Imatinib mesylate (IM) (Gleevec®
, Novartis), a 2-phenylaminopyrimidine derivative, is a potent inhibitor of targeted protein tyrosine kinases, including BCR-ABL, c-kit, and platelet-derived growth factor receptor (PDGF-R), and was developed in the mid-1990s against a background of some uncertainty.1
The drug appears to work principally by occupying the ATP binding site of the BCR-ABL oncoprotein and thereby preventing phosphorylation of the substrate and interrupting contact with the effector protein. This results in abrogating the enzymatic function of the Bcr-Abl oncoprotein ().
Figure 1 Mode of action of imatinib mesylate. The phosphorylation of a substrate is shown schematically. ATP occupies the pocket in the ABL component of BCR-ABL oncoprotein. The substrate then detaches itself from the BCR-ABL oncoprotein and makes functional contact (more ...)
IM was first used in 1998 to treat patients with chronic myeloid leukemia (CML) in chronic phase (CP) resistant to interferon-α, and early results showed that it was able to re-establish Ph-negative (presumably normal) hematopoiesis in a proportion of these patients.4
This led to an international prospective clinical study (IRIS) in which newly diagnosed patients with CML in CP were randomly allocated to receive either IM at a dose of 400 mg daily administered orally or a combination of interferon-α and cytarabine. The preliminary results were published in 2003 and updated periodically, the latest being in 2009.5
The results clearly demonstrated that nearly all patients achieved a complete hematologic response, with a significant proportion achieving a complete cytogenetic response (CCyR) and a minority achieving a complete molecular remission.
Although IM at a dose of 400 mg daily yields excellent clinical results, higher doses (600–800 mg daily) have been shown to yield more rapid hematologic control and more rapid achievement of CCyR compared with the cohort receiving 400 mg/day. The toxicity, however, associated with higher doses can sometimes be excessive resulting in frequent dose interruption and dose reduction.8
It is of interest that one of the recent studies confirmed this more rapid response with the higher dosage but suggested that by 18 months the short-term superiority had been lost.10
At present, it therefore seems reasonable to recommend that the best starting dose remains 400 mg/day.
IM is associated with toxicity, though most of the adverse effects attributed occur within the first 2 years of starting therapy and some reverse with continued treatment at the same dose. Toxicity appears mild to moderate in most instances and appears easily manageable and potentially reversible. Some patients may experience lethargy and develop different types of rashes; others gain weight from fluid retention, especially infraorbital edema but occasionally much more generalized, which responds in some cases to diuretics. Other effects include bone pain, which can sometimes be debilitating. Liver chemistry can be abnormal, and this may, on rare occasions, progress to liver failure. Rare incidences of prolongation of the QTc interval on the electrocardiograph have been reported. A small proportion of patients in CP who start IM at 400 mg/day experience cytopenias within the first year of therapy. They typically develop neutropenia and/or thrombocytopenia and sometimes anemia.
In general, all these side effects have been grade 1 or 2 and reversible on temporarily interrupting or stopping the drug. It is possible that some patients, for example older patients, and those with impaired cardiac function might perhaps be more susceptible to the adverse effects, particularly those which are long term. Herein, we assess the scenario with an emphasis on the long-term adverse effects associated with IM treatment for patients with CML in CP.