Mutations in CHIP-associated genes at myeloid neoplasm diagnosis and risk of cardiovascular/cerebrovascular events.

BACKGROUND

Clonal hematopoiesis of indeterminate potential (CHIP)-associated somatic mutations are associated with increased cardiovascular and cerebrovascular risk in the general population; whether mutations detected at myeloid neoplasm (MN) diagnosis predict incident cardiovascular and cerebrovascular events (CCVEs) is unclear.

METHODS

We retrospectively studied 203 adults with newly diagnosed myelodysplastic neoplasms, myelodysplastic/myeloproliferative neoplasms, or acute myeloid leukemia unfit for intensive chemotherapy (2016-2023) who underwent pretreatment next-generation sequencing. Cause-specific hazard models adjusted for cardiovascular risk factors assessed associations between CHIP-associated gene mutations and incident CCVEs, including age-stratified and age-by-mutation interaction analyses.

RESULTS

Median age was 68 years (IQR, 61-75); 127 (62.6%) were male; 141 (69.5%) carried ≥1 CHIP-associated gene mutation, most commonly ASXL1, TET2, TP53, or DNMT3A. Over median 12-month follow-up, 74 (36.5%) experienced a first CCVE. Any CHIP-associated gene mutation was associated with CCVE risk in univariable analysis; this association was not significant after multivariable adjustment (adjusted hazard ratio [aHR], 1.58; 95% CI, 0.87-2.88; p=0.13). In joint age-mutation analyses, mutation-positive patients aged ≥70 years had the highest CCVE risk (aHR, 2.77; 95% CI, 1.17-6.56), whereas younger mutation-positive patients showed a nonsignificant trend (aHR, 2.16; 95% CI, 0.90-5.20; p=0.085); interaction was not significant (p=0.29). In multivariable models, CHIP-associated gene mutations, higher-risk MN, and incident CCVEs were each associated with higher all-cause mortality.

CONCLUSIONS

CHIP-associated gene mutations at MN diagnosis were not independently associated with incident CCVEs. Older mutation-positive patients had higher observed CCVE risk, predominantly heart failure, with limited precision. These exploratory findings warrant prospective multicenter validation.