Introduction: The International Prognostic Scoring System-Molecular (IPSS-M) ( Bernard NEJM Evidence 2022) and the 2023 International Working Group (IWG) response criteria for myelodysplastic syndrome (MDS) ( Zeidan Blood 2023) are used to more accurately assess prognosis and therapeutic response in MDS. However, it is unknown if these tools can be used to predict outcomes post-allogeneic hematopoietic stem cell transplant (HCT). We sought to understand the impact of pre-HCT IPSS-M on post-HCT outcomes in patients (pts) with MDS who responded to hypomethylating agent (HMA) therapy.

Methods: Pts with MDS treated with HMA (azacitidine or decitabine) who received an HCT post-HMA at Dana-Farber Cancer Institute from January 2014 to December 2020 were included. Response to HMA was assessed by 2023 IWG response criteria and was defined as complete remission (CR) + CR with bi-lineage blood count recovery (CRbi) + CR with uni-lineage blood count recovery (Cruni) + CR with partial hematological recovery (CRh). Combined clinical and molecular risk was assessed by IPSS-M at times of diagnosis and of HCT, the latter using the bone marrow biopsy and sequencing data collected closest to HCT. High risk was defined as IPSS-M moderately high, high, and very high, whereas low risk was defined as IPSS-M very low, low, and moderately low.

Results: A total of 148 pts with MDS who received HMA and underwent subsequent HCT were included. Median age was 64 years (range 26-79) and 61.5% were men. Pts were diagnosed with MDS-EB1 (26.4%), MDS-EB2 (45.3%), and other MDS subtypes (28.3%). IPSS-M at time of diagnosis was very low (2%), low (10.1%), moderate low (6.1%), moderate high (8.8%), high (31.8%), and very high (22.3%). IPSS-M pre-HCT was very low (12.8%), low (8.8%), moderate low (10.8%), moderate high (12.8%), high (20.3%), and very high (10.8%). IPSS-M at diagnosis and pre-HCT could not be calculated because of missing molecular data in 18.9% and 23.6% of pts, respectively. Pts received a median of 4 HMA cycles (range 1-20) and were treated with azacitidine for 7 days (54.1%), decitabine for 5 days (39.2%), and other schedules (6.7%). Prior to HCT, IWG 2023 responses were: CR (15.5%), CRbi (14.9%), CRuni (19.6%), CRh (0.7%), partial remission (PR: 1.4%), hematological improvement (HI: 9.5%), and no response (38.5%). Most pts received HCT from either a matched unrelated (60.8%) or matched related donor (18.2%) with reduced intensity conditioning (74.3%). Pts received graft versus host disease prophylaxis with tacrolimus (tac)/methotrexate (MTX) (54.7%), tac/MTX/sirolimus (19.6%), post-transplant cyclophosphamide/mycophenolate mofetil/tac (15.5%), tac/sirolimus (8.1%), other (2%). Median HCT-comorbidity index (CI) was 2 (range 0-13) and 48.6% pts had HCT-CI ≥ 3. For the entire cohort, the median follow-up time among ongoing survivors was 48.3 months (range 5.5-101.3). Among pts who responded to HMA per IWG 2023 criteria (CR/CRbi/CRuni/CRh), those who had high risk by IPSS-M prior to HCT had significantly shorter median overall survival (OS) (27 months; 95% CI 7.5-51) compared to pts with a low risk by IPSS-M (not reached; p=0.016) ( Figure A). Cumulative incidence of relapse (CIR) at 4 years was 66% for pts with high risk and 31% for low risk (p=0.034) ( Figure B). Pts with response to HMA with high risk by IPSS-M had lower OS (4-year OS: 27% versus 53%; p=0.016) and progression-free survival (4-year PFS: 19% versus 50%; p=0.018) but similar non-relapse mortality (NRM) (4-year NRM: 16% vs. 19%; p=0.66) post-HCT compared to pts with low risk at time of HCT.

Conclusion: For pts with MDS who achieve a response to HMA prior to HCT, combined clinical/molecular risk, as assessed by IPSS-M, has an important prognostic impact on post-HCT outcomes. Pre-HCT risk should be evaluated for prognostication and to guide patient care, including future prospective studies evaluating novel agents for post-HCT therapy.

Kelkar:CareDx: Research Funding. Ho:Allovir: Consultancy; Jazz: Consultancy, Research Funding; Omeros: Consultancy; Alexion: Consultancy; CareDx: Research Funding. Koreth:BMS: Research Funding; Clinigen Labs: Consultancy, Research Funding; Amgen: Research Funding; Tr1x: Consultancy; Biolojic Design: Consultancy; Cue Biopharma: Consultancy; Gentibio: Consultancy; Equillium: Consultancy; Mallinckrodt: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotec: Research Funding; Regeneron: Research Funding; Cugene: Membership on an entity's Board of Directors or advisory committees; Equillium: Research Funding. Romee:Biohaven: Research Funding; Inndura: Consultancy. Nikiforow:Sobi: Other: Participation in ad hoc advisory board; Kite/Gilead: Other: Participation in ad hoc advisory board; Iovance: Other: Participation in ad hoc advisory board; GlaxoSmithKline: Other: Participation in ad hoc advisory board; A2 Bio: Other: Participation in ad hoc advisory board. Soiffer:Bluesphere Bio: Consultancy; Astellas: Consultancy; Vor Bipharma: Consultancy; Juno Therapeutics/ BMS/Celgene USA: Other: Data Safety Monitoring Board; NMPD - Be the Match, USA: Membership on an entity's Board of Directors or advisory committees; Smart Immune: Consultancy; Jasper: Consultancy; Neovii: Consultancy. Luskin:Novartis: Honoraria; Novartis: Research Funding; Pfizer: Honoraria; Jazz: Honoraria; AbbVie: Research Funding. Garcia:AbbVie: Consultancy, Research Funding; Pfizer: Research Funding; Prelude: Research Funding; New Wave: Research Funding; AstraZeneca: Research Funding; Servier: Consultancy; Gilead: Consultancy; Astellas: Consultancy; Genentech: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy. Chen:Rigel: Consultancy; Abbvie: Consultancy. Lane:AbbVie: Research Funding; Cimeio Therapeutics: Consultancy; IDRx: Consultancy; Jnana Therapeutics: Consultancy; ProeinQure: Consultancy; Qiagen: Consultancy; Medzown: Current equity holder in private company; Stemline Therapeutics: Research Funding. Winer:Abbvie: Consultancy; Curis Inc: Consultancy. Stone:Ligand Pharma: Consultancy; BerGenBio: Consultancy; Cellularity: Consultancy; Syntrix: Other: DSMB; Lava Therapeutics: Consultancy; Takeda: Other: DSMB; Amgen: Consultancy; Jazz: Consultancy; GSK: Consultancy; Rigel: Consultancy; Hermavant: Consultancy; Kura One: Consultancy; AvenCell: Consultancy; Epizyme: Other: DSMB; Aptevo: Other: DSMB; CTI Biopharma: Consultancy; Abbvie: Consultancy. DeAngelo:Incyte: Honoraria; Novartis: Research Funding; Novartis: Honoraria; Kite: Honoraria; Autolus: Honoraria; Takeda: Honoraria; Jazz: Honoraria; Gilead: Honoraria; GlycoMimetics: Research Funding; Blueprint: Honoraria; Pfizer: Honoraria; Servier: Honoraria; AbbVie: Research Funding; Blueprint: Research Funding; Amgen: Honoraria. Zeidan:Gilead: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Tyme: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Orum: Consultancy, Honoraria; Foran: Consultancy, Research Funding; Astex: Research Funding; Geron: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Shattuck Labs: Research Funding; Amgen: Consultancy, Honoraria; Mendus: Consultancy, Honoraria; BioCryst: Consultancy, Honoraria; Zentalis: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Syros: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Otsuka: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Schrödinger: Consultancy, Honoraria; ALX Oncology: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Syndax: Consultancy, Honoraria; Kura: Consultancy, Honoraria; Lox Oncology: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Chiesi: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria; Notable: Consultancy, Honoraria; Genentech: Consultancy, Honoraria. Lindsley:Vertex Pharmaceuticals: Consultancy; Qiagen: Consultancy; Jazz Pharmaceuticals: Consultancy; Verve Therapuetics: Consultancy; Sarepta Therapuetics: Consultancy; Bluebird bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Consultancy. Cutler:Sanofi: Consultancy; Ruth L. Kirschstein Postdoctoral Individual National Research Service Award: Research Funding; Allovir: Other: Data Safety Monitoring Board (DSMB); Pluristem Therapeutics: Other: DSMB; Oxford Immune Algorithmics: Membership on an entity's Board of Directors or advisory committees; InhibRx: Consultancy; Astellas: Consultancy; Rigel: Consultancy; Cimeio: Membership on an entity's Board of Directors or advisory committees. Stahl:Sierra Oncology: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: GME activity ; Dedham group: Consultancy; Boston Consulting: Consultancy; Haymarket Media: Other: GME activity ; Curis Oncology: Other: GME activity ; Clinical care options: Other: GME activity ; GSK: Membership on an entity's Board of Directors or advisory committees; Kymera: Membership on an entity's Board of Directors or advisory committees.

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2023
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