Luspatercept May Reduce the Need for Transfusion in Lower-Risk Myelodysplastic Syndromes

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IN THE RANDOMIZED, double-blind, phase III MEDALIST trial, the experimental drug luspatercept significantly reduced the need for frequent red blood cell transfusions in patients with lower-risk myelodysplastic syndromes (MDS) and ring sideroblasts. With luspatercept, 37.8% of patients remained transfusion-free for 8 weeks or longer, compared with 13.2% of patients who received a placebo, reported Alan List, MD. Dr. List presented the data during the Plenary Session at the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition.1

Alan List, MD

Alan List, MD

Luspatercept is an investigational first-in-class erythroid maturation agent that neutralizes select transforming growth factor-ß (TGF- ß) superfamily ligands to inhibit aberrant Smad2/3 signaling and enhance late-stage erythropoiesis in MDS models.

Dr. List is a senior member of the Department of Malignant Hematology and the Experimental Therapeutics Program at Moffitt Cancer Center in Tampa, as well as President and Chief Executive Officer. “In lower-risk, ring sideroblast–positive MDS, treatment with luspatercept resulted in a significantly higher percentage of patients who achieved red blood cell transfusion independence, a major reduction in red blood cell transfusion, or hemoglobin increases, compared with placebo,” Dr. List said. “Erythroid responses were durable, with approximately 40% of patients achieving red blood cell transfusion independence sustained after 12 months of treatment,” he added.

Dr. List described the need for an effective agent in this population. “In lower-risk MDS, anemia is the most common symptomatic cytopenia that we deal with. For most of these patients, over time, the disease becomes transfusion- dependent. With that come the complications of iron loading.”

“The primary endpoint—red blood cell transfusion independence for 8 or more weeks—was achieved by 37.9% of patients in the luspatercept arm and 13.2% of those in the placebo arm.”
— Alan List, MD

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Study Details

THE 65-CENTER international trial included 229 patients with very low–risk, low-risk, or intermediate- risk MDS by the Revised International Prognostic Scoring System with either ≥ 15% ring sideroblasts or ≥ 5% ring sideroblasts with an SF3B1 mutation; bone marrow blasts < 5%; and requirement of ≥ 2 units of red blood cells every 2 months. All patients had either failed to respond to erythropoiesis-stimulating agents or had a serum erythropoietin level > 200 U/L so were unlikely to respond to erythropoiesis- stimulating agents and had received no prior treatment with disease-modifying agents. The median time since diagnosis of MDS was 42 months.

Patients were randomly assigned 2:1 to receive luspatercept or placebo, and  both were administered subcutaneously every 3 weeks for at least 6 months. Luspatercept was started at 1 mg/kg, with titration up to 1.75 mg/ kg if needed. More than half of the patients ultimately received the higher dose. At data cutoff, 54% of the luspatercept arm had discontinued treatment, as had 92% of the placebo arm.

Improvement in Multiple Parameters

THE PRIMARY ENDPOINT—red blood cell transfusion independence for 8 or more weeks—was achieved by 37.9% of patients in the luspatercept arm and 13.2% of those in the placebo arm (odds ratio [OR] = 5.1; P < .0001), Dr. List reported. The median duration of response to luspatercept was 30.6 weeks, vs 13.6 weeks with placebo.

Other secondary endpoints were also met: 28.1% of the luspatercept arm vs 7.9% of the placebo arm achieved red blood cell transfusion independence for 12 weeks or more (odds ratio = 5.1; P = .0002), and 52.9% and 11.8%, respectively, achieved a modified hematologic improvement/erythroid response by week 24 (P < .0001). This included a reduction of 4 or more units of red blood cells per every 8 weeks in 48.6% and 14.3%, respectively, and a hemoglobin increase 1.5 g/dL or greater in 63% and 5.0%, respectively (P < .0001). The median peak hemoglobin increase in patients who responded to luspatercept was 2.55 g/dL, Dr. List reported.

ASH 2018: Outside the 59th Annual Meeting. Photo by © ASH/Scott Morgan 2018

Treatment-emergent adverse events were balanced between the arms, including grade 3 or greater adverse events, which were seen in 42.5% of patients treated with luspatercept and 44.7% treated with placebo. Approximately 8% of patients in each arm discontinued treatment because of toxicity. Progression to acute myeloid leukemia occurred in 2.0% and 1.3%, respectively. The safety profile of luspatercept was consistent with that reported for the drug in the dose-finding phase II PACE-MDS study.2

The phase III COMMANDS trial ( identifier NCT03682536) is now evaluating luspatercept vs erythropoietin-stimulating agents as a first-line treatment of patients with lower-risk MDS (not just those with ring sideroblasts). In a press briefing, Dr. List predicted that outcomes with luspatercept will be better than those achieved with erythropoietin-stimulating agents.

“Two factors predict for response to erythropoietin-stimulating agents: very low transfusion burden or absence of transfusion requirement and a serum erythropoietin level that is ‘inappropriately’ low,” he said. “Luspatercept worked in the current trial regardless of serum erythropoietin level, and all patients were transfusion-dependent. Since it worked in those patients, my expectation is that luspatercept will probably be more effective than erythropoietin-stimulating agents.”

DISCLOSURE: Dr. List has received research funding from Celgene.


1. Fenaux P, Platzbecker U, Mufti GJ, et al: The MEDALIST trial: Results of a phase 3, randomized, double-blind, placebo-controlled study of luspatercept to treat anemia in patients with very low-, low-, or intermediate-risk myelodysplastic syndromes with ring sideroblasts who require red blood cell transfusions. 2018 ASH Annual Meeting & Exposition. Abstract 1. Presented December 2, 2018.

2. Platzbecker U, Germing U, Götze KS, et al: Luspatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS). Lancet Oncol 18:1338-1347, 2017.