Cardiovascular toxicity in patients with chronic myeloid leukemia treated with second‐generation tyrosine kinase inhibitors in the real‐life practice: Identification of risk factors and the role of prophylaxis

To the Editor: Long-term treatment with the second-generation tyrosine kinase inhibitors (2TKIs) nilotinib and dasatinib may result in cardiovascular (CV) complications. Accumulating evidence suggests that the combination of a median age at the time of chronic myeloid leukemia (CML) diagnosis of greater than 60 years, when CV adverse events (AEs) are common, and the CV toxicity of 2TKIs represents per se a potential predisposing factor, which requires preventive strategies and CV surveillance in patients with CML. Previous studies have suggested the usefulness of the systematic coronary risk evaluation (SCORE) assessment at disease baseline, a 10-year risk estimation of fatal CV disease based on sex, age, smoking habits, systolic blood pressure, and total cholesterol levels, to identify patients who are at heightened risk of CV AEs during nilotinib treatment. A preventive strategy with primary prophylaxis based on aspirin remains under discussion. We therefore analyzed a large real-life cohort of Italian patients with CML treated with a 2TKIs as firstor subsequent-line of treatment. The primary objective was to evaluate the incidence of CV AEs and the association with the SCORE assessment and other baseline risk factors. The secondary objectives were to evaluate the role of primary prophylaxis in preventing CV atherothrombotic events. We identified consecutive adult patients with CML who initiated nilotinib or dasatinib as firstor subsequent-line treatment, between January 2012 and December 2015 in 20 Italian centers. Patients were stratified into low-moderate (SCORE 5%) or high-very high (SCORE >5%) CV risk. Additional risk factors were the presence of diabetes, body mass index>24.5 kg/m, mild or severe renal insufficiency, and dyslipidemia. Patients were also evaluated for comorbidities and a positive anamnesis of CV diseases, including angina, myocardial infarction, stroke, heart failure, arterial hypertension, cardiomyopathy, heart arrhythmia, valvular heart disease, aortic aneurysms, ischemic cerebrovascular events, peripheral artery disease, thromboembolic disease, and venous thrombosis. The presence of antithrombotic prophylaxis before initiating CML treatment was also recorded. The probability of the cumulative incidence of CV and atherothrombotic AEs was estimated after initiating treatment with 2TKIs. The cumulative incidence of deep molecular response (MR) was evaluated from the initiation of 2TKIs treatment. Multivariate analyses were performed using the Cox proportional hazards regression model. A total of 506 patients with CML were retrospectively recruited. The patients’ characteristics are shown in Supporting Information Table S1. The mean age at diagnosis was 52 years (range 18–87) and 57% were men. Sokal score was intermediate-high in 55% of patients. The mean follow-up time since CML diagnosis was 5.4 years (range 0.2–23). Overall, 286 patients were treated with nilotinib and 220 with dasatinib. 2TKIs were administered as first-, second-, and third-line treatment in 61%, 32%, and 7% of cases, respectively. The reasons for switching treatments in 196 patients were inefficacy in 63.8%, intolerance in 29.6%, and protocol requirements in 6.6%. The majority of patients (93%) were classified as at low-intermediate risk (SCORE 5%) and 7% as at high-very high risk (SCORE>5%). A positive history for CV diseases was noted in 181 (35.8%) patients. The 60-month CV AE cumulative incidence registered in the total cohort of patients was 21.762.8%. Patients treated with nilotinib and dasatinib showed CV AE incidence of 24.763.9% and 16.463.7%, respectively (P5 .25; NS) (Supporting Information Figure S1). Patients treated with 2TKIs administered as firstor second-line of treatment and as subsequent-line treatment showed a CV AE incidence of 12.963.5% and 22.964.4%, respectively (P5 .004). Patients with high-very high SCORE showed significantly high incidence of CV AEs (46.6616.6% vs. 2062.8%; P< .001). The mean time between the initiation of 2TKI treatment and the occurrence of CV AEs was 35.5 (range 1–69) months. Overall, 68 CV AEs were registered, with 2 event-related deaths; 40% of CV AEs were graded as 3/4 of common toxicity criteria. Supporting Information Table S2 reports the CV AEs and their management in the reallife. We did not find any association between TKI dose and CV AE incidence. The frequency of peripheral arterial disease (PAOD or atheromasic carotid disease) was significantly high in patients undergoing nilotinib treatment. Two patients died due to myocardial infarction during treatment. Overall, in 44% of cases 2TKI treatment did not require dose modification; 16% of patients reduced the dose and