Assessment of Cardiovascular Events in Chronic Myeloid Leukemia Patients Treated with Tyrosine Kinase Inhibitors

Introduction: Treatment with tyrosine kinase inhibitors (TKIs) has dramatically increased the overall survival of patients with chronic myeloid leukemia (CML) but second generation TKI has been associated with an increased risk of cardiovascular events.

Objectives: The aim of this study was to evaluate the incidence of cardiovascular adverse events (CVE) in CML patients treated with TKIs and to correlate with the cardiovascular (CV) risk of the patients.

Methods: this is a retrospective analysis of consecutive CML patients treated with TKIs between 2005 and 2013 at our Institution. Baseline risk factors for CV diseases were collected at baseline and included age, arterial hypertension (AH), dyslipidemia, obesity, hypothireoidism, smoking, diabetes mellitus (DM), coronary artery disease and chronic renal failure. Cardiovascular events during TKI treatment were collected and included: myocardial infarction, unstable angina, peripheral arterial disease, stroke, arrythmia, hypertension and cardiac failure. Cardiovascular risk was calculated using the SCORE chart of the European Society of Cardiology and patients were classified in low, moderate, high and very high risk. 

Results: We analyzed CML patients treated with imatinib (n=117), dasatinib (n=91) and nilotinib (n=60). The median time of follow-up was 748, 519 and 851 days, respectively. Baseline risk factors: 90 patients (38,5%) had hypertension, 34 (14,5%) DM, 67 (28,6%) dyslipidemia, 51 (21,8%) obesity, 22 (9,4%) hypothyroidism, 14 (6%) coronary arterial disease, 21 (9%) systolic cardiac dysfunction, 4 (1,7%) stroke, 20 (8,5%) chronic kidney failure and 36 (15,4%) were smokers. SCORE chart classification: 106 patients (39,5%) were in the low-risk category, 70 (26%) in the moderate risk, 46 (17,2%) in the high risk, 46 (17,2%) in the very high risk group. Overall, the cumulative incidence of CVE was 4.1%. Five (5.5%) events occurred during dasatinib treatment (P=0.015), 6 (10%) events during nilotinib and no events during imatinib treatment (P=0.001). The incidence of CVE was 10.8% in the high and very high-risk groups and 0.52% in moderate and low risk group (P≤0.001). The incidence of arterial ischemic events (AIE) was 10% (n=6) in patients treated with nilotinib, 2.2% (n=2) with dasatinib and 0% with imatinib (P≤0.001). Arterial events were exclusively observed in high and very high-risk groups (8 events, 8.7%) (P≤0.001). The risk factors associated with a higher risk of CVE were hypertension (P≤0.001), dyslipidemia (P≤0.001), coronary arterial disease (P=0.003), congestive heart failure (P=0.002) and chronic renal failure (P=0.011). Disease progression was the main cause of death in all groups.

Conclusions: CVE were more frequent in patients treated with second generation TKIs. AIE were more frequent in patients treated with nilotinib, in those having a high or very high risk SCORE. The CV risk stratification of CML patients before and during TKI therapy can help in TKI selection and to identify patients at high risk, in order to reduce the morbidity and mortality associated with CVE.