Prediction of Risk for Myeloid Malignancy in Clonal Hematopoiesis

BackgroundClonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia undetermined significance (CCUS) are defined by somatic mutations in genes associated with myeloid neoplasms (MN) at a variant allele fraction (VAF) 0.02 or greater the absence presence cytopenia, respectively. CHIP/CCUS is highly prevalent adults, defining predictors MN risk would aid clinical management research.MethodsWe analyzed sequenced exomes healthy U.K. Biobank participants (N=438,890) separate derivation validation cohorts. Genetic mutations, laboratory values, outcomes were used conditional probability–based recursive partitioning Cox regression to determine incident MN. Combined statistical weights define score (CHRS). Independent patient cohorts test prognostic capability CHRS setting.ResultsRecursive distinguished patients 10-year probabilities ranging from 0.0077 0.85. Multivariable analysis validated variables as Key features, including single DNMT3A high-risk two more VAF 0.2 more, 65 years age older, having CCUS versus CHIP, red blood cell indices, influenced variable direction. was low-risk (n=10,018 [88.4%]), intermediate-risk (n=1196 [10.5%]), (n=123 [1.1%]) groups. In cohorts, most events occurred CHIP/CCUS.ConclusionsThe provides simple framework for CHIP/CCUS, distinguishing minority majority which has minimal progression (Funded National Institutes Health, Harold Amos Medical Faculty Development Program, others.)