Impact of Response to Hypomethylating Agent-Based Therapy on Survival Outcomes in the Context of Baseline Clinical-Molecular Risk and Transplant Status in Patients with Myelodysplastic Syndromes/Neoplasms (MDS): An Analysis from the International Consortium for MDS (icMDS) Validate Database

Introduction: Response assessment is used to evaluate effectiveness of hypomethylating agent (HMA)-based therapy in myelodysplastic syndromes/neoplasms (MDS) in clinical practice and trials. Recently, the clinical response criteria (IWG 2023) and the clinical-molecular risk assessment (IPSS-M) in MDS were published. However, it remains unknown whether the IWG 2023 response criteria have an independent impact on overall survival (OS) when adjusting for baseline IPSS-M risk. Additionally, the association of IWG 2023 response criteria with OS in patients (pts) undergoing allogeneic stem cell transplantation (allo-HCT) versus those who do not is unknown. Lastly, it is unclear if optimal time-to-transplant impacts OS in MDS pts who achieve a IWG 2023 defined remission with HMA therapy. We examined these questions in a large population of MDS pts within the multi-institutional international consortium for MDS (icMDS) VALIDATE database.

Methods: High-risk MDS pts with IPSS ≥1.5 or IPSS-R >3.5 treated with HMA-based therapy were included in the study. Baseline IPSS-M risk was stratified into very low/low/moderate low (VL+L+ML), moderate-high/high (MH+H), and very high (VH). Response to treatment was evaluated using the IWG 2023 criteria and grouped into: composite complete response (cCR) and no cCR. cCR included: complete response (CR), CR equivalent (CRequ), CR bilineage (CRbi), CR unilineage (CRuni), and CR with partial hematologic recovery (CRh). We analyzed the differential impact of achieving cCR on HMA-based therapy prior to transplant on OS in pts who either did or did not undergo allo-HCT, while adjusting for their baseline IPSS-M risk in Cox regression analysis. Optimal time-to-transplant was determined based on age and IPSS-M category as described by Tentori et al. (JCO 2024). Pts proceeding to allo-HCT were stratified on whether they underwent transplant within the optimal time-to-transplant timeframe after MDS diagnosis or not. VALIDATE protocol was exempted, acknowledged, or approved by all centers' IRBs. VALIDATE is supported by an independent grant from AbbVie.

Results: We analyzed 762 MDS pts. The median age at MDS diagnosis was 68 years (range: 19-95 years) and 64% of pts were male. Distribution of the baseline IPSS-M risk was: VL+L+ML in 110 (14%) pts, MH+H in 347 (46%) pts, VH in 305 (40%) pts. Pts received azacitidine monotherapy, decitabine monotherapy, and HMA-based combination therapy (e.g. HMA + venetoclax) in 52%, 21%, and 28% of cases, respectively. A total of 282/762 (37%) pts achieved cCR as their best response to HMA-based therapy. The median OS for all pts was 18.7 months (95% CI: 16.6-21.3 months). Pts who did not undergo allo-HCT (n=436, 57%) had an improved median OS if they achieved cCR when compared to pts in the no cCR group in all IPSS-M risk groups (VL+L+ML: 23.5 months vs. 10.7 months; MH+H: 20.8 months vs. 11.6 months; VH: 13.8 months vs. 7.5 months). Cox analysis demonstrated an independent effect of cCR on OS in these pts when adjusted for baseline IPSS-M risk (cCR vs. no cCR: HR 0.60, 95% CI 0.48-0.76, p<0.001). In contrast, in pts who subsequently received an allo-HCT (n=326, 43%), achieving cCR with HMA prior to allo-HCT did not provide an additional OS benefit, when adjusted for baseline IPSS-M risk (cCR vs. no cCR: HR 1.00, 95% CI 0.73-1.38, p=0.986). The median time-to-transplant was 6.7 months and 34% of transplanted MDS pts received their allo-HCT during the optimal timeframe. Among pts who achieved cCR with HMA-based therapy prior to allo-HCT, optimal time-to-transplant was associated with significantly improved OS (optimal vs. non-optimal timing: HR 0.55; p=0.033).

Conclusion: Baseline IPSS-M risk and allo-HCT had an independent impact on OS, while IWG 2023 defined cCR had an independent effect on OS only in non-transplanted MDS pts. While this retrospective analysis occurred at large academic centers with specific expertise in the management of MDS, our data may have an impact on clinical practice: (i) failure to achieve cCR on HMA therapy prior to transplant should not impact the decision to proceed to allo-HCT, (ii) upfront allo-HCT without prior HMA therapy might also be an option if the clinical situation and availability of donors allow, and (iii) allo-HCT should ideally be performed during the timeframe that is considered optimal as defined by pt age and baseline IPSS-M.

Stempel:Sobi: Other: Advisory Board Participation. DeZern: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; Keros: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; geron: Other: dsmb; Appellis: 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. 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. 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Zeidan:Shattuck Labs: Research Funding; Rigel: Consultancy, Honoraria; Faron: Consultancy, Honoraria; Astex: Research Funding; Karyopharm: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Orum: Consultancy, Honoraria; Notable: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Kura: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria; Glycomimetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Research Funding; Keros: Consultancy, Honoraria; Lava Therapeutics: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Treadwell: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Akeso Pharma: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Hikma: Consultancy, Honoraria; Otsuka: Consultancy, Honoraria, Research Funding; Zentalis: Consultancy, Honoraria; Syndax: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Chiesi: Consultancy, Honoraria; Vinerx: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria; Schroedinger: Consultancy, Honoraria; BioCryst: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Kyowa Kirin: Consultancy, Honoraria; Medus: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Geron: Consultancy, Honoraria, Research Funding; ALX Oncology: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Sumitomo: Consultancy, Honoraria; Syros: Consultancy, Honoraria, Research Funding. 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