Imatinib

Drugs - Tập 67 - Trang 299-320 - 2012
Marit D. Moen1, Kate McKeage1, Greg L. Plosker1, M. Asif A. Siddiqui1
1Wolters Kluwer Health / Adis, Mairangi Bay, Auckland, New Zealand

Tóm tắt

Imatinib (Gleevec®, Glivec®) is a synthetic tyrosine kinase inhibitor used in the treatment of chronic myeloid leukaemia (CML). It is specifically designed to inhibit the breakpoint cluster region (BCR)-Abelson (ABL) fusion protein that results from the chromosomal abnormality known as the Philadelphia chromosome. CML is characterised by this abnormality, which leads to abnormalities of the peripheral blood and bone marrow including an increase in the number of granular leukocytes. Imatinib is approved in numerous countries worldwide for the treatment of newly diagnosed Philadelphia chromosome-positive (Ph+) chronic-phase CML, Ph+ accelerated-phase or blast-crisis CML, and in patients with Ph+ chronic-phase CML who have failed to respond to interferon-α therapy. It is also indicated in paediatric patients with newly diagnosed Ph+ chronic-phase CML, in accelerated-phase or blast-crisis CML, or in chronic-phase CML after failure of interferon-α therapy or when the disease has recurred after haematopoietic stem cell transplantation (HSCT). Approved indications, however, may vary by country. Imatinib is effective and generally well tolerated in patients with Ph+ CML. In patients with newly diagnosed chronic-phase CML, imatinib was more effective than interferon-α plus cytarabine in preventing progression of the disease and in achieving haematological and cytogenetic responses. Overall survival rates remain high after 5 years of follow-up, and historical comparisons with other treatments demonstrate improved overall survival with imatinib in the long term. Patients with accelerated-phase or blast-crisis CML, or those who have not responded to prior interferon-α therapy also benefit from imatinib treatment. Some patients become resistant or intolerant to imatinib therapy; management strategies to overcome these problems include dosage adjustment, other treatments, or combination therapy with imatinib and other agents. Allogeneic HSCT is currently the only potentially curative treatment, but it is associated with high rates of morbidity and mortality and is not suitable for all patients. The introduction of imatinib has had a marked impact on outcomes in patients with CML. It remains a valuable treatment for all stages of the disease, especially initial treatment of newly diagnosed Ph+ chronic-phase CML, and is endorsed by European and US treatment guidelines as a first-line option. Imatinib inhibits BCR-ABL tyrosine kinase, which is expressed by CML cells with the Philadelphia chromosome abnormality. It also inhibits the receptor tyrosine kinases for platelet-derived growth factor and stem cell factor. Administration of imatinib to CML patients results in marked changes in bone marrow histopathology and normalisation of bone marrow vascularity in some patients. Primary or acquired resistance to imatinib is common in patients with advanced CML. There are several mechanisms of resistance and most involve reactivation of BCR-ABL signalling. Serial measurements of BCR-ABL transcript levels and ABL mutational screening can help identify the presence of BCR-ABL tyrosine kinase domain mutations and thereby emerging resistance. Following oral administration, imatinib is rapidly absorbed. The bioavailability of imatinib is 98%, and peak plasma concentrations are reached after 2–4 hours. Imatinib is metabolised by the liver and is primarily eliminated via the faeces as unchanged parent drug and metabolites. Dosage adjustments are recommended in patients with severe hepatic dysfunction. Systemic exposure of imatinib may be altered when the drug is coadministered with various cytochrome P450 inducers or inhibitors. In a randomised, nonblind, multicentre phase III trial in patients with newly diagnosed Ph+ chronic-phase CML, imatinib significantly improved the estimated rates of survival without progression and survival without progression to accelerated-phase or blast-crisis CML compared with interferon-α plus cytarabine at median follow-ups of 19 and 30 months. Haematological and cytogenetic responses were also significantly greater in the imatinib group at both follow-ups. Rates of freedom from progression and haematological and cytogenetic response remained high in imatinib recipients at a 60-month follow-up of the phase III trial, although comparisons with interferon-α plus cytarabine recipients were not possible, as the majority of those randomised to interferon-α plus cytarabine had crossed over to the imatinib treatment arm. For the same reason, a between-treatment group comparison of overall survival in the phase III study was not possible. In an historical comparison between different trials, overall survival rates at 36 months for imatinib recipients in the phase III trial were significantly higher than those for interferon-α plus cytarabine recipients in another study. Imatinib also produced high rates of haematological and cytogenetic responses in phase II trials of Ph+ patients with accelerated-phase or blast-crisis CML, and in those who received second-line imatinib, with long-term follow-up (median 60 months), after failure of interferon-α therapy. Cost-effectiveness analyses generally predict that imatinib is a costly, but generally cost-effective, treatment option; it is more effective and less costly than bone marrow transplantation. Imatinib was generally well tolerated. Most imatinib recipients in the phase II and III studies experienced adverse events, usually of mild to moderate severity. The most common nonhaematological adverse events in patients with chronic-phase CML were superficial oedema, muscle cramps, diarrhoea, nausea and musculoskeletal pain. Similar tolerability profiles were seen in the phase II studies in patients with accelerated-phase or blast-crisis CML, and in those who had failed to respond to prior therapy with interferon-α. Grade 3 or 4 neutropenia, thrombocytopenia and anaemia occurred in imatinib recipients in all phase II studies and in the phase III study, and appeared to be more severe in patients with advanced disease. In patients with chronic-phase CML in the phase III study, the incidences of grade 3 plus 4 neutropenia and thrombocytopenia were significantly lower in imatinib recipients than in those who received interferon-α plus cytarabine.

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