High-Risk Ccus Is Clinically Indistinguishable from Low-Risk Myelodysplastic Syndromes/Neoplasms

Background: Clonal Cytopenia of Undetermined Significance (CCUS) is a recently described entity that does not meet diagnostic criteria for myelodysplastic syndromes/neoplasms (MDS) but carries a significant risk of progressing to myeloid neoplasms (MN) (2-year cumulative incidence: 2.8-12.6%). The primary distinction between CCUS and lower-risk (LR)-MDS is the presence of pathologically defined dysplasia in >10% of any lineage. While some studies suggest that CCUS and LR-MDS are a single clinical entity, a comprehensive, prospective, multi-level pathologic evaluation comparing CCUS and LR-MDS cases is lacking.

Methods: This study leveraged a prospective, rigorously curated dataset from the National MDS Natural History Study (MDS NHS). Pathology was centrally reviewed by expert hematopathologists and, if distinct from local review, a third-party expert pathologist adjudicated the final diagnosis. Baseline characteristics were compared using Fisher's exact tests. For CCUS cases, the Clonal Hematopoiesis Risk Score (CHRS, Weeks et al., 2023), developed using a population-based study from the UK Biobank, and the Clonal Cytopenia Risk Score (CCRS, Xie et al., 2024), derived using real-world data from academic centers, were calculated to stratify patients into low-, intermediate-, and high-risk categories. Risk groups were compared to LR-MDS (IPSS-R). Progression-free survival (PFS) and overall survival (OS) were compared across risk categories, accounting for competing risks. Cox proportional hazards models were fit to time-to-event data, and hazard ratios (HR) were calculated to assess differences in PFS and OS between groups. Findings were validated using an independent cohort from Moffitt Cancer Center.

Results: The primary analysis included 258 pathologically confirmed CCUS and 274 LR-MDS patients from the MDS NHS (June 2016- February 2024). Patient demographics (age, sex, race) were similar between groups (p>0.05 in all cases). CCUS patients had higher Hb (11.9 vs. 10.5 g/dL, p<0.001) and ANC (2.8 vs. 2.0 X 10^9/L, p<0.01) compared to LR-MDS, with similar platelet counts (137 vs. 138 X 10^9/L, p=0.99). Median (95% CI) follow-up duration was 2 (0.4-5.7) years across both groups. 2-year OS and PFS were significantly superior in CCUS compared to LR-MDS (OS: 85% vs. 72%; PFS: 95% vs. 83%, both p<0.01). Collectively, these data suggest that CCUS and LR-MDS are two distinct clinical entities.

To determine if modern CCUS prognostic models could discriminate more MDS-like CCUS cases we calculated the CHRS and CCRS. CCRS effectively stratified CCUS patients into 3 risk groups with distinct clinical outcomes. Specifically, 127 (63.5%), 76 (38%), and 55 (27.5%) patients were classified as low-, intermediate-, and high-risk, respectively. The 2-year cumulative incidence of MN rose progressively from 3.3% in low- to 5.9% in intermediate- and 14% in high-risk patients. Compared to LR-MDS, CCRS-low-risk (PFS: HR [95% CI]=0.3 [0.12-0.75], p=0.01; OS: HR=0.55 [0.32-0.93], p=0.02) and CCRS-intermediate-risk CCUS (PFS: HR=0.17 [0.06-0.46], p<0.001; OS: HR=0.44 [0.27-0.73], p=0.001) had significantly improved PFS and OS. Conversely, CCRS-high-risk CCUS had comparable PFS and OS to LR-MDS, (PFS: HR=0.47 [0.18-1.18], p=0.10; OS: HR=0.76 [0.44-1.31], p=0.34) suggesting a similar clinical trajectory.

To validate these findings, we conducted an independent analysis on a cohort of 106 CCUS and 3217 LR-MDS patients using the same statistical approach. Results confirmed the distinctiveness of CCUS from LR-MDS. The CCRS effectively identified a high-risk CCUS subgroup with a significantly increased risk of disease progression compared to low/intermediate risk group (HR [95% CI]=5.2 [1.56-17.2], p=0.007). Notably, high-risk CCUS exhibited similar OS to LR-MDS (HR=0.68 [0.28-1.63], p=0.38), reinforcing the clinical similarity between these two groups. Comparable results were obtained using CHRS (data to be presented at the meeting).

Conclusion: Analysis of an independent, prospective cohort established CCUS as a distinct clinical entity. However, high-risk CCUS, as characterized by CHRS and CCRS, exhibited clinical features comparable to LR-MDS. These findings, replicated in two independent cohorts collectively constituting 364 CCUS and 3491 LR-MDS, suggest high-risk CCUS is clinically indistinguishable from LR-MDS and should be considered for LR-MDS clinical trials.

Sallman:Abbvie: Consultancy; Agios: Consultancy; Axiom: Consultancy; Gilead: Consultancy; Celyad: Consultancy; Froghorn: Consultancy; Incyte: Consultancy; Intellisphere, LLC: Consultancy; Johnson & Johnson: Consultancy; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; NextTech: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AvenCell: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; BlueBird Bio: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Dark Blue Therapeutics: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Jasper Therapeutics: Membership on an entity's Board of Directors or advisory committees; NKARTA: Membership on an entity's Board of Directors or advisory committees; Orbital Therapeutics: Membership on an entity's Board of Directors or advisory committees; Rigel Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Apera: Research Funding; Jazz: Research Funding. Lancet:Bristol Myers Squibb: Consultancy, Other: Consultant/Advisory Board; Prelude Therapeutics: Consultancy, Other: Bristol Myers Squibb; Tradewell Therapeutics: Consultancy, Other: Consultant/Advisory Board. DeZern:Keros: Membership on an entity's Board of Directors or advisory committees; servier: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Appellis: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibbs: Membership on an entity's Board of Directors or advisory committees; geron: Other: dsmb. Sekeres:Schroedinger: Membership on an entity's Board of Directors or advisory committees; Kurome: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. Komrokji:Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servio: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Rigel: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI biopharma: Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Research Funding; Sumitomo Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; DSI: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Keros: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Taiho: Membership on an entity's Board of Directors or advisory committees; DSI: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servio: Honoraria; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.