Abstract Body (Do not enter title and authors here): Introduction:
Venetoclax, a BCL-2 antagonist, is a novel anti-neoplastic agent used in various hematologic malignancies, including acute myeloid leukemia (AML). The aim of the current study is to evaluate the incidence, risk factors, and outcome of cardiovascular adverse events among newly diagnosed AML patients receiving venetoclax-based therapy.

Methods:
We conducted a retrospective, single-center cohort study of 214 patients with newly diagnosed AML who were treated with venetoclax and hypomethylating agents between August 2022 and October 2024. Inclusion criteria were newly diagnosed AML (de-novo, secondary [sAML], or treatment-related [tAML]). Major adverse cardiovascular event (MACE) was defined as new-onset heart failure (HF), HF exacerbation, coronary artery disease requiring intervention, or stroke during active venetoclax treatment. We modeled overall survival (OS) using multivariable Cox proportional hazard analysis with MACE as a time-dependent variable, and we adjusted for age, sex, AML subtype, and European LeukemiaNet (ELN) 2024 risk classification.

Results:
Among the 214 patients (91 de novo AML and 123 sAML or tAML), 14 (6.5%) developed a MACE during active venetoclax-based treatment. New-onset HF represented the majority of MACE (10/14). MACEs were more common in sAML or tAML, compared to de-novo AML (85.7% vs. 14.3%; p = 0.053). In multivariable Cox proportional hazard analysis, time-dependent MACE was independently associated with inferior OS (adjusted HR 3.5; 95% CI: 2.13–5.80) after adjusting for age, sex, AML category, and ELN 2024 classification.

Conclusion:
Venetoclax-associated MACE is relatively common in AML patients, especially those with sAML or tAML (12/123; 9.8%). The increased risk of MACE from venetoclax in this population could be through exposure to prior chemotherapies. Our novel findings linking MACE and inferior OS highlight the need for proactive cardiovascular risk assessment and monitoring, especially in the sAML/ tAML group. Prospective longitudinal studies, including comprehensive baseline cardiovascular assessment and echocardiogram-based surveillance, may be needed for validation of our findings and further risk stratification of these patients.