Clinical trialPhase 3Blood cancers (leukaemia, lymphoma and myeloma)Leukaemia

Luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): primary analysis of a phase 3, open-label, randomised, controlled trial

Lancet Haematol · 2024363 patients (182 luspatercept, 181 epoetin alfa)

Della Porta MG, Garcia-Manero G, Santini V, Zeidan AM, Komrokji RS, Shortt J, et al. Lancet Haematol. 2024. 11:e646-e658

Study type: Clinical trial
Study name: COMMANDS
Phase: Phase 3
Design: Randomised (1:1), open-label, active-controlled (epoetin alfa) trial at 142 centres in 26 countries; report of the primary analysis
Sample size: 363 patients (182 luspatercept, 181 epoetin alfa)
Source: Lancet Haematol · 2024
Trial registration: NCT03682536

In plain words

This report is the main, more complete analysis of the COMMANDS trial, which compared luspatercept (an injection under the skin every 3 weeks) with epoetin alfa (a weekly injection) in 363 patients with lower-risk MDS who depended on blood transfusions and had not had drugs that stimulate blood cell production before. 60% of patients in the luspatercept group versus 35% in the epoetin alfa group went at least 12 weeks without a transfusion and their haemoglobin also went up, and this benefit was seen in different groups of patients. The most common serious side effects with luspatercept were high blood pressure and anaemia (each in 10% of patients). Your doctor can tell you whether this treatment is right for you.

Key results

60% vs 35%

Primary endpoint: red blood cell transfusion independence ≥12 weeks with a mean haemoglobin increase ≥1.5 g/dL (weeks 1 to 24)

110 vs 63 patients (intention-to-treat population: 182 and 181); common risk difference in response rate 25.4% (95% CI 15.8–35.0); p<0.0001

17.2 vs 16.9 months

Median follow-up for the primary endpoint

10.4–27.7 vs 10.1–26.6 months; median safety follow-up 21.4 vs 20.3 months

10% vs 4%

Grade 3–4 hypertension

19 of 182 vs 8 of 179 patients

10% vs 8%

Grade 3–4 anaemia

18 vs 14 patients

5% vs 8%

Grade 3–4 pneumonia

10 vs 14 patients

5% vs 6%

Grade 3–4 neutropenia

9 vs 11 patients

3% vs 6%

Myelodysplastic syndrome reported as a grade 3–4 adverse event

6 vs 10 patients

5% (10 patients)

Grade 3–4 syncope with luspatercept

Not reported in the list of common adverse events in the epoetin alfa group

5% vs 7%

Serious pneumonia

9 vs 13 patients; the most common serious adverse event in both groups

4% vs 6%

Serious COVID-19

8 vs 10 patients

Dose and schedule cards

Epoetin alfa

Lower-risk MDS with haemoglobin ≤10 g/dL and low or moderate transfusion need; response more likely with serum EPO ≤500 U/LCycle length: WeeklyOn the page “Myelodysplastic syndrome (MDS): the 2022 classifications, IPSS-R and IPSS-M, and risk-adapted treatment” · Anaemia treatment and iron chelation in lower-risk MDS

Lower-risk MDS with haemoglobin ≤10 g/dL and low or moderate transfusion need; response more likely with serum EPO ≤500 U/L

Drug	Dose	Route	Schedule
Epoetin alfa	450 U/kg once a week (in COMMANDS escalated up to 1050 U/kg; maximum total 80,000 U)	Subcutaneous	Weekly

Cycle length: Weekly
Duration: Assess response by week 24; continue in responders

In EPOANE the dose was increased or reduced according to the weekly haemoglobin and was reduced or stopped at a haemoglobin above 12 g/dL; the dose and the escalation ceiling are from COMMANDS. ESA boxed warning: the lowest effective dose. The response prediction model was built with erythropoietin combined with G-CSF.

On the page “Myelodysplastic syndrome (MDS): the 2022 classifications, IPSS-R and IPSS-M, and risk-adapted treatment” · Anaemia treatment and iron chelation in lower-risk MDS

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Luspatercept

Luspatercept 1.0 to 1.75 mg per kg body weight, subcutaneously, once every 3 weeks, for at least 24 weeks (abstract of the paper); the starting dose was 1.0 mg/kg (abstract of the interim analysis, Lancet 2023).

Protocol details (FDA label, section 14.2): two dose-escalation steps were allowed (to 1.33 and then 1.75 mg/kg). The dose was interrupted and then reduced for adverse events, reduced if haemoglobin rose by 2 g/dL or more compared with the previous cycle, and interrupted if pre-dose haemoglobin was 12 g/dL or more. All patients received best supportive care, including red blood cell transfusions as needed. Treatment was given for 24 weeks and efficacy was assessed at that time; continuing treatment beyond 24 weeks was optional, based on response to treatment and absence of disease progression.

Current FDA label dosing for ESA-naive MDS (section 2.2, Table 3): start with 1 mg/kg subcutaneously every 3 weeks. If, after at least 2 consecutive doses (6 weeks) at one dose level, the patient has not become red blood cell transfusion-free or has haemoglobin below 10 g/dL with an increase of less than 1 g/dL compared with the previous dose, the dose is increased to 1.33 and then 1.75 mg/kg every 3 weeks; the dose should not be increased more often than every 6 weeks (2 doses) or beyond the maximum of 1.75 mg/kg. The dose is adjusted to keep haemoglobin within the target range of 10 to 12 g/dL; if pre-dose haemoglobin without transfusion is 12 g/dL or more, treatment is interrupted and resumed at the same dose when haemoglobin reaches 11 g/dL or less. If haemoglobin rises by more than 2 g/dL within 3 weeks without transfusion, the dose is reduced by one level (1.75 to 1.33, 1.33 to 1, 1 to 0.8 and 0.8 to 0.6 mg/kg; at the 0.6 dose, treatment is stopped). If there is no reduction in transfusion burden (including no haemoglobin increase from baseline) after at least 3 consecutive doses (9 weeks) at 1.75 mg/kg, treatment is stopped.

2Epoetin alfa (comparator group)

Epoetin alfa 450 to 1050 IU per kg body weight, subcutaneously, once weekly (maximum total dose 80,000 IU), for at least 24 weeks (abstract of the paper); the starting dose was 450 IU/kg (abstract of the interim analysis). All patients received best supportive care, including red blood cell transfusions as needed (FDA label, section 14.2).

Source of the regimen details: Abstract of the paper (Lancet Haematol 2024); starting doses from the abstract of the interim analysis (Lancet 2023); protocol details and current dosing from the FDA label for luspatercept (REBLOZYL, DailyMed; sections 14.2 and 2.2)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults aged 18 years and older with very low-‎, low-‎ or intermediate-risk myelodysplastic syndromes (MDS) according to the Revised International Prognostic Scoring System (IPSS-R), with no previous erythropoiesis-stimulating agent (ESA) use, transfusion-dependent and with a serum erythropoietin concentration below 500 U/L. Randomisation was stratified by baseline red blood cell transfusion burden, serum erythropoietin concentration and ring sideroblast status. Median age 74 years (interquartile range 69 to 80); 45% women and 55% men; 80% White, 12% Asian and 1% Black or African American.

According to the abstract of the interim analysis, the transfusion-dependence criterion was 2 to 6 units of packed red blood cells every 8 weeks (for at least 8 weeks immediately before randomisation); according to the FDA label (section 14.2), patients with MDS/MPN-RS-T were also eligible.

Endpoints

Primary endpoint: 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 to 24), in the intention-to-treat population.

Other outcomes: haematological improvement, subgroup results and safety (in all patients who received at least one dose of treatment); exact definitions of the secondary endpoints are given in the full text of the paper.

Safety and side effects

Median safety follow-up was 21.4 months (interquartile range 14.2–32.4) in the luspatercept group and 20.3 months (12.7–30.9) in the epoetin alfa group. Common grade 3–4 treatment-emergent adverse events with luspatercept (182 patients): hypertension (10%), anaemia (10%), pneumonia (5%), syncope (5%), neutropenia (5%), thrombocytopenia (4%), dyspnoea (4%) and myelodysplastic syndrome (3%); with epoetin alfa (179 patients): anaemia (8%), pneumonia (8%), neutropenia (6%), myelodysplastic syndrome (6%), hypertension (4%), iron overload (4%) and COVID-19 pneumonia (3%). The most common serious adverse events in both groups were pneumonia (5% versus 7%) and COVID-19 (4% versus 6%). One death (from acute myeloid leukaemia) related to luspatercept had been reported in the interim analysis.

According to the FDA label, blood pressure should be checked before each luspatercept dose, and new or worsening hypertension treated with antihypertensive drugs (section 5.2). Luspatercept may cause fetal harm; women of reproductive potential should be informed of this risk and use effective contraception (section 5.4).

Clinical significance and place in guidelines

Based on this primary analysis, the authors concluded that luspatercept is a new standard of care for ESA-naive, transfusion-dependent patients with lower-risk MDS: significantly more patients achieved red blood cell transfusion independence and haematological improvement with luspatercept, and this benefit was seen across different patient subgroups. These results were consistent with the findings of the interim analysis (59% versus 31%). The FDA label for luspatercept (REBLOZYL, section 1.2) covers the treatment of anaemia without previous ESA use in adults with very low-‎ to intermediate-risk MDS who may require regular red blood cell transfusions, and describes the COMMANDS trial in the Clinical Studies section (section 14.2).

Limitations

The trial was open-label. Most patients were White (80%; 12% Asian and 1% Black), which may limit the generalisability of the results. The study population was limited to ESA-naive patients with serum erythropoietin below 500 U/L. The abstract reports no data on overall survival or leukaemic transformation. According to the FDA label, more than 90% of participants were outside the United States and, for them, a non-US-licensed epoetin alfa product was used in the control group; a direct comparison of luspatercept with a US-licensed epoetin alfa product has not been established.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.