Abstract
The terms clonal monocytosis of undetermined significance (CMUS) and clonal cytopenia and monocytosis of undetermined significance (CCMUS) were introduced by the International Consensus Classification of Myeloid Neoplasms (ICC) to describe cases of clonal hematopoiesis (CH) and a concurrent monocytosis, that did not meet the diagnostic criteria of chronic myelomonocytic leukemia (CMML). To date, their practical relevance as clinicopathological entities at a population level has not been assessed. Here, we assess the prevalence, significance and natural history of CMUS and CCMUS amongst 431,531 UK Biobank participants through analysis of clinical, genomic and health outcome data. We find that CMUS with an absolute monocytosis and CCMUS are high-risk entities strongly associated with incident myeloid neoplasia (MN), cardiovascular and renal disease. Noting the overall higher monocyte counts in men and the low rate of progression of DNMT3A-CMUS, we show that amending the definition of CMUS/CCMUS to incorporate sex-specific monocyte thresholds and the exclusion of isolated DNMT3A mutations from the definition significantly strengthens the association with incident MN. Finally, given their association with poor outcomes, we develop MoSAIC, a machine learning classifier to infer the presence of SRSF2 mutations (associated with high MN risk) amongst individuals with monocytosis, based on complete blood count indices alone. We corroborate our findings in an independent cohort of 625,328 Danish primary care patients. Our findings underscore the clinical relevance of CMUS and CCMUS as distinct high-risk states within the spectrum of clonal hematopoiesis, and establish an evidence base to refine their diagnostic definition.