Clonal hematopoiesis and its progression to myeloid neoplasms: insights into risk, biology, and therapeutic strategies

Clonal hematopoiesis (CH) is defined by the clonal expansion of hematopoietic stem and progenitor cells harboring somatic mutations that confer a fitness advantage. CH is common with advancing age and becomes nearly ubiquitous in middle age. Although typically asymptomatic, CH is associated with an increased risk of hematologic malignancies particularly myeloid neoplasms (MN), diverse non-malignant conditions, and all-cause mortality. Over the past decade, research has provided major insights into the origins of CH. In addition to aging, CH is promoted by environmental exposures, inherited genetic predisposition, and acquired conditions. Large-scale population and longitudinal sequencing studies have identified determinants of clonal behavior. Characterization of the natural history of CH has enabled the development of risk stratification models to identify individuals with CH at high risk of progression to MN, thereby providing a rationale for selecting patient populations best suited for therapeutic intervention trials. Emerging strategies include targeting mutation-specific vulnerabilities, modulating inflammatory pathways, reducing genotoxic therapy-induced clonal selection, and repurposing agents with efficacy in MN. In this review, we summarize current knowledge of the risk factors underlying CH development, highlight recent advances in understanding the determinants of clonal behavior including progression to MN, and discuss emerging therapeutic approaches for preventing malignant transformation and clinical trial design considerations.