Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes
- Study type
- Clinical trial
- Study name
- MEDALIST
- Phase
- Phase 3
- Design
- Randomised, double-blind, placebo-controlled, multicentre trial; 2:1 randomisation stratified by baseline red cell transfusion burden and baseline IPSS-R (FDA label, section 14.3)
- Sample size
- 229 patients (153 luspatercept, 76 placebo)
- Source
- N Engl J Med · 2020
- Trial registration
- NCT02631070
In plain words
In some patients with lower-risk MDS, special cells called "ring sideroblasts" are seen in the bone marrow. When drugs that stimulate blood production do not work or are not suitable for these patients, they usually come to need regular blood transfusions. In this trial, an injection of luspatercept under the skin every 3 weeks was compared with a placebo: 38% of patients in the luspatercept group, versus 13% in the placebo group, needed no transfusion for at least 8 weeks. The most common side effects were tiredness, diarrhoea, weakness, nausea and dizziness, which became less frequent over time.
Key results
Treatment arms and regimens
Luspatercept at a dose of 1.0 up to a maximum of 1.75 mg/kg body weight, subcutaneously, every 3 weeks (abstract of the paper).
Protocol details (FDA label, section 14.3): started at 1 mg/kg subcutaneously every 3 weeks; after completing the first 2 cycles, the dose could be increased if the patient had had at least one red cell transfusion in the previous 6 weeks (two steps: 1.33 and 1.75 mg/kg). The dose was interrupted and then reduced for an adverse event, reduced if haemoglobin rose by 2 g/dL or more from the previous cycle, and interrupted if pre-dose haemoglobin was 11.5 g/dL or higher. All patients received best supportive care, including red cell transfusions as needed. The main efficacy assessment was performed after 24 weeks of treatment, and patients whose transfusion needs had decreased or whose haemoglobin had increased could continue double-blind study drug until unacceptable toxicity, loss of effect or disease progression.
Current FDA label dosing for ESA-refractory or ESA-intolerant MDS (section 2.2, Table 4): start at 1 mg/kg subcutaneously every 3 weeks. If the patient is not red cell transfusion-free after at least 2 consecutive doses (6 weeks) at one dose level, increase the dose to 1.33 and then 1.75 mg/kg every 3 weeks; do not increase the dose more often than every 6 weeks (2 doses) or above the maximum of 1.75 mg/kg. If pre-dose haemoglobin, without transfusion, is 11.5 g/dL or higher, interrupt treatment and resume at the same dose when haemoglobin reaches 11 g/dL or lower. If haemoglobin rises by more than 2 g/dL within 3 weeks without transfusion, reduce the dose by one level (1.75 to 1.33, 1.33 to 1, 1 to 0.8 and 0.8 to 0.6 mg/kg; at 0.6 treatment is discontinued). If the transfusion burden does not decrease after at least 3 consecutive doses (9 weeks) at 1.75 mg/kg (including no increase in haemoglobin from baseline), discontinue treatment.
Placebo, subcutaneously every 3 weeks (abstract of the paper), with best supportive care including red cell transfusions as needed (FDA label, section 14.3).
Source of the regimen details: Abstract of the paper (N Engl J Med 2020); protocol details and current dosing from the FDA label for luspatercept (REBLOZYL, DailyMed; sections 14.3 and 2.2)
Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.
Study population
Patients with very low-, low- or intermediate-risk myelodysplastic syndrome (MDS) by the Revised International Prognostic Scoring System (IPSS-R) with ring sideroblasts who were receiving regular red cell transfusions and whose disease was refractory to erythropoiesis-stimulating agents (ESA), or unlikely to respond to ESA, or who had stopped ESA because of an adverse event. Baseline characteristics were balanced between the two groups.
According to the FDA label (section 14.3): requirement for 2 or more units of red cells over 8 weeks; inadequate response to prior ESA, ESA intolerance or serum erythropoietin above 200 U/L. Patients with a 5q deletion [del(5q)], white cell count above 13 × 109/L, neutrophils below 0.5 × 109/L, platelets below 50 × 109/L or prior use of a disease-modifying agent for MDS were excluded.
Endpoints
Primary endpoint: transfusion independence for 8 weeks or longer during weeks 1 to 24.
Key secondary endpoint: transfusion independence for 12 weeks or longer, assessed during both weeks 1 to 24 and weeks 1 to 48.
Safety and side effects
The most common adverse events with luspatercept (any grade) were fatigue, diarrhoea, asthenia (weakness), nausea and dizziness, and the incidence of adverse events decreased over time. The exact frequency of adverse events and the rate of grade 3 or higher events are not reported in the abstract (details in the full text of the paper).
According to the FDA label, blood pressure should be monitored before each luspatercept dose, and new or worsening hypertension treated with antihypertensive drugs (section 5.2). Luspatercept may cause fetal harm; women of reproductive potential should be informed of this risk and use effective contraception (section 5.4).
Clinical significance and place in guidelines
MEDALIST showed that luspatercept, a recombinant protein that reduces SMAD2 and SMAD3 signalling by binding ligands of the TGF-β superfamily, reduces the severity of anaemia in patients with lower-risk MDS with ring sideroblasts who are transfusion-dependent and for whom ESA have not been effective or suitable. According to the FDA label for luspatercept (REBLOZYL, section 14.3), its efficacy in adults with MDS-RS and MDS/MPN-RS-T was established on the basis of MEDALIST; the corresponding indication (section 1.3): treatment of anaemia after ESA failure with a requirement for 2 or more red cell units over 8 weeks, in adults with very low- to intermediate-risk MDS with ring sideroblasts (MDS-RS) or myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T). In ESA-naive patients, the COMMANDS trial compared luspatercept directly with epoetin alfa.
Limitations
Only patients with lower-risk MDS with ring sideroblasts were enrolled, and the results cannot be directly applied to patients without ring sideroblasts. Most patients in the luspatercept group did not achieve 8-week transfusion independence (the primary endpoint was met in 38%). The control was placebo and there was no comparison with another active treatment. The exact frequency of adverse events, survival data and progression to leukaemia are not reported in the abstract. According to the FDA label, patients with del(5q) or prior use of a disease-modifying agent for MDS were excluded.
This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.