A Comprehensive Review of Clinical Cardiotoxicity Incidence of FDA-Approved Small-Molecule Kinase Inhibitors

Abstract

Numerous protein kinases encoded in the genome have become attractive targets for the treatment of different types of cancer. As of January 2020, a total of 52 small-molecule kinase inhibitors (SMKIs) have been approved by the FDA. With the numerous clinical trials and a heavy focus on drug safety, SMKI-induced cardiotoxicity, which is a life-threatening risk, has greatly attracted the attention of researchers. In this review, the SMKIs with cardiotoxicity incidence were described exhaustively. The data were collected from 42 clinical trials, 25 FDA-published documents, seven meta-analysis/systematic reviews, three case reports and more than 50 other types of articles. To date, 73% (38 of 52) of SMKIs have reported treatment-related cardiotoxicity. Among the 38 SMKIs with known cardiotoxicity, the rates of incidence of cardiac adverse events were QT prolongation: 47% (18 of 38), hypertension: 40% (15 of 38), left ventricular dysfunction: 34% (13 of 38), arrhythmia: 34% (13 of 38), heart failure: 26% (10 of 38) and ischemia or myocardial infarction: 29% (11 of 38). In the development process of novel SMKIs, more attention should be paid to balancing the treatment efficacy and the risk of cardiotoxicity. In preclinical drug studies, producing an accurate and reliable cardiotoxicity evaluation model is of key importance. To avoid the clinical potential cardiotoxicity risk and discontinuation of a highly effective drug, patients treated with SMKIs should be proactively monitored on the basis of a global standard. Moreover, the underlying mechanisms of SMKI-induced cardiotoxicity need to be further studied to develop new therapies for SMKI-induced cardiotoxicity.

Assessment and Management of Cardiotoxicity in Hematologic Malignancies

“…Ischemic heart disease is another complication shown in a clinical trial. After an average time on nilotinib therapy of 60 months, the incidences of ischemic heart disease-related cardiac events in the nilotinib 300 mg arm and 400 mg arm were 9.3 and 15.2%, respectively [7,8] (d) Ponatinib has the highest risk of cardiotoxicity from the TKIs, including congestive heart failure, cardiac arrhythmias, and hypertension. In the phase 2 ponatinib CML evaluation trial, ponatinib was shown to have dose-dependent cardiotoxicity in 267 evaluated patients.…”

Cardiotoxicity of Novel Targeted Hematological Therapies

“…An even closer monitoring could be performed in old and frail patients who receive BTK inhibitors, bosutinib, ponatinib, IMiDs, or bortezomib, and in those who have long-course treatment with BTK and BCR/ABL inhibitors or bortezomib. Patients could be monitored for cardiotoxicity also after the end of treatment, such as for ponatinib-treated patients who can develop cardiac adverse events after several months of drug discontinuation [ 103 , 104 ].…”

“…In addition, ponatinib can have pro-atherogenic properties by promoting surface adhesion receptor expression, and by enhancing platelet activation and aggregation [ 101 ]. Cumulative incidence of CAD, PAD, and cerebrovascular events is 26% [ 101 , 104 , 105 ]. In chronic phase CML, ACS and MI are the most frequent manifestations (12% of cases) and can precede CHF with a median time to initial onset of 11.5 months; cerebrovascular and peripheral arterial occlusive events occur in 6% and 8% of cases, respectively, and venous thromboembolic events (VTEs) are reported in 5% of subjects [ 101 , 104 , 105 ].…”

“…Hypertension is also frequent (14%). Serious cardiac adverse events are represented by AF (6%) and angina pectoris (5%) [ 104 ]. Incidence of cardiotoxicity is related to dose intensity with the highest rate (42%) at 45 mg/daily.…”

“…History of ischemia, age at study entry, baseline neutrophil count, and time to treatment are prognostic risk factors [ 103 ]. In addition, there might be a lag time between drug administration and onset of cardiovascular event, as 7% of patients experience cardiotoxicity after study discontinuation [ 103 , 104 ]. Cardiovascular events can occur in 7.1% of patients, cerebrovascular accidents in 3.6%, and peripheral vascular events in 4.9% of subjects, more frequently in patients with a history of cardiovascular diseases and/or the presence of one or more cardiovascular risk factors, such as hypertension, diabetes, hypercholesterolemia, and obesity [ 105 ].…”