What's hidden in plain sight? Impact of clonal hematopoiesis on the risk and progression of non-hematologic cancers.

Abstract

Clonal hematopoiesis (CH) is a frequently observed phenomenon in aging individuals without apparent illness and exhibits an increased prevalence in cancer patients. Mechanistic studies indicate that mutant immune cells alter the tumor microenvironment, leading to increased inflammation, blood vessel formation, and immune cell exhaustion. Paradoxically, these changes also preserve stem-like T-cell pools that can be utilized by immunotherapy. CH may be incidentally detected in patients whose solid tumors are profiled by next-generation sequencing. Clinically, CH confers higher risks of therapy-related myeloid neoplasms, cardiovascular and inflammatory toxicities, and context-specific changes in treatment efficacy. Moreover, tumorinfiltrating CH independently shortens survival. Two validated risk scores can inform the risk for myeloid malignancy, yet surveillance, cardiometabolic management, and regimen selection still primarily rely on expert consensus. Because CH may be discovered incidentally, rigorous confirmation of variant origin when CH is suspected is essential to avoid misdirected therapy. We propose a pragmatic approach: confirm CH with paired blood sequencing when feasible; integrate high-risk features into risk stratification, counseling, and monitoring for cytopenias and cardiovascular events; and prefer less genotoxic regimens when the oncologic benefit is comparable. Early trials blocking interleukin-1β suggest that targeting inflammation driven by CH may improve outcomes in patients with solid tumors. Prospective studies informed by mutation analysis and tracking clonal changes and inflammatory markers are needed to determine if routine CH assessment can be integrated into precision oncology to improve outcomes for patients with solid tumors and CH.