Prediction of Risk for Myeloid Malignancy in Clonal Hematopoiesis

Abstract

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