Luspatercept Induces High Response With Tolerable Safety in Low-Risk MDS


In the MEDALIST analysis that was presented at the 2021 ASH Annual Meeting, investigators sought to further characterize the effects of luspatercept in patients with low-risk myelodysplastic syndrome.

Uwe Platzbecker, MD

Uwe Platzbecker, MD

An analysis of the MEDALIST study (NCT02631070) showed more durable response with luspatercept-aamt (Reblozyl) treatment compared with placebo in patients with lower-risk myelodysplastic syndrome (LR-MDS) and anemia that is refractory to or ineligible for erythropoiesis-stimulating agent (ESA) therapy, findings presented during the ASH Annual Meeting 2021 demonstrate.1

Data showed that luspatercept also had a more tolerable safety profile when adjusted for exposure. Prior to this, there was a higher proportion of patients on luspatercept vs placebo who experienced fatigue at 30.1% vs 14.5%, respectively. Following exposure adjustment, these rates were more balanced at 26.2 vs 27.1 events per 100 patient-years, respectively.

Additionally, a small number of patients progressed to higher-risk MDS or acute myeloid leukemia (AML), the incidence of which proved to be comparable between the arms. However, those on luspatercept had a longer median time of progression to AML vs those on the placebo arm.

“Up through week 48, patients randomized to luspatercept in the MEDALIST study remained on treatment longer and had more durable and repeated episodes of red blood cell–transfusion independence [RBC-TI] response events than patients on placebo,” Uwe Platzbecker, MD, director of the medical clinic, University Hospital Leipzig, said in a virtual poster presentation on the data.

Patients with LR-MDS who are refractory or ineligible for treatment with ESAs have limited therapeutic options for anemia, Platzbecker noted. Luspatercept, a first-in-class erythroid maturation agent that enhances late-stage erythropoiesis, has FDA and European Medicines Agency indications for the treatment of patients with LR-MDS.

Specifically, the FDA approved luspatercept in April 2020 for the treatment of anemia failing an ESA and requiring 2 or more red blood cell (RBC) units over 8 weeks in adult patients with very low- to intermediate-risk MDS with ring sideroblasts (MDS-RS) or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis.2

The regulatory decision is based on overall findings from the phase 3 MEDALIST trial, which showed that luspatercept significantly reduced transfusion burden compared with placebo in patients with LR-MDS.3

In the MEDALIST analysis that was presented at the 2021 ASH Annual Meeting, investigators sought to further characterize the effects of luspatercept in this patient population, including duration of treatment and response, median number of study treatment doses received, duration of RBC-TI responses, number of responses per patient, exposure-adjusted rates of treatment-emergent adverse effects (TEAEs), and time to progression to AML.

In MEDALIST, patients had the following: MDS-RS, which comprised at least 15% ring sideroblasts or at least 5% with a SF3B1 mutation, with less than 5% blasts in bone marrow and without del(5q); Revised International Prognostic Scoring System very low-, low-, or intermediate-risk MDS; RBC transfusion dependence (mean ≥2 units per 8 weeks). Moreover, patients must have been either refractory or intolerant to ESAs or be ESA naïve and unlikely to respond to these agents. Patients could not have received prior treatment with disease-modifying agents.

Participants were randomized 2:1 to receive luspatercept at 1.0 mg/kg subcutaneously every 21 days (n = 153) or placebo every 3 weeks (n = 76). On the luspatercept arm, doses were titrated up to a maximum of 1.75 mg/kg. Crossover between the 2 groups was not permitted.

Disease and response assessments were done at week 25 and again every 6 months. Patients were followed for at least 3 years after the final dose for AML progression, subsequent MDS treatment, and overall survival.

As of November 26, 2020, the median duration of treatment was 50.9 weeks (range, 6-207) in the luspatercept arm vs 24.0 weeks (range, 7-103) in the placebo arm; the median doses of study treatment were 17 (range, 2-66) and 8 (range, 3-34), respectively. Moreover, the highest dose level received was 1.75 mg/kg in 68.6% of luspatercept-treated patients and 84.2% in placebo-treated patients.

Duration of response (DOR) was longer with luspatercept than placebo. In patients who achieved RBC-TI for 8 weeks or longer in weeks 1 to 24, the median DOR was 30.2 weeks (range, 8.1-201.1) and 13.6 weeks (range, 9.1-66.4) in patients on luspatercept vs placebo, respectively. In those who achieved RBC-TI for 8 weeks or more in weeks 1 to 48, the median DOR was 29.9 weeks (range, 8.1-201.1) and 17.4 weeks (range, 9.1-66.4), respectively.

Investigators also evaluated the number of responses occurring in responders during the entire treatment period. In the luspatercept responders (n = 58), patients either had 1 (20.7%), 2 (29.3%), 3 (22.4%), or 4 or more responses (27.6%). In the placebo responders (n = 10), 6 patients had 1 response (60.0%), 3 had 2 responses (30.0%), and 1 had 3 responses (10.0%).

“Most responding patients in the luspatercept group had multiple, separate responses,” Platzbecker said.

Regarding safety, luspatercept was still found to have a tolerable safety profile after adjusting for exposure. Exposure-adjusted TEAE incidence rates per 100 person-years included: dizziness (19.2% with luspatercept vs 8.9% with placebo), bronchitis (10.7% vs 2.2%, respectively), diarrhea (25.8% vs 18.4%), nausea (20.1% vs 13.7%), fatigue (26.2% vs 27.1%), asthenia (22.3% vs 21.5%), nasopharyngitis (8.8% vs 9.0%), cough (19.8% vs 25.0%), anemia (8.2% vs 13.6%), and arthralgia (6.3% vs 21.1%).

When investigating the median time from initial MDS diagnosis to AML progression, which occurred in 2.6% of luspatercept-treated patients and 3.9% of those on placebo, Platzbecker noted that this was 61.7 months (range, 56.7-223.6) with luspatercept and 32.7 months (range, 30.1-60.4) with placebo.

In December 2021, the FDA granted priority review to a supplemental biologics license application for luspatercept for the treatment of anemia in adults with non–transfusion dependent β-thalassemia. The European Medicines Agency has also validated the Type II variation for the agent’s use in the same indication.4


1. Platzbecker U, Santini V, Komrokji RS, et al. Analysis of duration of response, exposure-adjusted safety, and progression to acute myeloid leukemia for patients with lower-risk myelodysplastic syndromes receiving luspatercept in the MEDALIST study. Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 1524.

2. US Food and Drug Administration (FDA) approves Reblozyl (luspatercept-aamt), the first and only erythroid maturation agent, to treat anemia in adults with lower-risk myelodysplastic syndromes (MDS). New release. Bristol Myers Squibb; April 3, 2020. Accessed December 12, 2021.

3. Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. N Engl J Med 2020;382(2):140–151). doi:10.1056/NEJMoa1908892

4. US Food and Drug Administration accepts for priority review supplemental biologics license application for Reblozyl (luspatercept-aamt) in adults with non-transfusion dependent (NTD) beta thalassemia. News release. Bristol Myers Squibb; December 3, 2021. Accessed December 12, 2021.

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