Real-world cardiovascular risk of ponatinib in chronic Phase CML: Insights from a nationwide Korean claims-based cohort study

Abstract Background Ponatinib was introduced relatively late in Korea and has been reimbursed under the national health insurance system since April 2018 for the treatment of chronic myeloid leukemia (CML). It is indicated for patients who have failed second-generation TKIs or as a third-line or later therapy. While cardiovascular adverse events are a recognized concern with ponatinib, real-world data (RWD) remain limited, particularly in Asian populations. This study aimed to assess the incidence and risk factors for significant arterial occlusive events (AOEs) associated with ponatinib in patients with chronic phase CML (CP-CML), using nationwide Korean claims data. Methods This retrospective cohort study utilized Korean Health Insurance Review and Assessment (HIRA) clamis data from 2007 to 2023. Among 10,288 TKI-treated CML patients (excluding those treated in 2007), 468 received ponatini. After applying clinical exclusion criteria (e.g., treatment duration <4 weeks, blast phase, etc), 288 patients who initiated ponatinib between April 2018 and October 2022 were included in the final analysis. In this study, AOEs were defined as hospitalization events with diagnostic codes for ischemic heart disease (IHD), peripheral arterial occlusive disease (PAD), or cerebrovascular accident (CVA). Results The median age at ponatinib initiation was 55.5 years (IQR 45.5–65), and the median time from CML diagnosis to ponatinib initiation was 3.12 years. Ponatinib was used as second-line therapy in 25%, third-line in 40%, and ≥fourth-line in 35% of patients. Initial ponatinib doses were 45 mg (78%), 30 mg (10%), and 15 mg (12%). Dose reduction was reported in 53%, with final doses of 30 mg in 21% and 15 mg in 46% of patients. Median treatment duration was 19 months (IQR 9.5–41). During ponatinib treatment, 57 patients (19.8%) experienced AOEs requiring hospitalization, including IHD (n=29, 10.1%), PAD (n=11, 3.8%), and CVA (n=30, 10.4%). The 1-year cumulative incidence of significant AOEs 12.5% (95% CI 8.7-17.0). Additionally, heart failure-related hospitalizations occurred in 20 patients (6.9%) and 103 patients (35.8%) newly initiated anti-hypertensive medication after starting ponatinib. In univariate Cox regression analysis of AOE-free survival, significant risk factors included age ≥60 years (HR 2.38, 95% CI 1.40–4.04), hypertension (HR 2.70, 95% CI 1.64-4.66), history of prior AOEs (HR 3.60, 95% CI 2.05-6.22), and heart failure (HR 4.70, 95% CI 2.64-8.4) (all p < 0.05). In multivariate analysis, hypertension (HR 2.10), prior AOE (HR 2.20), and prior heart failure (HR 3.70) remained independently significant. Prior exposure to nilotinib was not statistically significant but showed a trend toward increased AOE risk. Conclusion In this large, nationwide Korean cohort of CP-CML patients, ponatinib treatment was associated with a substantial risk of clinically significant cardiovascular events. Older age, pre-existing hypertension, prior AOEs, and heart failure were key risk factors. These findings highlight the importance of individualized cardiovascular risk stratification and close monitoring in real-world ponatinib-treated patients.