Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial.

Background: Erythropoiesis-stimulating agents (ESAs) are the standard-of-care treatment for anaemia in most patients with lower-risk myelodysplastic syndromes but responses are limited and transient. Luspatercept promotes late-stage erythroid maturation and has shown durable clinical efficacy in patients with lower-risk myelodysplastic syndromes. In this study, we report the results of a prespecified interim analysis of luspatercept versus epoetin alfa for the treatment of anaemia due to lower-risk myelodysplastic syndromes in the phase 3 COMMANDS trial.
Methods: The phase 3, open-label, randomised controlled COMMANDS trial is being conducted at 142 sites in 26 countries. Eligible patients were aged 18 years or older, had a diagnosis of myelodysplastic syndromes of very low risk, low risk, or intermediate risk (per the Revised International Prognostic Scoring System), were ESA-naive, and required red blood cell transfusions (2-6 packed red blood cell units per 8 weeks for ≥8 weeks immediately before randomisation). Integrated response technology was used to randomly assign patients (1:1, block size 4) to luspatercept or epoetin alfa, stratified by baseline red blood cell transfusion burden (<4 units per 8 weeks vs ≥4 units per 8 weeks), endogenous serum erythropoietin concentration (≤200 U/L vs >200 to <500 U/L), and ring sideroblast status (positive vs negative). Luspatercept was administered subcutaneously once every 3 weeks starting at 1·0 mg/kg body weight with possible titration up to 1·75 mg/kg. Epoetin alfa was administered subcutaneously once a week starting at 450 IU/kg body weight with possible titration up to 1050 IU/kg (maximum permitted total dose of 80 000 IU). The primary endpoint was red blood cell transfusion independence for at least 12 weeks with a concurrent mean haemoglobin increase of at least 1·5 g/dL (weeks 1-24), assessed in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. The COMMANDS trial was registered with ClinicalTrials.gov, NCT03682536 (active, not recruiting).
Findings: Between Jan 2, 2019 and Aug 31, 2022, 356 patients were randomly assigned to receive luspatercept (178 patients) or epoetin alfa (178 patients), comprising 198 (56%) men and 158 (44%) women (median age 74 years [IQR 69-80]). The interim efficacy analysis was done for 301 patients (147 in the luspatercept group and 154 in the epoetin alfa group) who completed 24 weeks of treatment or discontinued earlier. 86 (59%) of 147 patients in the luspatercept group and 48 (31%) of 154 patients in the epoetin alfa group reached the primary endpoint (common risk difference on response rate 26·6; 95% CI 15·8-37·4; p<0·0001). Median treatment exposure was longer for patients receiving luspatercept (42 weeks [IQR 20-73]) versus epoetin alfa (27 weeks [19-55]). The most frequently reported grade 3 or 4 treatment-emergent adverse events with luspatercept (≥3% patients) were hypertension, anaemia, dyspnoea, neutropenia, thrombocytopenia, pneumonia, COVID-19, myelodysplastic syndromes, and syncope; and with epoetin alfa were anaemia, pneumonia, neutropenia, hypertension, iron overload, COVID-19 pneumonia, and myelodysplastic syndromes. The most common suspected treatment-related adverse events in the luspatercept group (≥3% patients, with the most common event occurring in 5% patients) were fatigue, asthenia, nausea, dyspnoea, hypertension, and headache; and none (≥3% patients) in the epoetin alfa group. One death after diagnosis of acute myeloid leukaemia was considered to be related to luspatercept treatment (44 days on treatment).
Interpretation: In this interim analysis, luspatercept improved the rate at which red blood cell transfusion independence and increased haemoglobin were achieved compared with epoetin alfa in ESA-naive patients with lower-risk myelodysplastic syndromes. Long-term follow-up and additional data will be needed to confirm these results and further refine findings in other subgroups of patients with lower-risk myelodysplastic syndromes, including non-mutated SF3B1 or ring sideroblast-negative subgroups.
Funding: Celgene and Acceleron Pharma.
Competing Interests: Declaration of interests UP reports receiving grant support, paid to GWT-TUD, from Amgen; lecture fees and grant support, paid to the University of Leipzig, from Amgen; fees for serving on a steering committee, consulting fees, and travel support from Bristol Myers Squibb; grant support, paid to GWT-TUD, from Janssen Biotech; grant support, paid to University Dresden, from Merck and Novartis; lecture and consulting fees from Novartis; and consulting fees from AbbVie, Curis, and Geron. UP is also a member of the Medical and Scientific Advisory Board of the MDS Foundation. VS reports receiving research funding, paid to University of Florence, from Bristol Myers Squibb; honoraria from Bristol Myers Squibb; honoraria and travel support from Janssen; advisory board fees from AbbVie, Bristol Myers Squibb, CTI BioPharma, Geron, Gilead, Novartis, Otsuka, Servier, and Syros; and serving as the President of the Scientific Committee of the Italian Foundation of Myelodysplastic Syndromes. AMZ reports receiving grant support from AbbVie, ADC Therapeutics, Amgen, Aprea, Astex, AstraZeneca, Boehringer-Ingelheim, Cardiff Oncology, Bristol Myers Squibb, Incyte, Medimmune, Novartis, Otsuka, Pfizer, Takeda, and Trovagene; consulting fees from AbbVie, Acceleron, Agios, Amgen, Aprea, Astellas Pharma, BeyondSpring, Bristol Myers Squibb, Boehringer-Ingelheim, Cardiff Oncology, Cardinal Health, Daiichi Sankyo, Epizyme, Geron, Gilead, Incyte, Ionis, Janssen, Jazz Pharmaceuticals, Kura, Novartis, Otsuka, Pfizer, Seattle Genetics, Syndax, Taiho, Takeda, Trovagene, and Tyme; travel support from Cardiff Oncology, Novartis, and Pfizer; and serving on clinical trial committees of AbbVie, Bristol Myers Squibb, Geron, Gilead, Kura, and Novartis. RSK reports receiving grant support from Bristol Myers Squibb; speaker bureau fees from AbbVie, CTI BioPharma, Jazz Pharmaceuticals, Pharma Essentia, and Servio; and advisory board fees from AbbVie, Bristol Myers Squibb, CTI BioPharma, Geron, Jazz Pharmaceuticals, Novartis, Taiho, and Rigel Pharmaceuticals. JS reports receiving trial-related costs, paid to Monash Health, from Bristol Myers Squibb; grant support, paid to Monash University, from Amgen Australia, Astex Pharmaceuticals, and Bristol Myers Squibb; consultancy fees from Astellas Pharma, Bristol Myers Squibb, Mundipharma, Novartis, Otsuka, and Pfizer; speaker bureau fees from Mundipharma; holding patents WO2017/059319 A2 and WO2011/160170 A1, assigned to Peter MacCallum Cancer Centre, and WO2021/243421 A1, assigned to Monash University; and serving as a Deputy Chair of the Australasia Leukaemia and Lymphoma Group, Scientific Advisory Committee. DV reports receiving consulting fees from Amgen, Astellas Pharma, Bristol Myers Squibb, Jazz Pharmaceuticals, Kite Pharma, Merck Sharp & Dohme, Novartis, Sanofi, and Sobi; honoraria from Amgen, Astellas Pharma, Bristol Myers Squibb, Gebro, Grifols, Janssen, Jazz Pharmaceuticals, Kite Pharma, Merck Sharp & Dohme, Novartis, Pfizer, Sanofi, and Sobi; travel support from Amgen, Bristol Myers Squibb, and Jazz Pharmaceuticals; and advisory or data safety monitoring board fees from Novartis. AJ reports receiving consulting fees from AbbVie and Bristol Myers Squibb; honoraria from AbbVie, Bristol Myers Squibb, and Novartis; travel support from AbbVie; advisory or data safety monitoring board fees from AbbVie and Bristol Myers Squibb; and a leadership or fiduciary role in the Czech MDS Group. IST reports receiving consulting and speaker bureau fees from Pfizer. JL reports being employed by and owning stock in Bristol Myers Squibb. JZ reports being employed by and owning stock in Bristol Myers Squibb. ACG reports being employed by and owning stock in Bristol Myers Squibb. SK reports being employed by and owning stock in Bristol Myers Squibb. VP reports being employed by Bristol Myers Squibb and owning stock in Merck. KLK reports being employed by and owning stock in Bristol Myers Squibb and owning stock in Pfizer. SR reports being employed by, owning stock in, and receiving travel support from Bristol Myers Squibb. JKS reports being employed by and owning stock in Bristol Myers Squibb. SH reports being employed by Bristol Myers Squibb. SV reports being employed by and owning stock in Bristol Myers Squibb. TP reports being employed by and owning stock in Bristol Myers Squibb. TC reports receiving consulting fees from AbbVie, Celgene, Jazz Pharmaceuticals, Novartis, and Servier; honoraria from Celgene, Novartis, Servier, Syros, and Takeda; travel support from AbbVie, Celgene, Novartis, and Pfizer; and advisory or data safety monitoring board fees from Novartis. PF reports receiving honoraria from Bristol Myers Squibb and the Groupe Francophone des Myélodysplasies and serving as the chairman of the Groupe Francophone des Myélodysplasies. GG-M reports receiving grant support from Celgene. All other authors declare no competing interests.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)