Compared with placebo, treatment with luspatercept improved the 12- to 16-week rate of red blood cell (RBC) transfusion independence in patients with lower-risk myelodysplastic syndromes (MDS) with ring sideroblasts and disease that is either refractory or unlikely to respond to erythropoiesis-stimulating agents (ESAs), according to findings from the phase III MEDALIST trial published in the New England Journal of Medicine. Luspatercept also was associated with “mainly low-grade toxic effects that seldom led to the discontinuation of treatment,” lead study author Pierre Fenaux, MD, PhD, from the Hôpital Saint Louis in Paris, and colleagues reported.
The trial was conducted at 65 sites in 11 countries and enrolled 229 adult patients with Revised International Prognostic Scoring System (IPSS-R) very low-, low-, or intermediate-risk MDS with ring sideroblasts, defined as either ≥15% ring sideroblasts or ≥5% ring sideroblasts if an SF3B1 mutation was present, and <5% bone marrow blasts. Participants had received transfusions with ≥2 RBC units per 8 weeks during a 16-week period prior to randomization. Patients either had a serum erythropoietin level >200 U/L and were considered unlikely to respond to an ESA or had discontinued ESAs due to an adverse event (AE) or lack of efficacy.
Among the participants (median age = 71 years; range = 26-93), most (72%) had IPSS-R low-risk MDS. Almost all patients (95%) had received ESAs previously, and nearly half (48%) had received iron chelation therapy. Overall, the median transfusion burden prior to treatment was 5 units per 8 weeks (range = 1-20).
Patients were randomized to receive either:
- luspatercept at a starting dose of 1.0 mg/kg and escalating to 1.75 mg/kg of body weight (n=153)
- placebo (n=76)
Luspatercept or placebo was subcutaneously administered every 3 weeks and patients were monitored for the following endpoints:
- transfusion independence for 8 weeks or longer during weeks 1-24 (primary)
- transfusion independence for 12 weeks or longer, assessed at week 1 through weeks 24 and 48 (secondary)
A significantly higher proportion of patients who were randomized to luspatercept achieved transfusion independence for 8 weeks or longer, compared with those who were randomized to placebo (38% vs. 13%, respectively; p<0.001). Approximately 62% of luspatercept-treated patients who achieved the primary endpoint had at least 2 response intervals of transfusion independence that lasted at least 8 weeks during the treatment period. Comparatively, all the patients in the placebo group who had a response had 2 or fewer response intervals.
In addition, a significantly greater proportion of patients assigned to luspatercept experienced transfusion independence for 12 weeks or longer during the first 24 weeks of treatment (28% vs. 8%) and through 48 weeks (33% vs. 12%; p<0.001 for both).
The researchers also noted that a greater percentage of patients in the luspatercept arm had transfusion independence for 16 weeks or longer during weeks 1 through 24 (19% vs. 4%) and during weeks 1 through 48 (28% vs. 7%), according to the International Working Group’s 2018 response criteria.
Common AEs associated with luspatercept (any grade and ≥10% of patients) included:
- fatigue (27%)
- diarrhea (22%)
- asthenia (20%)
- nausea (20%)
- dizziness (20%)
“So far, luspatercept has been mainly used in patients with non-del5q lower-risk, ESA-refractory MDS and can be compared with other treatments used in this situation,” Dr. Fenaux told ASH Clinical News.
In his discussion of the study’s findings, he explained that the first treatment approach used in these patients, as in the case of this study, is typically chronic RBC transfusion. “This treatment often requires the use of chelating agents to prevent major iron overload. However, patients are generally transfused at hemoglobin thresholds ranging from 8 g/dL to 9 g/dL and therefore live most of the time with levels known to be associated with fatigue and poor quality of life,” he said. “Treatments capable of avoiding RBC transfusions and maintaining the hemoglobin level over 10 g/dL are therefore preferred whenever possible.”
In MEDALIST, “luspatercept yielded RBC transfusion independence in about 40% of [patients with] sideroblastic lower-risk MDS and in 25 to 30% of nonsideroblastic patients, with very limited side effects,” he concluded. According to Dr. Fenaux, this finding appears to be higher than response rates observed with lenalidomide and relatively equal to response rates observed with the combination of lenalidomide and ESAs.
However, he added that future studies should explore increasing the dose or frequency of luspatercept injections in these patients. “Luspatercept [is being studied now as] upfront treatment of anemia of lower-risk MDS with or without ring sideroblasts,” he said. “The randomized COMMANDS trial comparing luspatercept and an erythropoiesis-stimulating agent in this situation is ongoing.”
Several study authors reported relationships with Celgene and Acceleron Pharma, which funded the study.
Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. N Engl J Med. 2020;382:140-151.