Cardiovascular toxicity of second-generation TKIs versus imatinib in first-line chronic myeloid leukemia: An updated systematic review and meta-analysis.

Abstract

e18604 Background: BCR–ABL1 tyrosine kinase inhibitors (TKIs) are the standard first-line therapy for chronic myeloid leukemia (CML). Second-generation TKIs (nilotinib, dasatinib, bosutinib) achieve deeper and more rapid molecular responses than imatinib. However, cardiovascular adverse events have emerged as a key safety concern as patients experience long-term survival and remain on therapy for years. Given the high prevalence of baseline cardiovascular risk factors in CML patients, updated quantitative estimates of cardiovascular toxicity are needed to inform individualized first-line TKI selection. While prior analyses were largely based on 5-year follow-up from pivotal trials, this updated meta-analysis incorporates new available 10-year follow-up data to better characterize long-term cardiovascular risk. Methods: A systematic review and meta-analysis were conducted in accordance with PRISMA guidelines. PubMed, Embase, Cochrane Central Register, and Scopus were searched through December 2025. After removing 110 duplicates from 808 identified records, 698 records were screened. Four randomized controlled trials comparing second-generation TKIs [nilotinib (300–400 mg twice daily), dasatinib (100 mg once daily), or bosutinib (400–500 mg once daily)] versus imatinib (400 mg once daily) met eligibility criteria and reported cardiovascular toxicity outcomes. Primary outcomes included composite cardiovascular events, cardiovascular death, and all-cause mortality. Pooled analyses used random-effects models, with effect estimates expressed as risk ratios (RRs) with 95% confidence intervals (CIs). Results: Four randomized controlled trials comprising 1,944 patients were included. In pooled analyses, imatinib was associated with significantly lower risk of composite cardiovascular events—myocardial infarction and peripheral arterial disease (other cardiovascular outcomes were inconsistently defined across trials)—compared with second-generation TKIs (RR 0.28; 95% CI, 0.09–0.82; p=0.02; I²=70%). Imatinib was also associated with lower cardiovascular death (RR 0.17; 95% CI, 0.09–0.30; p<0.00001; I²=0%). All-cause mortality did not differ between groups (RR 1.28; 95% CI, 0.85–1.92; p=0.24; I²=0%). Conclusions: Among patients with chronic-phase CML receiving first-line therapy, second-generation TKIs are associated with increased cardiovascular toxicity compared with imatinib, including higher risks of composite cardiovascular events and cardiovascular death. These updated pooled estimates incorporating 10-year follow-up data support integrating baseline cardiovascular risk stratification into first-line TKI selection to balance efficacy advantages against cardiovascular toxicity. Prospective studies with standardized cardiovascular endpoints and extended follow-up are warranted.