DP016 | PREDICTING MYELOID NEOPLASMS IN CLONAL HEMATOPOIESIS: VALIDATION OF THE CHRS SCORE IN A POPULATION-BASED COHORT

The identification of premalignant conditions and their progression risks is a major focus in hematology. Clonal hematopoiesis (CH), including clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS), is now recognized as a precursor to myeloid neoplasms. Recently, the Clonal Hematopoiesis Risk Score (CHRS) was developed to stratify individuals based on genetic mutations, clonal burden, and clinical features (PMID: 37483562). We validated the CHRS in a prospective, population-based cohort from the “Health and Anemia” study, which included 4140 elderly individuals aged >65 years, of whom 941 (22.7%) fulfilled CHIP or CCUS criteria based on next-generation sequencing of 47 myeloid-related genes. Of these, 784 had CHIP and 157 had CCUS. The cohort had a median age of 74 years and a median follow-up of 12.5 years. MN development occurred in 25 individuals (2.6%), with a significantly higher incidence among CCUS compared to CHIP (7% vs 1.9%, p<0.0001). The most frequently mutated genes were DNMT3A (46.6%) and TET2 (24.4%), but mutations in SRSF2, JAK2, and RUNX1 were most strongly associated with MN progression, whereas single DNMT3A mutations were associated with reduced risk (HR 0.36, p=0.029). Application of the CHRS showed effective stratification of MN risk. The 15-year cumulative incidence was 1.7% for low-risk, 8.7% for intermediate-risk, and 30.9% for high-risk individuals. Hazard ratios (HRs) compared to low-risk were 5.97 (95% CI 2.54–14.07, p<0.0001) for intermediate- and 20.91 (95% CI 6.55–66.78, p<0.0001) for high-risk subjects. Median overall survival decreased from 159 months in low-risk to 100 months in high-risk groups (p=0.0018). The CHRS demonstrated strong predictive performance with a concordance index (C-index) of 0.73. Calibration remained excellent across time points, with Brier scores of 0.001 at 12 months and 0.032 at 180 months. These findings validate the CHRS as a robust tool for risk stratification in clonal hematopoiesis, applicable to unselected elderly populations. Its use can guide clinical decision-making, identifying individuals at high risk who may benefit from enhanced monitoring or early therapeutic strategies, while avoiding unnecessary interventions in low-risk cases. Further prospective studies are warranted to refine risk prediction and assess the impact of targeted interventions.