Clinical and Genomic Convergence of High-Risk CCUS and Lower-Risk Myelodysplastic Syndromes/Neoplasms

Clonal cytopenia of undetermined significance (CCUS) is defined by unexplained cytopenias with myeloid-associated somatic mutations not meeting diagnostic criteria for myelodysplastic syndromes/neoplasms (MDS) yet carries a highly risk-stratified probability of progression to myeloid neoplasms. The clinical distinction between CCUS and lower-risk MDS (LR-MDS) is challenging because current criteria rely heavily on semi-quantitative morphologic thresholds, despite substantial clinical and molecular overlap. In this prospective study of 409 patients with CCUS and 241 with LR-MDS, we applied harmonized diagnostic and progression criteria, rigorous centralized pathology review, and uniform genomic profiling to compare clinical, molecular, and outcome data. Risk stratification was performed using two independent models-the Clonal Hematopoiesis Risk Score (CHRS) and the Clonal Cytopenia Risk Score (CCRS). Patients with high-risk CCUS, as defined by CHRS or CCRS, exhibited clinical features and event rates comparable to those with LR-MDS. In contrast, patients with low- or intermediate-risk CCUS had markedly improved outcomes, supporting conservative management. These findings underscore that CHRS and CCRS are clinically informative tools that extend beyond morphology-based classification and enable a risk-adapted approach to the management of CCUS. Importantly, a subset of patients with high-risk CCUS demonstrated substantial clinical and genomic convergence with LR-MDS, supporting their consideration for enrollment in prospective clinical trials designed for LR-MDS. These observations highlight the need for further study of risk-adapted therapeutic approaches in this population and underscore the importance of prospective clinical evaluation.