Principal long-term adverse effects of imatinib in patients with chronic myeloid leukemia in chronic phase

Abstract

Imatinib mesylate (IM), an original Abl tyrosine kinase inhibitor, entered the clinics in 1998 for the treatment of patients with chronic myeloid leukemia (CML). The drug is universally considered the treatment of choice for most, if not all, patients with CML. Importantly, lessons learned from patients with CML have been applied successfully for the treatment of patients with other disorders where IM has since been found to be active by virtue of its ability to target other kinases, such as c-kit in patients with gastrointestinal stromal tumors. IM is associated with mild to moderate toxicity, mostly reversible by dose reduction or discontinuation of the drug. Most adverse effects occur within the first 2 years of starting therapy; however, late effects, many being unique, are now being recognized. In this report, we assess the toxicity associated with IM, with an emphasis on the long-term adverse effects.

Frontline imatinib treatment of chronic myeloid leukemia: no impact of age on outcome, a survey by the GIMEMA CML Working Party

“…When considering the causes of death, it is important to evaluate the potential role played by IM, especially in elderly patients. Available data from the literature suggest that IM has no relevant long-term side effects 44 able to impact significantly on mortality unrelated to CML progression. However, specific subset of patients may have higher grades of toxicity and side effects; for example, although the potential cardiotoxicity of IM has been already suspected 45 and substantially excluded by different groups of investigators and by the company marketing IM, older patients are considered at higher risk of such complications.…”

The Ph-positive and Ph-negative myeloproliferative neoplasms: some topical pre-clinical and clinical issues

“…The adverse events attributable to imatinib are relatively mild and usually manageable. [94][95][96] Conversely this means that one-third of CP patients cannot tolerate imatinib or have a leukemia that proves to be resistant to the drug. 96 The best characterized mechanism of resistance is the acquisition of mutations in the BCR-ABL1 kinase domain (KD), of which the T315I mutation is the leading example, 97 although the majority of CP patients resistant to imatinib have no identifiable KD mutation.…”

Rapidly progressive dyspnea in gastrointestinal stromal tumor (GIST) with imatinib cardiac toxicity

“…Side effects include fluid retention, edema, fatigue, and liver profile abnormalities, commonly reversible after drug cessation. Imatinib’s toxicity, in general, has been associated with higher dose exposure and long-term usage [4]. In most cases, management includes imatinib discontinuation, and alternative tyrosine kinase inhibitors are considered.…”

“…Overt heart failure remains rare [4]. These literature assertions contradict findings by Kim et al, who suggest that fluid retention in imatinib treatment for GIST can either be acute, associated with drug initiation or dose escalation, or chronic.…”