Introduction: ESAs are an established treatment (tx) for pts with TD LR-MDS and endogenous serum erythropoietin (sEPO) levels ≤ 500 U/L; however, eligible pts often do not respond, or the response duration is limited. Luspatercept is approved in the US and EU to treat anemia due to LR-MDS after ESA failure. The preplanned interim analysis of the phase 3 COMMANDS trial (NCT03682536), comparing luspatercept with epoetin alfa in ESA-naive TD pts with anemia due to LR-MDS (with or without ring sideroblasts [RS]) showed for the first time the superiority of another therapy over ESAs in improving red blood cell transfusion independence (RBC-TI) rates (Platzbecker U, et al. Lancet 2023. doi:10.1016/S0140-6736[23]00874-7). Here we report the full efficacy and safety analysis of the COMMANDS trial.

Methods: Eligible pts were ≥ 18 y of age, had Revised International Prognostic Scoring System-defined LR-MDS with < 5% bone marrow blasts, sEPO < 500 U/L, and were TD (received 2-6 RBC U/8 wk for ≥ 8 wk before randomization). Pts were randomized 1:1 to luspatercept (1.0-1.75 mg/kg) subcutaneously (SC) Q3W, or epoetin alfa (450-1050 IU/kg) SC Q1W for ≥ 24 wk and stratified by baseline RBC transfusion burden (< 4 vs ≥ 4 RBC U/8 wk), RS status (RS+ vs RS−), and sEPO (≤ 200 vs > 200 U/L). The primary endpoint was the achievement of RBC-TI ≥ 12 wk with a concurrent mean hemoglobin (Hb) increase ≥ 1.5 g/dL (wk 1-24). Key secondary endpoints (wk 1-24) included achievement of RBC-TI ≥ 12 and for 24 wk and hematologic improvement-erythroid (HI-E) ≥ 8 wk. Other endpoints included duration of RBC-TI ≥ 12 wk, progression to acute myeloid leukemia (AML), and safety.

Results: As of Mar 31, 2023, 182 pts were randomized to luspatercept and 181 to epoetin alfa, with a median (range) tx duration of 51.3 (3-196) and 37.0 (1-202) wk and median (range) follow-up of 17.2 (1-46) and 16.9 (0-46) months, respectively. The primary endpoint was achieved by110 (60.4%) pts in the luspatercept arm versus 63 (34.8%) in the epoetin alfa arm ( P < 0.0001). Subgroup analysis of the primary endpoint response showed that response rates achieved with luspatercept versus epoetin alfa, respectively, were greater for SF3B1-mutated and non-mutated pts (Table), greater for pts with baseline sEPO ≤ 200 U/L and with baseline sEPO > 200 to < 500 U/L (Table), and greater for RS+ pts (Table). The response rates were comparable between tx arms for RS− pts (Table).

RBC-TI ≥ 12 wk was achieved by 124 (68.1%) and 88 (48.6%) pts in the luspatercept and epoetin alfa arms, respectively, RBC-TI for 24 wk by 87 (47.8%) and 56 (30.9%) pts, and HI-E ≥ 8 wk by 135 (74.2%) and 96 (53.0%) pts. The median (95% CI) duration of RBC-TI ≥ 12 wk was longer with luspatercept versus epoetin alfa (128.1 wk [108.3-not estimable (NE)] versus 89.7 wk [5.9-157.3]; HR, 0.534; Figure), and longer for clinically relevant subgroups, including RS+ and RS−.

The median duration of tx was longer in the luspatercept arm compared with the epoetin alfa arm (51.3 versus 37.0 wk). Five (2.7%) and 6 (3.3%) pts in the luspatercept and epoetin alfa arms, respectively, progressed to AML. Overall, 178 (97.8%) and 165 (92.2%) pts receiving luspatercept and epoetin alfa reported tx-emergent adverse events (TEAEs) of any grade; 107 (58.8%) and 88 (49.2%) pts reported grade 3/4 TEAEs, respectively. The most common any-grade TEAEs in either arm (≥ 10% of pts) were diarrhea (17.6% luspatercept vs 14.0% epoetin alfa), COVID-19 (14.8% vs 15.6%), asthenia (13.7% vs 16.2%), and anemia (12.1% vs 10.6%). TEAEs of interest were reported by 105 (57.7%) and 81 (45.3%) pts receiving luspatercept and epoetin alfa, respectively, with asthenia including fatigue, malaise, and lethargy (30.8% vs 24.6%), hypertension (15.9% vs 9.5%), malignancies and premalignant disorders (14.3% vs 12.8%), kidney toxicity (8.8% vs 6.7%), and injection site reactions (6.6% vs 2.2%), occurring in > 5% pts. In both tx arms, rates of on-tx deaths (8.2% for luspatercept and 7.2% for epoetin alfa) and post-tx deaths (13.2% and 13.4%) were similar.

Conclusions: Results of this full analysis confirm the findings from the interim analysis; RBC-TI duration and erythroid responses achieved with luspatercept are superior compared with epoetin alfa. Luspatercept safety results were consistent with previous MDS studies. These data show that luspatercept could represent a new standard of care for pts with TD LR-MDS.

Garcia-Manero:Bristol Myers Squibb: Other: Medical writing support, Research Funding; AbbVie: Research Funding; Genentech: Research Funding. Platzbecker:Takeda: Consultancy, Honoraria, Research Funding; Celgene: Honoraria; Fibrogen: Research Funding; Curis: Consultancy, Research Funding; BeiGene: Research Funding; Roche: Research Funding; Servier: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy; Syros: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Silence Therapeutics: Consultancy, Honoraria, Research Funding; Geron: Consultancy, Research Funding; MDS Foundation: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; medical writing support, Research Funding; Merck: Research Funding; Janssen Biotech: Consultancy, Research Funding; BMS: Research Funding. Santini:AbbVie: Other: Advisory boards; Otsuka: Other: Advisory boards; Novartis: Other: Advisory boards; BMS/Celgene: Other: Advisory boards; Gilead: Other: Advisory boards; Geron: Other: Advisory boards; CTI: Other: Advisory boards; Janssen: Other: travel grant; Syros: Other: Advisory boards; Servier: Other: Advisory boards. Zeidan:Astex: Research Funding; Celgene/BMS: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Zentalis: Consultancy, Honoraria; Kura: Consultancy, Honoraria; Lox Oncology: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Orum: Consultancy, Honoraria; Schrödinger: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Chiesi: Consultancy, Honoraria; Mendus: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Syndax: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria; Otsuka: Consultancy, Honoraria; Notable: Consultancy, Honoraria; Shattuck Labs: Research Funding; Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Tyme: Consultancy, Honoraria; Geron: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; ALX Oncology: Consultancy, Honoraria; BioCryst: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Syros: Consultancy, Honoraria; Foran: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Fenaux:AbbVie: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; French MDS Group: Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Komrokji:Novartis: Membership on an entity's Board of Directors or advisory committees; Rigel, Taiho, 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, Research Funding; AbbVie, CTI biopharma, Jazz, Pharma Essentia, Servio: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Consultancy. Shortt:Amgen: Research Funding; Pfizer: Consultancy; Otsuka: Consultancy; Novartis: Consultancy, Speakers Bureau; Imago BioSciences, Inc., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA: Research Funding; Mundipharma: Consultancy, Speakers Bureau; Astellas: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding. Valcarcel:Amgen: Consultancy, Other: travel expense reimbursement, Speakers Bureau; MSD: Consultancy, Speakers Bureau; GSK: Consultancy, Other: Travel expense reimbursement; Novartis: Consultancy, Other: Travel expense reimbursement, Speakers Bureau; Takeda: Consultancy; Pfizer: Consultancy, Other: Travel expense reimbursement, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Other: Travel expense reimbursement, Speakers Bureau; SOBI: Consultancy, Speakers Bureau; Agios: Speakers Bureau; Astellas Pharma: Consultancy, Speakers Bureau; Kyte: Consultancy, Speakers Bureau; Gebro Pharma: Speakers Bureau; BMS/Celgene: Consultancy, Other: Travel expense reimbursement, Speakers Bureau; Grifols: Speakers Bureau; Jansen: Speakers Bureau. Jonasova:Medical Department, Hematology, Charles University General Hospital, Prague, CZ: Current Employment; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Li:Bristol Myers Squibb: Current Employment, Current holder of stock options in a privately-held company. Zhang:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Giuseppi:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Kreitz:Celgene: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Pozharskaya:Bristol Myers Squibb: Current Employment, Current holder of stock options in a privately-held company; R&D partners: Ended employment in the past 24 months; Merck: Current holder of stock options in a privately-held company. Keeperman:Celgene: Divested equity in a private or publicly-traded company in the past 24 months; Pfizer: Divested equity in a private or publicly-traded company in the past 24 months; Bristol Myers Squibb: Current Employment. Rose:Celgene: Current equity holder in private company; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Prebet:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Degulys:Novartis: Consultancy, Honoraria, Speakers Bureau; Astra Zeneca: Honoraria, Other: support attending meetings/travel, Speakers Bureau; Abbvie: Honoraria, Other: support attending meeting/travel, Speakers Bureau; Sanofi: Honoraria, Other: support attending meetings/travel, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Roche: Other: support attending meetings/travel; Janssen: Other: support attending meetings/travel; Amgen: Other: support attending meetings/travel. Cluzeau:Pfizer: Other: support attending meetings/travel; Jazz Pharma: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: support attending meetings/travel; Agios: Consultancy; Servier: Consultancy, Honoraria, Other: support attending meetings/travel; BluePrint: Consultancy; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: support attending meetings/travel; Astellas: Honoraria; Incyte: Honoraria; AbbVie: Consultancy, Other: support attending meetings/travel. Della Porta:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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