Early initiation of luspatercept derives greater benefit in ESA-naive TD LR-MDS: Post-hoc analysis of the phase 3 COMMANDS trial

10 Apr 2026

STUDY DESIGN

The phase 3 COMMANDS trial demonstrated the superiority of luspatercept over epoetin alfa (EA) in erythropoiesis-stimulating agent (ESA)-naive patients with transfusion-dependent (TD) lower-risk myelodysplastic syndromes (LR-MDS).¹ Luspatercept achieved higher rates of red blood cell-transfusion independence (RBC-TI) and durable clinical benefit, supporting its use as the first-line treatment for anemia.¹ Patient characteristics such as higher hemoglobin (Hb) levels, lower transfusion burden (TB), and lower serum erythropoietin (sEPO) levels reflect less advanced disease and are associated with greater treatment responsiveness, guiding the identification of patients most likely to benefit from treatment.¹

In light of these findings, a post-hoc analysis of the COMMANDS trial was conducted to assess the impact of baseline disease severity on treatment outcomes with luspatercept compared with EA.¹ Eligible patients were aged ≥18 years, ESA-naive, red blood cell-TD, and had LR-MDS, defined as Revised International Prognostic Scoring System (IPSS-R) very low-, low-, or intermediate-risk disease according to World Health Organization (WHO) classification, with <5% bone marrow blasts and endogenous sEPO levels <500U/L.¹ Patients were randomized 1:1 to receive luspatercept (starting dose 1.0mg/kg, titrated up to 1.75mg/kg) administered subcutaneously every 3 weeks or EA (starting dose 450IU/kg, titrated up to 1,050IU/kg) administered subcutaneously weekly, and were followed until the end of treatment (EOT).¹

The post-hoc analysis evaluated achievement and duration of RBC-TI ≥12 weeks, and erythroid hematologic improvement (HI-E) from week 1 to EOT as main efficacy outcomes, stratified by baseline Hb (<8g/dL vs. ≥8g/dL), sEPO (≤100U/L vs. >200U/L), and TB (2U vs. ≥4U of packed red blood cells over 8 weeks).¹

FINDINGS

Efficacy:

The outcomes assessed were achievement and duration of RBC-TI ≥12 weeks, and HI-E from week 1 to EOT, stratified by:
- Baseline Hb¹
  - With luspatercept, patients with Hb ≥8g/dL achieved higher rates of RBC-TI ≥12 weeks than those with Hb <8g/dL (87.5% vs. 69.1%; odds ratio [OR]=3.10; 95% CI: 1.40-7.00), with a similar trend for EA
  - Median duration of RBC-TI ≥12 weeks was longer with luspatercept in patients with Hb ≥8g/dL vs. Hb <8g/dL (150.0 vs. 108.3 weeks; HR=0.62; 95% CI: 0.39-1.00); whereas durations were similar between Hb subgroups with EA
  - Among patients with Hb ≥8g/dL, luspatercept was associated with a 40% lower risk of RBC-TI failure vs. EA (HR=0.60; 95% CI: 0.36-1.00); no difference was observed in those with Hb <8g/dL (HR=1.04; 95% CI: 0.64-1.71)
  - In patients treated with luspatercept, the odds of achieving a HI-E response was higher in patients with Hb ≥8g/dL vs. Hb <8g/dL (83.3% vs. 78.2%; OR=1.40; 95% CI: 0.60-3.00), whereas HI-E responses were comparable between Hb subgroups with EA
- Baseline sEPO¹
  - Luspatercept achieved higher RBC-TI ≥12-week rates in patients with sEPO ≤100U/L compared with sEPO >200U/L (87.4% vs. 54.1%; OR=5.9; 95% CI: 2.5-14.0), with a similar trend observed with EA
  - Median RBC-TI duration favored sEPO ≤100U/L with luspatercept vs. sEPO >200U/L (143.3 vs. 48.3 weeks; HR=0.41; 95% CI: 0.22-0.75), with a comparable pattern seen with EA
  - Luspatercept reduced the risk of RBC-TI failure vs. EA across sEPO subgroups, with the greatest reduction in patients with sEPO >100 to ≤200U/L (HR=0.51; 95% CI: 0.25-1.07)
  - HI-E response rates were higher with luspatercept in patients with sEPO ≤100U/L vs. sEPO >200U/L (90.3% vs. 62.2%; OR=5.7; 95% CI: 2.20-14.1), with a similar trend for EA
- Baseline TB¹
  - Patients with lower TB achieved higher RBC-TI ≥12-week rates with luspatercept than those with higher TB (86.4% vs. 60.9%; OR=4.1; 95% CI: 1.80-9.20), with a similar trend observed with EA
  - Median duration of RBC-TI ≥12 weeks favored patients with lower TB vs. higher TB with luspatercept (120.9 vs. 110.0 weeks; HR=0.70; 95% CI: 0.41-1.18), with a comparable pattern seen in EA
  - Luspatercept reduced the risk of RBC-TI failure vs. EA across TB subgroups, with greater benefit in patients with lower TB (HR=0.80; 95% CI: 0.49-1.30)
  - HI-E response rates with luspatercept were higher in patients with lower TB compared with those with higher TB (87.7% vs. 73.4%; OR=2.6; 95% CI: 1.10-6.10), while EA responses were broadly comparable

‘Patients with less advanced disease, characterized by higher Hb, lower sEPO, and lower TB, achieved greater clinical benefit with luspatercept, supporting its early use in TD LR-MDS to maximize TI rates and duration.’

Professor Valeria Santini
University of Florence, Florence, Italy

References

Santini V, et al. Clinical benefit of luspatercept in erythropoiesis-stimulating agent (ESA)-naive patients with early disease characteristics and very low-, low-, or intermediate-risk myelodysplastic syndromes (LR-MDS): A post hoc analysis from the COMMANDS trial. Presented at the American Society of Hematology (ASH) Annual Meeting 2025; December 6-9, 2025.