ASH 2024 | High-risk CCUS is clinically indistinguishable from LR-MDS

First, I’m going to highlight that this abstract number 354, high-risk Ccus is clinically indistinguishable from low-risk MDS, a collaboration study between Moffitt Cancer Center and NHLBI MDS Natural History Study. So first of all, Ccus or clonal cytopenia of undetermined significance is characterized by the unexplained cytopenia and the clonal hematopoiesis, but without meeting the diagnostic criteria for MDS, meaning there is no pathologically defined more than 10% of the dysplasia in any of the bone marrow lineage. Ccus carries a significant risk of progression to myeloid neoplasms, with two years cumulative incidence ranging from 2.8% to 12.6%. So using the modern risk stratification tools, the CHRS or the CCRS, patients with CHIP or Ccus could be stratified into risk categories based on their likelihood of disease progression. In a real-world clinical setting, however, distinguishing Ccus from low-risk MDS poses significant challenges. Both conditions share overlapping features such as cytopenia and genetic mutations, making it difficult to differentiate based solely on the blood work or genetic findings. In addition, genetic sequencing may not be universally available in some of the community practices, and identifying dysplasia requires expert pathology review as dysplasia can be subtle and subject to variabilities among pathologists. So the primary objectives of our research was to comprehensively compare Ccus and low-risk MDS by examining the clinical characteristics and analyzing the clinical outcomes such as progression-free survival and overall survival, utilizing the prognostic models such as the CHRS and the CCRS, within a prospective pathologically confirmed cohorts. So our hypothesis is that the high-risk Ccus case exhibit clinical features and outcomes that are comparable to those of low-risk MDS. Our study analyzed the two independent cohorts, the MDS Natural History Study cohort and the Moffitt cohort. The both cohorts have adequate follow-up and sequencing data. The Moffitt cohort also represents one of the largest MDS data sets, comprising over more than 4,000 patients. Therefore the MDS natural history study cohort, all cases were reviewed by the expert heme pathologist. So this centralized pathology review ensured the diagnostic consistency and accuracy. Similarly, in the Moffitt cohort, all the pathology diagnoses were evaluated by the same expert heme pathologist who reviewed the natural history study as well, further ensuring the consistency in diagnostic criteria. What made our study unique is the combination of the prospective data and the centralized pathologic review, ensuring the high quality and consistency of the findings. So we found that there were no statistical differences regarding the patient’s demographics, cytopenia, severity of the cytopenia, progression-free survival, and overall survival between high-risk Ccus and low-risk MDS. Our data validated the CHRS and CCRS as a viable tool for prediction of Ccus risk using the two distinct cohorts, the MDS Natural History Study and the Moffitt cohort, providing a framework for more precise evaluation of Ccus, enabling risk-based approaches to patient care. The results suggest that there is no discernible clinical overlap between high-risk Ccus and low-risk MDS regarding the age, sex, cytopenia, severity of the cytopenia, PFS, and OS, supporting that clinical decision-making should be tailored to risk categories. In addition, anemia further stratified the overall survival using the CCRS, suggesting improving anemia and its associated mortality is a priority for both MDS and high-risk Ccus. Most importantly, given the clinical similarities, the high-risk Ccus mirrors inclusion in low-risk MDS clinical trials, ensuring access to potential therapy that improves the patient’s quality of life and mortality.

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