The Influence of Cardiovascular Comorbidities in Adverse-Risk Acute Myeloid Leukemia

Background: Acute Myeloid Leukemia (AML) is a hematologic malignancy characterized by the rapid proliferation of abnormal myeloid progenitor cells, predominantly affecting older adults. The prognosis of AML is influenced by various genetic alterations, which guide treatment strategies. Clonal Hematopoiesis of Indeterminate Potential (CHIP) mutations, which may lead to the development of AML, are independently associated with increased risk cardiovascular events and heart failure. It is not yet known whether the presents of CHIP mutations are more common in patients with AML with known underlying cardiovascular disease, nor is the precise impact these mutations and cardiovascular comorbidities may have on clinical outcomes in adverse-risk AML. The objective of this study aims to evaluate the impact of cardiovascular disease and CHIP mutations on the prognosis of patients with adverse-risk AML to identify potential predictive biomarkers for clinical outcomes.

Methods: This retrospective cohort study included all patients diagnosed with acute myeloid leukemia (AML) classified as adverse risk according to the European Leukemia Net (ELN) 2022 genetic risk criteria treated at Massey Comprehensive Cancer Center from January 1, 2013 to April 1, 2024 and included all consecutive adult patients (age 18 or greater) with confirmed diagnosis of adverse risk AML. Data on demographics, comorbidities, genetic mutations, and survival outcomes were analyzed. Clinically significant cardiovascular disease (CVD) was defined by the presence of myocardial infarction or congestive heart failure prior to diagnosis of AML. This study focused on epigenetic-type CHIP mutations common in AML, including ASXL1, DNMT3A, and TET2. OS an PFS analysis was completed using the Kaplan-Meier method and compared using cox proportional hazards regression.

Results: A total of 267 patients were identified with adverse-risk AML during the specified timeframe. Thirty-six (13.5%) were identified as having clinically significant underlying CVD. The median overall survival was approximately half in patients with CVD (178 days) compared to those without (302 days, p = 0.03). Similarly, patients with an ejection fraction (EF) < 55% (n=23) had a median overall survival of 116 days compared to 302 days for those with EF ≥ 55% (n=191)at time of diagnosis, a clinically significant result although this did not reach statistical significance. Next-generation sequencing data necessary for determining presence of CHIP-type mutations were available for 167 of the 267 identified patients. Seventy-nine (47.3%) patients were identified as having at least one of the assessed epigenetic-type CHIP mutations. There was no significant difference in median overall survival between patients with CHIP mutations (271 days) and those without (302 days, p = 0.41), nor were any patterns noted between those with epigenetic CHIP type mutations and clinically significant cardiovascular disease as predefined in this study.

Conclusion:

This work demonstrates that known clinically significant history of underlying cardiovascular disease is an independent predictor of poorer overall survival in adverse-risk AML, potentially irrespective of underlying AML disease biology. Presence of underlying epigenetic CHIP-type mutations were common in this population, but did not have an impact on overall survival nor were they predictive of those with underlying cardiovascular disease in this retrospective cohort. Presence of clinically significant cardiovascular disease or EF < 55% at time of diagnosis lead to inferior clinical outcomes, with median overall survival on the order of half of those without these co-morbidities. This striking finding may suggest the need for comprehensive cardiovascular evaluation and cardiovascular subspecialty intervention to improve this particularly dismal prognosis for this population. A prospective pilot study further examining team-based medicine approach with cardio-oncology is planned.

No relevant conflicts of interest to declare.