A planned interim analysis of the phase III, open-label, randomised COMMANDS study shows greater efficacy with use of luspatercept than with epoetin alfa for the treatment of anaemia in erythropoiesis-stimulating agents (ESA)-naive patients with lower-risk myelodysplastic syndromes (MDS) who require red blood cell (RBC) transfusions. Additionally, treatment with luspatercept was associated with clinically meaningful and statistically significant improvements in RBC transfusion independence and its durability, erythroid response, and reduction of transfusion burden, compared with epoetin alfa treatment.

This study is the first to show improved benefit with innovative therapy, luspatercept over an established standard-of-care treatment for lower-risk MDS-associated anaemia. The results are published on 10 June 2023 in The Lancet by Prof. Uwe Platzbecker of the Medical Clinic and Policlinic 1, Hematology and Cellular Therapy, University Hospital Leipzig in Leipzig, Germany, and study colleagues, including Prof. Guillermo Garcia-Manero of the Department of Leukemia, University of Texas M.D. Anderson Cancer Center in Houston, TX, US, who presented the findings at 2023 ASCO Annual Meeting on 2 June in Chicago, IL, US.

MDS are a heterogeneous group of haematopoietic stem cell disorders characterised by ineffective haematopoiesis, blood cytopenias (predominantly anaemia), and the potential to progress to acute myeloid leukaemia (AML). Among patients with lower-risk MDS, defined as disease of very low risk, low risk, or intermediate risk per the 2012 Revised International Prognostic Scoring System (IPSS-R), the main goals of therapy are the treatment of anaemia and improvement of quality-of-life (QoL). Treatment of chronic anaemia due to lower-risk MDS often necessitates regular RBC transfusions, which are associated with increased morbidities, iron overload, and reduced overall survival. ESAs such as epoetin alfa are the standard-of-care treatment for patients with lower-risk MDS, but responses are limited and transient.

Luspatercept is indicated for the treatment of anaemia after failure of ESA treatment in adults with lower-risk MDS per the IPSS-R with ring sideroblasts, or with a myelodysplastic or myeloproliferative neoplasm with ring sideroblasts and thrombocytosis, in cases requiring at least 2 RBC units per 8 weeks. In the double-blind, placebo-controlled, phase III MEDALIST study, luspatercept reduced the severity of anaemia in transfusion-dependent patients with lower-risk MDS with ring sideroblasts who were refractory to or unlikely to respond to ESAs, or who had discontinued ESA treatment previously because of an adverse event. The authors wrote in the background that to date, no study has compared the efficacy and safety of luspatercept versus ESAs for the treatment of anaemia in ESA-naive patients with lower-risk MDS.

The phase III, open-label, randomised controlled COMMANDS study is conducted at 142 sites in 26 countries. Eligible patients were aged 18 years or older, had a diagnosis of MDS of very low risk, low risk, or intermediate risk per the IPSS-R, were ESA-naive, and required RBC transfusions, 2-6 packed RBC units per 8 weeks for ≥ 8 weeks immediately before randomisation. Patients were randomly assigned 1:1 to luspatercept or epoetin alfa, stratified by baseline RBC transfusion burden (< 4 units per 8 weeks versus ≥ 4 units per 8 weeks), endogenous serum erythropoietin concentration (≤ 200 U/L versus >200 to < 500 U/L), and ring sideroblast status (positive versus negative).

Luspatercept was administered subcutaneously once every 3 weeks starting at 1.0 mg/kg body weight with possible titration up to 1.75 mg/kg. Epoetin alfa was administered subcutaneously once a week starting at 450 IU/kg body weight with possible titration up to 1050 IU/kg with maximum permitted total dose of 80 000 IU. The primary endpoint was RBC transfusion independence for at least 12 weeks with a concurrent mean haemoglobin increase of at least 1.5 g/dL (weeks 1-24), assessed in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. The COMMANDS study is currently active, but not recruiting. The study investigators reported data from a prespecified interim analysis.

Between 2 January 2019 and 31 August 2022, 356 patients were randomised of whom 178 patients to receive luspatercept and 178 patients to receive epoetin alfa. There were 198 men (56%) and 158 women (44%); median age was 74 years. The interim efficacy analysis was done for 301 patients, 147 in the luspatercept group and 154 in the epoetin alfa group, who completed 24 weeks of treatment or discontinued earlier.

A total, 86 of 147 patients (59%) in the luspatercept group and 48 of 154 patients (31%) in the epoetin alfa group reached the primary endpoint with common risk difference on response rate 26.6 (95% confidence interval 15.8–37.4; p < 0.0001). Median treatment exposure was longer for patients receiving luspatercept versus epoetin alfa (42 weeks versus 27 weeks).

The most frequently reported grade 3 or 4 treatment-emergent adverse events (TRAEs) with luspatercept (≥ 3% patients) were hypertension, anaemia, dyspnoea, neutropenia, thrombocytopenia, pneumonia, COVID-19, MDS, and syncope; and with epoetin alfa anaemia, pneumonia, neutropenia, hypertension, iron overload, COVID-19 pneumonia, and MDS. The most common suspected TRAEs in the luspatercept group (≥3 % patients, with the most common event occurring in 5% patients) were fatigue, asthenia, nausea, dyspnoea, hypertension, and headache; and none (≥ 3% patients) in the epoetin alfa group. One death after diagnosis of AML was considered as related to luspatercept treatment in a case of 44 days on treatment.

The findings from this interim analysis suggest that luspatercept might change the current treatment landscape, and reduce patient reliance on RBC transfusions, and decrease transfusion-related morbidities. Nevertheless, further testing of long-term data and assessments of other subgroups of patients with lower-risk MDS, including non-mutated SF3B1 or ring sideroblast-negative subgroups, will be needed to refine and validate the present findings.

Luspatercept is currently approved for the treatment of anaemia in adult patients with lower-risk MDS with ring sideroblasts who require RBC after failure of ESA treatment. The higher response rates observed with luspatercept compared with epoetin alfa in ESA-naive patients in this interim analysis suggest that altering the therapeutic approach and treating patients with luspatercept earlier in the disease course might be beneficial. However, further longer-term studies are needed to fully understand the consequences of such a treatment approach. Additionally, evaluation of patient-reported QoL and pharmaco-economic data from COMMANDS will help in understanding the full potential of luspatercept and how it can affect future clinical decision making. 

In an accompanied comment, Hetty E Carraway of the Leukemia Program, Taussig Cancer Institute, Cleveland Clinic and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in Cleveland, OH, US wrote that it is desirable to have alternative upfront effective therapies to treat transfusion-dependent patients. However, some questions remain, among which if it will be needed to identify the patients for whom upfront luspatercept versus ESA will be most beneficial and if so, by serum erythropoietin concentration, SF3B1 mutation status, ring sideroblast status, or other factors. Furthermore, for patients who do not have a clinical response to luspatercept in an upfront setting, should ESA be administered, and what is the likelihood of response. She also commented that African Americans comprised only 1% of the study cohort and questioned if the results will be applicable to them and other patients who might be under-represented in this study.  

The study was supported by Celgene, a Bristol-Myers Squibb Company, in collaboration with Acceleron Pharma, a subsidiary of Merck & Co (Rahway, NJ, USA).

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