Luspatercept outperforms epoetin alfa in transfusion-dependent, lower-risk myelodysplastic syndromes

The final analysis of the phase III COMMANDS study confirms that treatment with luspatercept compared to epoetin alfa results in a superior duration of red blood cell transfusion independence  and erythroid response in erythropoiesis-stimulating agents (ESA)-naïve patients with transfusion-dependent lower-risk myelodysplastic syndromes (MDS). Safety results were consistent with previous MDS studies, and progression to acute myeloid leukaemia and total deaths were similar between both study arms.

Despite the fact that erythropoiesis-stimulating agents (ESAs) are an established treatment option for patients with transfusion-dependent lower-risk myelodysplastic syndromes (LR-MDS) and endogenous serum erythropoietin (sEPO) levels ≤ 500 U/L, patients often do not respond or only have a short response duration. Luspatercept is an erythroid maturing agent that stimulates erythropoiesis and is EMA-approved to treat anaemia due to LR-MDS, after the failure of ESA.  The COMMANDS study investigated the efficacy and safety of luspatercept in patients who had not previously been treated with erythropoietic growth factor. The preplanned interim analysis of the phase III COMMANDS trial, comparing luspatercept with epoetin alfa in ESA-naive transfusion-dependent (TD) patients with anaemia 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. At ASH 2023, the full efficacy and safety analyses of the COMMANDS trial were presented.

Study design

COMMANDS is an international, randomised, open-label, phase III study. Adult patients with anaemia due to MDS and a very low, low or intermediate risk score according to the International Prognostic Scoring System Revised (IPSS-R) were randomised (1:1) to treatment with luspatercept (1.0-1.75 mg/kg subcutaneously [SC] every 3 weeks) or epoetin alfa (450-1,050 IU/kg SC every week) for at least 24 weeks. Only patients who were ESA-naive, transfusion dependent (defined as 2-6 units of red blood cell units per 8 weeks for ≥8 weeks) and had a bone marrow blast percentage <5% and a sEPO <500 mU/ ml were eligible to participate. The primary endpoint was the percentage of patients with RBC-TI for at least 12 weeks with a concurrent mean haemoglobin (Hb) increase of ≥1.5 g/dl (week 1-24). Key secondary endpoints were the percentage of patients with a haematologic improvement-erythroid (HI-E) response for at least 12 weeks, and the achievement of RBC-TI ≥12 weeks and for 24 weeks.

Results

In total, 363 patients were randomised to treatment with luspatercept (N= 182) or epoetin alfa (N= 181). Median age of the patients was 74.0 years, 44.6% were female, 72.5% had ring sideroblasts and 59.2% had an SF3B1 mutation. The median treatment duration was 51.3 weeks with luspatercept and 37.0 weeks with epoetin alfa. The median follow-up was 17.2 months and 16.9 months, respectively.

The primary endpoint was achieved by 110 patients (60.4%) in the luspatercept arm versus 63 patients (34.8%) in the epoetin alfa arm (p< 0.0001). Subgroup analyses revealed that treatment with luspatercept led to higher response rates, regardless of SF3B1 mutation status, baseline sEPO, or transfusion burden. In the group of patients with ring sideroblasts, treatment with luspatercept also resulted in a higher response rate in the luspatercept group (65.4% vs. 29.2%), while in the group of patients without ring sideroblasts, response rates were comparable between the treatment groups (46.9% vs. 50.0%). Patients in the luspatercept arm were more likely to achieve HI-E for ≥ 8 weeks (74.2% vs. 53.0%; p< 0.0001), RBC-TI for ≥12 weeks (68.1% vs. 48.6%; p< 0.0001) and RBC-TI for 24 weeks (47.8% vs. 30.9%; p= 0.0003). The median duration of RBC-TI ≥ 12 weeks was longer with luspatercept vs. epoetin alfa (126.6 vs. 89.7 weeks; HR[95%CI]: 0.59[0.38-0.90]), regardless of SF3B1 mutation status, sEPO, transfusion burden or presence of ring sideroblasts.

Five patients (2.7%) in the luspatercept group and 6 patients (3.3%) in the epoetin alfa group progressed to AML. One or more treatment-emergent adverse events (TEAEs) were reported in 178 patients (97.8%) treated with luspatercept and in 165 patients (92.2%) receiving epoetin alfa; 107 (58.8%) and 88 (49.2%) patients reported grade 3 or 4 TEAEs, respectively. The most common any-grade TEAEs were: diarrhoea (17.6% vs. 14.0%), COVID-19 (14.8% vs. 15.6%), asthenia (13.7% vs. 16.2%) and anaemia (12.1% vs. 10.6%). Mortality rates during treatment (8.2% vs. 7.8%) and after treatment (13.2% vs. 13.4%) were comparable between treatment groups.

Conclusion

The final analysis of the COMMANDS study shows that treatment with luspatercept compared to epoetin alfa leads to a superior duration of RBC-TI and erythroid response in ESA-naïve patients with transfusion-dependent LR-MDS. These findings are consistent with the results of the interim analysis. No new safety signals were observed.

Reference

Garcia-Manero G, et al. Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent (ESA)-naive patients (Pts) with transfusion-dependent (TD) lower-risk myelodysplastic syndromes (LR-MDS): full analysis of the COMMANDS trial. Presented at ASH 2023; Abstract 193.