denotes an abstract that is clinically relevant.
denotes that this is a recommended PHD Trainee Session.
denotes that this is a ticketed session.Session: 637. Myelodysplastic Syndromes: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Research, Adult, Epidemiology, Clinical Research, Health outcomes research, Education, Diseases, Real-world evidence, Myeloid Malignancies, Study Population, Human
IDH1 mutation is described in 3-5% of MDS patients (pts) and is enriched among those with neutropenia. Pts with higher risk MDS (HR-MDS) typically have poor outcomes post hypomethylating agent (HMA) failure, with a median overall survival (OS) of 4-6 months. Ivosidenib was approved for relapsed and refractory IDH1-mutant (MT) MDS, demonstrating a median OS of 3 years in a small cohort of pts, highlighting its potential efficacy. The historical outcome of IDH1-MT HR-MDS post-HMA failure is not well known. Similarly, in lower risk MDS (LR-MDS), we previously reported that IDH1 mutation is enriched among 9% of pts who progressed directly to acute myeloid leukemia (AML). The impact of IDH1 mutation among LR-MDS is not well characterized.
Methods
We retrospectively analyzed the outcomes of a large cohort of MDS pts. Our study aimed to compare outcomes between IDH1-MT and wild-type (WT). We examined 2 separate cohorts comparing IDH1-MT vs. WT. Cohort (A): HR-MDS (intermediate, high, and very high risk by IPSS-R) to assess response of IDH1-MT MDS to HMA, provide historical data on outcomes post-HMA failure and to assess the impact of IDH1 inhibitor use in real-world settings post-HMA failure. Cohort (B): LR-MDS (very low and low by IPSS-R) to assess impact of IDH1 mutation on OS and leukemia transformation.
Results
Cohort (A): A total of 1,057 HR-MDS pts who received frontline HMA therapy were included. IDH1 mutations were detected in 32 pts (3%), with the R132C mutation being the most common (50%). Age, white blood cell count, absolute neutrophil count, hemoglobin, platelets count, and bone marrow blast percentages were comparable between IDH1-MT and IDH1-WT groups. Mutations of EZH2 (12.5% vs. 4.6%), DNMT3A (37.5% vs. 0.1%), and CBL (6.3% vs. 2%) were more frequent in IDH1-MT cases (p<0.05), whereas ASXL1 mutations (22.7% vs. 6.3%) were more common in IDH1-WT (p<0.05). The upfront HMA regimens included azacitidine (61.5%), decitabine (14.4%), oral decitabine (1.5%), HMA with venetoclax (11.1%), and other HMA combinations (11.5%). Complete response rates to HMA therapy were similar between IDH1-MT and WT pts (16% vs 14%, p=0.78). Following HMA therapy failure, the median OS was 10 months: 9.6 months for IDH1-MT and 10.3 months for IDH1-WT pts. Four IDH1-MT pts received IDH1 inhibitors post-HMA failure (ivosidenib, n=3; olutasidenib, n=1), showing a significantly improved median OS of 28.6 months compared to 5.1 months for those who did not receive IDH1 inhibitors (n=28) (p<0.05).
Cohort (B): Among 1,321 LR-MDS pts, we identified 37 (2.8%) with IDH1 mutation. Baseline characteristics were similar between IDH1-MT and WT groups except for younger age and leukopenia in the IDH-1 MT pts. More pts were upstaged to higher risk by IPSS-M among IDH1-MT (35% vs. 16% WT, p=0.008). SRSF2 and RUNX-1 were more observed among IDH1-MT pts. No difference in median OS between IDH1-MT and WT (92 vs. 75 months, p=0.25). Leukemia free survival (LFS) was not reached in IDH1-WT compared to 92 months in IDH1-MT pts (p = 0.006). The rate of AML transformation was higher in IDH1-MT (27% vs 11%, p=0.003). No difference in response to LR-MDS therapies was observed and many pts were in observation until disease progression.
Conclusion
For HR-MDS, response to HMA therapy is similar between IDH1-MT and WT pts. Historically, the median OS for IDH1-MT MDS post-HMA failure without IDH1 inhibitor is poor (5.1 months). However, IDH1 inhibitors significantly improve survival in IDH1-MT pts in real world data (OS 28.6 months). In IDH1-MT LR-MDS, a higher rate of AML transformation and worse LFS are observed. Our data provide the historical outcomes for IDH1-MT HR-MDS post-HMA and provide rational to target IDH1 mutation among LR-MDS given high rate of leukemia transformation.
Disclosures: Chan: Abbvie: Honoraria, Research Funding; Novartis: Honoraria; Jazz: Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Aptitude Health: Honoraria. Kuykendall: Protagonist Therapeutics: Honoraria, Research Funding; Novartis: Research Funding; PharmaEssentia: Honoraria; Incyte: Honoraria. Lancet: Prelude Therapeutics: Consultancy, Other: Bristol Myers Squibb; Bristol Myers Squibb: Consultancy, Other: Consultant/Advisory Board; Tradewell Therapeutics: Consultancy, Other: Consultant/Advisory Board. 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. Komrokji: Rigel: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servio: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Keros: Membership on an entity's Board of Directors or advisory committees; DSI: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sumitomo Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; CTI biopharma: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, 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; Genentech: Consultancy; DSI: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servio: Honoraria; Taiho: 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; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: 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.
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