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

Program: Oral and Poster Abstracts
Type: Oral
Session: 637. Myelodysplastic Syndromes: Clinical and Epidemiological: Defining and Treating Low Risk MDS
Hematology Disease Topics & Pathways:
Research, Clinical Research, Diseases, Myeloid Malignancies
Saturday, December 7, 2024: 5:15 PM

Zhuoer Xie, MD, MS1, Zena Komrokji2*, Michael Otterstatter, PhD3*, Ling Zhang, MD4, Lynn C. Moscinski, MD5, Najla H. Al Ali, Ms6*, David Sallman, MD7, Jeffrey E Lancet, MD6, Amy E. DeZern, MD, MHS8, Mikkael A. Sekeres, MD9, Rami S. Komrokji, MD6, Nancy Gillis, PhD10 and Eric Padron, MD6

1Department of Malignant Hematology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL
2Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL
3The Emmes Company, LLC, Rockville, MD
4Department of Pathology and Laboratory Medicine, H. Lee Moffitt Cancer and Research Institute, Tampa, FL
5Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
6Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
7Department of Malignant Hematology, H Lee Moffitt Cancer Center, Tampa, FL
8Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD
9Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL
10Department of Cancer Epidemiology, Moffitt Cancer Center and Research Institute, Tampa, FL

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.

Disclosures: 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.

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