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

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

Lancet · 2023356 patients randomised (178 luspatercept, 178 epoetin alfa); 301 patients in the interim efficacy analysis

Platzbecker U, Della Porta MG, Santini V, Zeidan AM, Komrokji RS, Shortt J, et al. Lancet. 2023. 402:373-385

A newer report of this study has been published: 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 (2024)

Study type: Clinical trial
Study name: COMMANDS
Phase: Phase 3
Design: Randomised (1:1, block size 4), open-label, active-controlled (epoetin alfa) trial at 142 centres in 26 countries; report of a prespecified interim analysis
Sample size: 356 patients randomised (178 luspatercept, 178 epoetin alfa); 301 patients in the interim efficacy analysis
Source: Lancet · 2023
Trial registration: NCT03682536

In plain words

Many patients with lower-risk MDS need frequent blood transfusions because of anaemia, and the usual first treatment for them is a drug that stimulates blood cell production, such as epoetin alfa. In this trial, the injectable drug luspatercept (once every 3 weeks, under the skin) was compared with epoetin alfa (once a week) in patients who had not had these drugs before. In this interim analysis, 59% of patients in the luspatercept group versus 31% in the epoetin alfa group did not need a transfusion for at least 12 weeks, and their haemoglobin also went up. Common side effects linked to luspatercept were tiredness, weakness, nausea, shortness of breath, high blood pressure and headache. Talk to your doctor about whether this treatment is right for you.

Key results

59% vs 31%

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

86 of 147 vs 48 of 154 patients; common risk difference in response rate 26.6 (95% CI 15.8–37.4); p<0.0001

42 vs 27 weeks

Median duration of exposure to treatment

Interquartile range 20–73 vs 19–55 weeks

301 of 356 randomised patients

Interim efficacy analysis population

147 luspatercept and 154 epoetin alfa; patients who had completed 24 weeks of treatment or discontinued earlier

6 events with luspatercept; none with epoetin alfa

Suspected treatment-related adverse events (in 3% of patients or more)

Fatigue, asthenia, nausea, dyspnoea, hypertension and headache; the most frequent in 5% of patients

1 patient

Death related to luspatercept

After a diagnosis of acute myeloid leukaemia (AML); after 44 days of treatment

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 subcutaneously once every 3 weeks; starting dose 1.0 mg per kg body weight, with possible stepwise escalation up to 1.75 mg/kg (abstract of the paper); for at least 24 weeks (abstract of the primary analysis, Lancet Haematol 2024).

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 subcutaneously once weekly; starting dose 450 IU per kg body weight, with possible stepwise escalation up to 1050 IU/kg (maximum total dose allowed 80,000 IU) (abstract of the paper); for at least 24 weeks (abstract of the primary 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 2023); minimum duration of 24 weeks from the abstract of the primary analysis (Lancet Haematol 2024); 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), who had not previously received erythropoiesis-stimulating agents (ESAs) and required red blood cell transfusions (2 to 6 units of packed red blood cells every 8 weeks for at least 8 weeks immediately before randomisation). Randomisation was stratified by baseline red blood cell transfusion burden (fewer than 4 versus 4 or more units per 8 weeks), serum endogenous erythropoietin concentration (200 U/L or less versus more than 200 to less than 500 U/L) and ring sideroblast status (positive versus negative). Median age 74 years (interquartile range 69 to 80); 56% men and 44% women.

According to the FDA label (section 14.2), patients with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (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.

Safety: in all patients who received at least one dose of study treatment. Other secondary endpoints are given in the full text of the paper.

Safety and side effects

The most common grade 3 or 4 treatment-emergent adverse events (in 3% of patients or more) with luspatercept: hypertension, anaemia, dyspnoea, neutropenia, thrombocytopenia, pneumonia, COVID-19, myelodysplastic syndrome and syncope; and with epoetin alfa: anaemia, pneumonia, neutropenia, hypertension, iron overload, COVID-19 pneumonia and myelodysplastic syndrome (the frequency of each event is not given in the abstract of the interim analysis). The most common suspected treatment-related adverse events in the luspatercept group (in 3% of patients or more; the most frequent in 5%) were fatigue, asthenia (weakness), nausea, dyspnoea, hypertension and headache; in the epoetin alfa group no suspected treatment-related adverse event occurred in 3% of patients or more. One death after a diagnosis of acute myeloid leukaemia (AML) was considered related to luspatercept (after 44 days of treatment).

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

This prespecified interim analysis showed that in ESA-naive, transfusion-dependent patients with lower-risk MDS, luspatercept compared with epoetin alfa (the standard treatment of anaemia in most of these patients) nearly doubled the proportion of patients achieving transfusion independence with a haemoglobin increase (59% versus 31%). According to the FDA label for luspatercept (REBLOZYL, section 14.2), the efficacy of this drug in anaemia in ESA-naive adults with MDS was established at the time of this COMMANDS interim analysis; the corresponding indication in the label (section 1.2): treatment of anaemia without previous ESA use in adults with very low-‎ to intermediate-risk MDS who may require regular red blood cell transfusions. The primary analysis with 363 patients confirmed these findings (60% versus 35%; card "COMMANDS (primary analysis)").

Limitations

This report is an interim analysis, and efficacy was assessed in only 301 of the 356 randomised patients (those who had completed 24 weeks of treatment or discontinued earlier). The trial was open-label. Median duration of exposure to treatment was longer in the luspatercept group (42 versus 27 weeks). According to the authors, longer follow-up and more data are needed to confirm the results and refine the findings in subgroups such as patients without SF3B1 mutations or without ring sideroblasts. 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.