JPB and TK Co-first; RK and AMZ are Co-senior authors

Introduction

HMAs remain the mainstay for frontline treatment of HR-MDS. Azacitidine (AZA) and decitabine (DEC; including oral cedazuridine/decitabine) are the only FDA-approved HMAs. However, AZA and DEC have not been compared directly in randomized trials. In this study, we aimed to assess the clinical outcomes of pts with HR-MDS treated with different HMA regimens, focusing on overall survival (OS) and treatment responses.

Methods

The VALIDATE database includes pts with HR-MDS treated with HMA-based therapies in the frontline setting from 14 specialized MDS centers. HR-MDS pts treated with HMA-based therapies in the frontline setting were included. HR-MDS was defined as having an IPSS ≥1.5 or IPSS-R >3.5 (n=213 pts excluded). Pts were excluded from the survival analysis if age at diagnosis was <18 years (n=1), bone marrow (BM) blasts ≥20% or unknown at HMA initiation (n=61), or if survival status, follow-up time, date of HMA initiation, or HMA type was unknown (n=28). To be included in the analysis of response based on IWG 2023 criteria (Zeidan A et al, Blood 2023), pts had to have a BM response assessment within 180 days after HMA initiation to allow determination of response (n=290 pts excluded). Time to event analyses were estimated using the Kaplan-Meier method and treatment groups (AZA vs DEC monotherapy) were compared by log-rank test and assessed from the time of HMA initiation. Multivariable Cox regression models were performed among pts treated with AZA and DEC monotherapy to identify predictors of response and OS. This study was supported by an independent research grant from AbbVie.

Results

1,223 pts were screened of whom 919 were included in the survival analysis. Median age was 68 years (Range [R]: 19-95) with 66% males. Our cohort was enriched for pts with adverse genetic features including complex karyotype (38%) and TP53 mutations (36%). Overall, 76% of pts were treated with HMA monotherapy (56% AZA, 20% DEC) and 24% received HMA-based combination therapy (HMA/VEN: 15%, other HMA combinations: 9%). 38.2% underwent allogeneic hematopoietic cell transplant (allo-HCT). The median HMA duration was 5 cycles (R: 1 - 94).

Due to the small number and the heterogeneity of pts receiving HMA combinations, as well the multiple partner drugs used in these pts ( Table), we compared OS and responses only between pts treated with AZA (n = 512 pts) or DEC monotherapy (n = 186 pts). In unadjusted analyses, median OS differed by treatment type (p = 0.002) and was 19.8 months (mo) with AZA (95% CI: 17.0 - 23.1 mo) and 14.3 mo with DEC (95% CI: 11.2 - 18.5 mo). Among 629 pts evaluable for response, rates of complete remission (CR) and overall response (ORR) were 14.8% and 48.6% for AZA monotherapy and 5.6% and 50.4% for DEC monotherapy, respectively. In a Cox multivariable regression model ( Figure) adjusted for age, sex, TP53 mutation status, complex karyotype, IPSS-M category (compared to very high risk), and receipt of allo-HCT, there was no difference in OS when comparing AZA and DEC monotherapy (Hazard ratio [HR]: 0.95, 95% CI: 0.72 - 1.26; p = 0.740). Variables associated with adverse OS were male sex (HR: 1.52; 95% CI: 1.16 - 2.00; p = 0.002) and presence of TP53 mutation (HR: 1.50, 95% CI: 1.05 - 2.14; p = 0.027). Conversely, receipt of allo-HCT (HR: 0.26, 95% CI: 0.19 - 0.37; p<0.001) and IPSS-M moderate-high (HR: 0.57, 95% CI: 0.37 - 0.87; p=0.009) and moderate-low (HR: 0.58, 95% CI: 0.36 - 0.95; p = 0.031; both compared to IPSS-M very high risk) were associated with improved OS. Similarly, there were no statistically significant differences in ORR between AZA and DEC (OR: 1.05, 95% CI: 0.66 - 1.68; p = 0.832) in a Cox multivariable regression model adjusted for age, sex, TP53 mutation, complex karyotype, IPSS-M category, and treatment type.

Conclusions:

Among pts included in the real-world VALIDATE database, there were no significant difference in OS or ORR (IWG 2023) between AZA- and DEC-treated pts in adjusted analyses. Other factors (e.g., TP53 mutations, complex karyotype) are substantially more relevant to outcomes than the specific HMA used. The small number of pts and heterogeneity of partner drugs in HMA-based combinations precluded robust analyses or conclusions regarding differences in efficacy. Additional analyses evaluating the impact of combinations and molecular subtypes on response and survival will be presented during the meeting as more pts are added to the database.

Stahl:GSK: Membership on an entity's Board of Directors or advisory committees; Curis Oncology: Other: GME activity ; Kymera: Membership on an entity's Board of Directors or advisory committees; Boston Consulting: Consultancy; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees; Haymarket Media: Other: GME activity ; 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 ; Clinical care options: Other: GME activity ; Dedham group: Consultancy. DeZern:Appellis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Caribou: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy. Sekeres:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kurome: Consultancy, Current holder of stock options in a privately-held company; Geron: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Uy:Jazz: Other: Advisory Board. Carraway:Novartis: Consultancy, Other: Travel, Accommodations, Expenses , Speakers Bureau; Stemline Therapeutics: Consultancy, Speakers Bureau; Daiichi: Consultancy; BMS: Consultancy, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Other: Travel, Accommodations, Expenses , Speakers Bureau; Celgene: Research Funding; AbbVie: Other; Agios: Consultancy, Speakers Bureau; Genentech: Consultancy; Astex Pharmaceuticals: Other; Syndax: Other: DSMB; Takeda: Other. Desai:Janssen Pharmaceuticals: Current Employment; Servier: Consultancy, Other: Advisory role; BMS: Consultancy, Other: Advisory role; Abbvie: Consultancy, Other: Advisory role; Janssen Research & Development: Research Funding. Griffiths:Bristol Myers Squibb: Consultancy, Research Funding; Apellis Pharmaceuticals: Consultancy, Research Funding; AAMDSIF: Honoraria; Artis Ventures: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines, Inc: Research Funding; MDS International Foundation: Honoraria; Alexion Pharmaceuticals: Consultancy, Research Funding; Abbvie: Consultancy; S. Karger Publishing: Honoraria; Picnic Health: Membership on an entity's Board of Directors or advisory committees; NextCure, Inc: Research Funding; Vera and Joseph Dresner Foundation: Membership on an entity's Board of Directors or advisory committees; Medscape: Honoraria; Partner Therapeutics: Consultancy; Physicians Educational Resource: Honoraria; Genentech, Inc.: Consultancy, Research Funding; American Society of Hematology: Honoraria; Takeda Oncology: Consultancy; CTI Biopharma: Consultancy; MediCom Worldwide, Inc.: Honoraria; Astex Pharmaceuticals: Research Funding; Taiho Oncology: Consultancy; Novartis: Consultancy, Research Funding; Celldex Therapeutics: Research Funding; AstraZeneca Rare Disease: Consultancy, Research Funding. Stein:Eisai: Research Funding; Bristol Myers Squib: Consultancy, Research Funding; Novartis: Consultancy; PinotBio: Consultancy; Janssen: Consultancy; Agios: Consultancy; Jazz: Consultancy; Menarini: Consultancy; Genentech: Consultancy; Genesis: Consultancy; Abbvie: Consultancy; Neoleukin: Consultancy; Gilead: Consultancy; Syndax: Consultancy; CTI Biopharma: Consultancy; OnCusp: Consultancy; Foghorn: Consultancy; Servier: Consultancy; Daiichi: Consultancy; Calithera: Consultancy; Aptose: Consultancy; Syros: Consultancy; Astellas: Consultancy; Ono Pharma: Consultancy; Blueprint: Consultancy. Brunner:Agios: Consultancy, Research Funding; Taiho: Consultancy; Novartis: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; AstraZeneca: Research Funding; Gilead: Consultancy; Takeda: Consultancy; Keros Therapeutics: Consultancy; Janssen: Research Funding; GSK: Research Funding; Acceleron: Consultancy. McMahon:Syndax Pharmaceuticals: Research Funding; Syros Pharmaceuticals: Research Funding; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Arcellx: Membership on an entity's Board of Directors or advisory committees. Zeidner:Stemline: Research Funding; Shattuck Labs: Honoraria, Research Funding; Servier: Consultancy, Honoraria; Sellas: Consultancy; Novartis: Consultancy; Merck: Research Funding; Jazz: Research Funding; Immunogen: Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Foghorn: Consultancy; Daiichi Sankyo: Honoraria; Astex: Research Funding; Arog: Research Funding; Sumitomo Dainippon Pharma: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Takeda: Research Funding. Savona:AbbVie Inc.: 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; CTI BioPharma Corp.: Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Geron Corporation: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics Inc.: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Ryvu Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology, Inc.: Membership on an entity's Board of Directors or advisory committees; Taiho: Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceutical Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Patents & Royalties; ALX Oncology: Research Funding; Astex Pharmaceuticals: Research Funding; Incyte Corporation: Research Funding. Roboz:GSK: Consultancy; Janssen: Consultancy, Research Funding; Astellas: Consultancy; Blueprint: Consultancy; AbbVie: Consultancy; Actinium: Consultancy; AZ: Consultancy; Bluebird bio: Consultancy; MEI: Consultancy; Novartis: Consultancy; Mesoblast: Consultancy; BMS: Consultancy; Jazz: Consultancy; Jasper: Consultancy; Amgen: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Syndax: Consultancy; Takeda: Consultancy. Wang:BMS: Consultancy; Gilead: Consultancy; PharmaEssentia: Consultancy; Jazz: Consultancy; Pfizer: Consultancy, Speakers Bureau; Kite: Consultancy, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Takeda: Consultancy; Dava oncology: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Kura Oncology: Speakers Bureau; GlaxoSmithKline: Consultancy; Abbvie: Consultancy. Shallis:Curio Science: Consultancy; Gilead Sciences: Consultancy; Servier: Consultancy; Bristol Myers Squibb: Consultancy; Rigel: Consultancy. Xie:Novartis: Speakers Bureau; Moffitt Cancer Center: Current Employment. Maciejewski:Alexion: Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy, Honoraria; Novartis: Honoraria, Speakers Bureau; Omeros: Consultancy. Sallman:Aprea, Jazz: Research Funding; AbbVie, Affimed Gmbh, Gilead, Incyte, Intellisphere, LLC, Molecular Partners AG, PGEN Therapeutics, Inc., Takeda, Zentalis; Advisory board for AvenCell, BlueBird Bio, BMS, Intellia, Jasper Therapeutics, Kite, Magenta Therapeutics, NKARTA, Novartis, Orbita: Consultancy. Della Porta:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Komrokji:Geron: Consultancy; AbbVie, CTI biopharma, Jazz, Pharma Essentia, Servio: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Rigel, Taiho, DSI: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Zeidan:Takeda: Consultancy, Honoraria; Syros: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Notable: Consultancy, Honoraria; Orum: Consultancy, Honoraria; Chiesi: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Otsuka: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Tyme: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Schrödinger: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Astex: Research Funding; Celgene/BMS: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Syndax: Consultancy, Honoraria; Geron: Consultancy, Honoraria; Mendus: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Kura: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Shattuck Labs: Research Funding; ALX Oncology: Consultancy, Honoraria; Zentalis: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Lox Oncology: Consultancy, Honoraria; BioCryst: Consultancy, Honoraria; Foran: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria; Amgen: Consultancy, Honoraria.

Figure 1
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2023
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