Molecular targeting agents and cardiovascular adverse events

Abstract

ABL tyrosine kinase inhibitor (TKI) imatinib mesylate dramatically improves chronic myeloid leukemia (CML) prognosis. It has also become possible to utilize second-generation ABL TKIs including nilotinib, dasatinib and bosutinib that were developed to overcome imatinib resistance and intolerance. Moreover, third-generation, ponatinib was developed to overcome second-generation TKIs, especially for T315I mutation which showed resistance to all first- and second-generation ABL TKIs. As a result of the introduction of these ABL TKIs, most CML patients are now able to lead lives that are equivalent to those of healthy individuals. However, in spite of improvements in prognosis, high cost to CML patients and adverse effects (AEs), especially cardiovascular AEs have become bigger problems. Recent reports show that nilotinib may be associated with an increased risk of vascular AEs compared with imatinib, including peripheral artery occlusive disease (PAOD). Pulmonary arterial hypertension has raised concerns in the CML patients treated with dasatinib about the long-term sequelae of drugs that may need to be administered for decades. Although ponatinib is most potent ABL TKI, it is suspected to cause cardiovascular events most frequently among all TKIs. A meta-analysis based on ten randomized clinical trials revealed that dasatinib, nilotinib, and ponatinib increased the risk of vascular occlusive events in patients with CML when compared with imatinib. Interestingly, there was no significant difference between bosutinib and imatinib. Here, I would like to review what is currently known about the cardiovascular AEs of ABL TKIs and discuss how to prevent cardiovascular AEs including TKI stop in CML patients who obtain enough deep molecular response.