phase II trial in patients with CML in blast crisis (n = 135) also showed promising results, with 39% of patients achieving haematologic response with nilotinib. Adverse events reported with nilotinib have generally been of mild to moderate severity. Grade 3 or 4 neutropenia and thrombocytopenia were reported in 29% of patients each. [Graphics] Chronic myeloid leukaemia (CML) accounts for 15% of adult leukaemias.([1]) In the US in 2006, an estimated 4500 patients were diagnosed with CML and 600 patients died from the disease. [21 CML results from the clonal expansion of haematopoictic stem cells that have a reciprocal translocation between chromosomes 9 and 22.([1]) The consequence of this translocation, referred to as the Philadelphia chromosome (Ph) and present in approximately 95% of patients with CML, is the formation of the chimeric protein BCR-ABL, in which the tyrosine kinase component of the ABL protein is activated.([1,3-6]) This, in turn, results in enhanced cellular proliferation, inhibition of apoptosis and alteration of the adhesive properties of CML cells. Most patients with CML are in the initial chronic phase at diagnosis, which is usually followed by progression to the accelerated phase and ultimately results in blast crisis.([3]) If left untreated, patients diagnosed with CML have a life expectancy of approximate to 3-5 years.([1]) However, the introduction of the BCR-ABL tyrosine kinase inhibitor imatinib, which demonstrated high overall survival and response rates after at least 5 years of follow-up,111 has revolutionized the treatment of CML, and the drug has become the standard primary treatment for patients with this condition.([1]) While imatinib has shown good results in patients in chronic-phase CML,([7]) response rates are lower and often transient in patients with more advanced disease.([8]) In addition, disease progression occurs at an annual rate of 4% among patients with chronic-phase CML who are treated with imatinib.([9]) Resistance to imatinib can occur by various mechanisms, with the most common cause of acquired drug resistance being the emergence of point mutations in the kinase domain of the BCR-ABL protein, reducing the binding affinity of ima tinib.([10-12]) Other important mechanisms include amplification of Ph-[13] and clonal evolution.([14]) Dasatinib, an inhibitor of multiple tyrosine kinases including BCR-ABL, SRC-family, proto-oncogene protein c-KIT, ephrin A receptor and platelet-derived growth factor beta kinases,([15]) has shown promising results in the treatment of imatinib-resistant CML[16-19] and, until recently, has been the main treatment option in this setting.([1]) Nilotinib (Tasigna (R))(1) is an orally administered selective inhibitor of BCR-ABL tyrosine kinase including most imatinib-resistant BCR-ABL mutants. This article provides an overview of the pharmacological properties of nilotinib and reviews the clinical trial data available on the efficacy and tolerability of the drug in patients with imatinib-resistant or -intolerant CML. Medical literature on the use of nilotinib in imatinib-resistant or -intolerant CM was identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database Additional references were identified from the reference lists of published articles.