Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2025 Jul;42(7):3576-3589.
doi: 10.1007/s12325-025-03208-5. Epub 2025 May 16.

Long-Term Transfusion Independence with Luspatercept Versus Epoetin Alfa in Erythropoiesis-Stimulating Agent-Naive, Lower-Risk Myelodysplastic Syndromes in the COMMANDS Trial

Guillermo Garcia-Manero  1 , Valeria Santini  2 , Amer M Zeidan  3 , Rami S Komrokji  4 , Veronika Pozharskaya  5 , Shelonitda Rose  5 , Karen Keeperman  5 , Yinzhi Lai  5 , Sameer Kalsekar  6 , Barkha Aggarwal  5 , Dimana Miteva  7 , David Valcárcel  8 , Pierre Fenaux  9 , Jake Shortt  10 , Matteo Giovanni Della Porta  11 , Uwe Platzbecker  12
Affiliations
Clinical Trial

Long-Term Transfusion Independence with Luspatercept Versus Epoetin Alfa in Erythropoiesis-Stimulating Agent-Naive, Lower-Risk Myelodysplastic Syndromes in the COMMANDS Trial

Guillermo Garcia-Manero et al. Adv Ther. 2025 Jul.

Abstract

Introduction: The efficacy of erythropoiesis-stimulating agents (ESAs) for transfusion-dependent (TD) anemia in lower-risk myelodysplastic syndromes (LR-MDS) is limited. Luspatercept achieved significantly greater rates of red blood cell (RBC) transfusion independence (TI) versus epoetin alfa (an ESA) in the phase 3 COMMANDS trial. This analysis assessed long-term RBC-TI, cumulative response, and safety with luspatercept in COMMANDS.

Methods: Eligible patients aged ≥ 18 years, with ESA-naive, RBC TD LR-MDS were randomized 1:1 to receive luspatercept (1.0 mg/kg, titration to 1.75 mg/kg permitted) or epoetin alfa (450 IU/kg, titration to 1050 IU/kg). Disease assessment was carried out at week 24 (day 169) and every 24 weeks thereafter. Treatment continued until disease progression, lack of clinical benefit, unacceptable toxicity, or consent withdrawal.

Results: At data cutoff (September 22, 2023; median follow-up: luspatercept 21.4 months, epoetin alfa 20.3 months), a greater proportion of patients treated with luspatercept (n = 182) versus epoetin alfa (n = 181) achieved a longest single RBC-TI period ≥ 1 year (44.5% vs. 27.6%; P = 0.0003) and ≥ 1.5 years (30.2% vs. 13.8%; P < 0.0001). Higher rates of RBC-TI ≥ 1.5 years with luspatercept over epoetin alfa were consistent across all prespecified subgroups, including patients with ring sideroblast-negative status and low baseline serum erythropoietin. Longer cumulative RBC-TI response [sum of all durations of RBC-TI for ≥ 12 weeks; week 1 to end of treatment (95% CI)] was observed with luspatercept [154.7 weeks (118.4-NR)] versus epoetin alfa [91.1 weeks (73.1-123.9)]. Rates of treatment-emergent adverse events, including asthenia and hypertension, generally decreased over time in both arms. Progression rates to high-risk MDS and acute myeloid leukemia were similarly low (< 5%) in both treatment arms.

Conclusions: These data demonstrated sustained, durable clinical benefit across subgroups and support luspatercept as the treatment of choice for anemia in patients with LR-MDS who are TD and ESA-naive.

Trial registration number: NCT03682536.

Keywords: Anemia; Epoetin alfa; Erythroid-stimulating agents; Luspatercept; Myelodysplastic syndromes; Transfusion-independence.

Plain language summary

Myelodysplastic syndromes (MDS) are a group of blood disorders, where the bone marrow fails to make enough healthy blood cells. MDS is also considered a blood cancer. Patients who have lower-risk MDS (LR-MDS) have a lower chance of progressing to more serious conditions, like high-risk MDS or acute myeloid leukemia. Most patients with LR-MDS have anemia (low red blood cells [RBC]) and need frequent RBC transfusions. Erythropoiesis-stimulating agents (ESAs), like epoetin alfa, are commonly used to treat anemia. However, ESAs may not be as effective in all patients and the effects may not last as long. The COMMANDS trial looked at patients with LR-MDS and compared 2 treatments, luspatercept and epoetin alfa. The aim was to see which treatment could help patients avoid transfusions for a longer time, or be “transfusion-free.” The results showed that there were more patients on luspatercept who were transfusion-free, compared with epoetin alfa, at both the 1-year and the 1.5-year timepoints. These results were similar across different patient subgroups, including patients with specific genetic mutations. Patients treated with luspatercept and epoetin alfa had similar rates of side effects, which decreased over time. Additionally, the risk of progression to more serious conditions was low and similar between the two groups. In conclusion, luspatercept helped patients with LR-MDS avoid transfusions for over 1.5 years. This supports the use of luspatercept as a first-choice treatment in patients with LR-MDS.

PubMed Disclaimer

Conflict of interest statement

Declarations. Conflicts of Interest: Valeria Santini has been a member of the board of directors or an advisory board for AbbVie, Bristol Myers Squibb/Celgene, CTI, Geron, Jazz, Keros, Novartis, Servier, and Syros. Amer M. Zeidan has consulted for AbbVie, Agios, Akeso Pharma, ALX Oncology, Amgen, Astellas, BeiGene, BioCryst, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Chiesi, Daiichi Sankyo, Epizyme, Faron, Genentech, Geron, Gilead, GlycoMimetics, Hikma, Janssen, Karyopharm, Kura Oncology, Kyowa Kirin, LAVA Therapeutics, Mendus, Notable Labs, Novartis, Orum, Otsuka, Pfizer, Regeneron, Rigel, Schrödinger, Servier, Sumitomo, Syndax, Syros, Taiho, Takeda, Treadwell, Vincerx, and Zentalis; has received research funding from AbbVie, Amgen, Astex, Bristol Myers Squibb, Celgene, Geron, Kura, Novartis, Otsuka, Shattuck Labs, Syros, and Takeda; and has received honoraria from AbbVie, Agios, Akeso Pharma, ALX Oncology, Amgen, Astellas, BeiGene, BioCryst, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Chiesi, Daiichi Sankyo, Epizyme, Faron, Genentech, Geron, Gilead, GlycoMimetics, Hikma, Janssen, Karyopharm, Kura Oncology, Kyowa Kirin, LAVA Therapeutics, Mendus, Notable Labs, Novartis, Orum, Otsuka, Pfizer, Regeneron, Rigel, Schrödinger, Servier, Sumitomo, Syndax, Syros, Taiho, Takeda, Treadwell, Vincerx, and Zentalis. Rami S. Komrokji has participated in advisory boards for Bristol Myers Squibb, Daiichi Sankyo, Jazz, PharmaEssentia, Rigel, Servier, Sobi, and Sumitomo; has received research grants from Bristol Myers Squibb; has consulted for Geron and Genentech; and has participated in speakers’ bureaux for PharmaEssentia, Rigel, Servier, and Sobi. Veronika Pozharskaya is an employee of Bristol Myers Squibb and holds stock in Bristol Myers Squibb and Merck. Shelonitda Rose has received travel support from Bristol Myers Squibb and holds stock in Bristol Myers Squibb/Celgene. Yinzhi Lai, Sameer Kalsekar, Barkha Aggarwal, and Karen Keeperman are employees of and hold stock in Bristol Myers Squibb. Dimana Miteva is an employee of Bristol Myers Squibb. David Valcárcel has consulted for Amgen, Astellas, Bristol Myers Squibb/Celgene, Janssen, Jazz, Merck Sharpe & Dohme, Novartis, Pfizer, Sanofi, Sobi, and Takeda; has received honoraria from Amgen, Astellas, Bristol Myers Squibb/Celgene, Janssen, Jazz, Merck Sharpe & Dohme, Novartis, Pfizer, Sanofi, Sobi, and Takeda; and has received meeting and travel support from AbbVie, Bristol Myers Squibb/Celgene, Jazz, Novartis, and Sobi. Pierre Fenaux has received research funding (as the GFM chairperson) from AbbVie, Astex, Bristol Myers Squibb, Novartis, and Servier; and has received honoraria from AbbVie and Bristol Myers Squibb. Jake Shortt has received research funding from Astex/Taiho; has consulted for Astellas, Bristol Myers Squibb, Novartis, Otsuka, and Pfizer; has received honoraria from Novartis and Mundipharma; and has participated on the ELEMENT trial steering committee for Bristol Myers Squibb (paid to institution). Matteo Giovanni Della Porta has received honoraria from and participated on a data safety monitoring or advisory board for Bristol Myers Squibb. Uwe Platzbecker has received grant support (paid to GWT-TUD) from Amgen and Janssen; has received lecture fees and grant support (paid to the University of Leipzig) from Amgen; has received grant support (paid to the University of Dresden) from Merck and Novartis; has consulted for AbbVie, Bristol Myers Squibb, Curis, Geron, and Novartis; has received honoraria from Bristol Myers Squibb; has received travel support from Bristol Myers Squibb; and is a member of the board of directors or an advisory board for the MDS Foundation. Guillermo Garcia-Manero has nothing to disclose. Ethical Approval: The trial was performed in accordance with the Declaration of Helsinki and International Counsel on Harmonisation guidelines and received review board approval from each participating site’s institutional review board/ethics committee. All patients provided written informed consent documentation prior to trial entry.

Figures

Fig. 1
Fig. 1
Long-term RBC-TI responses. EOT end of treatment, RBC-TI red blood cell transfusion-independent. © American Society of Hematology (2024). Reused with permission
Fig. 2
Fig. 2
Continuous RBC-TI ≥ 1.5 years across patient subgroups. Continuous response defined as patients achieving a single, uninterrupted period of RBC-TI for ≥ 1.5 years from week 1 to end of treatment. CI confidence interval, EPO erythropoietin, SF3B1 splicing factor 3B subunit 1, RBC red blood cell; RBC-TI red blood cell transfusion-independence, RS ring sideroblast. © American Society of Hematology (2024). Reused with permission
Fig. 3
Fig. 3
Patients with multiple consecutive RBC-TI periods. Multiple periods of RBC-TI ≥ 12 weeks for individual patients are shown in the plot interrupted by evaluation periods or RBC transfusion events. Continuous response defined as patients achieving a single, uninterrupted period of RBC-TI for ≥ 1.5 years from week 1 to end of treatment. RBC red blood cell, RBC-TI red blood cell transfusion-independence. © American Society of Hematology (2024). Reused with permission
Fig. 4
Fig. 4
Patients with ≥ 1 TEAE or suspected-related TEAE (A), ≥ 1 grade 3/4 TEAE or serious TEAE (B), ≥ 1 EOI of asthenia or hypertension (C) up to 1.5 years. aNo reported grade 3/4 TEAEs in weeks 25–36 in the epoetin alfa arm. bNo reported grade 3/4 TEAEs in weeks 37–48 in the epoetin alfa arm. cNo reported grade 3/4 TEAEs in weeks 61–84 in the epoetin alfa arm. dEOI of asthenia included fatigue, malaise, and lethargy. eEOI of hypertension included hypertension, essential hypertension, hypertensive urgency, labile hypertension, and hypertensive nephropathy. fNo reported EOIs of hypertension in weeks 61–72 in the epoetin alfa arm. gNo reported EOIs of hypertension in weeks 73–84 in either. EOI event of interest, TEAE treatment-emergent adverse event. © American Society of Hematology (2024). Reused with permission
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Braga Lemos M, Rodrigues SR, Schroeder T, Kulasekararaj AG, Matos JE, Tang D. Association between red blood cell transfusion dependence and burden in patients with myelodysplastic syndromes: a systematic literature review and meta-analysis. Eur J Haematol. 2021;107:3–23. - PubMed
    1. Hiwase DK, Singhal D, Strupp C, et al. Dynamic assessment of RBC-transfusion dependency improves the prognostic value of the revised-IPSS in MDS patients. Am J Hematol. 2017;92:508–14. - PubMed
    1. Balleari E, Filiberti RA, Salvetti C, et al. Effects of different doses of erythropoietin in patients with myelodysplastic syndromes: a propensity score-matched analysis. Cancer Med. 2019;8:7567–76. - PMC - PubMed
    1. Santini V, Schemenau J, Levis A, et al. Can the revised IPSS predict response to erythropoietic-stimulating agents in patients with classical IPSS low or intermediate-1 MDS? Blood. 2013;122:2286–8. - PubMed
    1. Park S, Hamel JF, Toma A, et al. Outcome of lower-risk patients with myelodysplastic syndromes without 5q deletion after failure of erythropoiesis-stimulating agents. J Clin Oncol. 2017;35:1591–7. - PubMed

MeSH terms

Associated data