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, 37.9% remained transfusion-free for 8 weeks or longer, compared with 13.2% treated with placebo, according to Alan List, MD, of Moffitt Cancer Center, Tampa, who presented the findings at the Plenary Session during the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition.¹

Erythroid responses were durable [with luspatercept], with approximately 40% of patients achieving red blood cell transfusion independence sustained after 12 months of treatment.

— Alan List, MD

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“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.”

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.”

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, he said.

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, both 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 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 weeks—was achieved by 37.9% of the luspatercept arm and 13.2% of the placebo arm (odds ratio [OR] = 5.1; P < .0001), reported Dr. List, who is a senior member of the Department of Malignant Hematology and the Experimental Therapeutics Program at Moffitt as well as President and Chief Executive Officer. 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 = 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 units per every 8 weeks in 48.6% and 14.3%, respectively, and a hemoglobin increase ≥ 1.5 g/dL in 63% and 5.0%, respectively (P < .0001). The median peak hemoglobin increase in luspatercept responders was 2.55 g/dL, Dr. List reported.

Treatment-emergent adverse events were balanced between the arms, including grade ≥ 3 adverse events, which were seen in 42.5% treated with luspatercept and 44.7% treated with placebo. Approximately 8% of 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 appeared consistent with that reported for the drug in the dose-finding phase II PACE-MDS study.²

The phase III COMMANDS trial (ClinicalTrials.gov identifier NCT03682536) is now evaluating luspatercept vs erythropoietin-stimulating agents as a first-line treatment of patients with lower-risk MDS. 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 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 is a consultant/advisor for, has received honoraria and research funding from, has patent or intellectual property interest in, and has received travel/accommodations/expenses from Celgene.

REFERENCES

1. Fenaux P, et al: The MEDALIST trial. 2018 ASH Annual Meeting & Exposition. Abstract 1. Presented December 2, 2018.

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