Luspatercept reduces transfusion burden for certain patients with lower-risk myelodysplastic syndrome
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Luspatercept reduced the severity of anemia compared with placebo among certain patients with lower-risk myelodysplastic syndrome, according to results of a randomized phase 3 trial published in The New England Journal of Medicine.
Researchers observed the benefit specifically among patients with ring sideroblasts who had been receiving regular red blood cell transfusions and were refractory to or intolerant of erythropoiesis-stimulating agents.
“Treatment goals for patients with lower-risk myelodysplastic [syndrome] include transfusion independence, improvement in hemoglobin levels, and maintenance of or improvement in quality of life,” Pierre Fenaux, MD, PhD, professor of hematology at Hôpital Saint-Louis in Paris, and colleagues wrote. “Erythropoiesis-stimulating agents are a first-line treatment for lower-risk myelodysplastic [syndrome], targeting early stages of erythropoiesis by inhibiting apoptosis and stimulating erythropoietin-responsive erythroid precursor proliferation.”
Lenalidomide (Revlimid, Celgene) has been a standard treatment for patients with lower-risk myelodysplastic syndrome with chromosome 5q deletion who require blood transfusions, regardless of prior treatment with erythropoiesis-stimulating agents. However, only 39% of other patients with lower-risk myelodysplastic syndrome receive second-line therapy beyond the ongoing transfusions.
“Given the limited number of approved and effective treatments, new treatment strategies are needed for patients with nonchromosome 5q deletion lower-risk myelodysplastic [syndrome] who are dependent on transfusions,” Fenaux and colleagues wrote.
The FDA approved luspatercept (Reblozyl, Acceleron Pharma) in November for the treatment of anemia among adults with beta-thalassemia who require regular red blood cell transfusions. Luspatercept — a recombinant fusion protein that reduces SMAD2 and SMAD3 signaling by binding transforming growth factor beta superfamily ligands — showed promise among patients with lower-risk myelodysplastic syndrome in a phase 2 study.
The current double-blind, phase 3 study by Fenaux and colleagues included 229 patients with very low-risk, low-risk or intermediate-risk myelodysplastic syndrome with ring sideroblasts who had been receiving regular red blood cell transfusions. Researchers randomly assigned patients to luspatercept (n = 153; median age, 71 years; range, 40-95; 61% men) or placebo (n = 76; median age, 72 years; range, 26-91; 63% men), administered subcutaneously every 3 weeks.
Patients received luspatercept at doses of 1 mg/kg to 1.75 mg/kg.
Transfusion independence for 8 weeks or longer during weeks 1 to 24 served as the study’s primary endpoint. Transfusion independence for 12 weeks or longer, assessed during both weeks 1 to 24 and weeks 1 to 48, served as a secondary endpoint.
Results showed 38% of patients in the luspatercept group achieved transfusion independence for 8 weeks or longer, compared with 13% of patients in the placebo group (P < .001).
Further, a greater percentage of patients in the luspatercept group achieved transfusion independence for 12 weeks or longer (28% vs. 8% during weeks 1-24; 22% vs. 12% during weeks 1-48; P < .001 for both) and 16 weeks or longer (19% vs. 4% during weeks 1-24; 28% vs. 7% during weeks 1-48) compared with the placebo group.
By data cutoff, median duration of the longest single period of transfusion independence among patients who met the primary endpoint was 30.6 weeks in the luspatercept group and 13.6 weeks in the placebo group.
Erythroid response occurred in 81 patients (53%) in the luspatercept group during weeks 1 to 24 compared with nine patients (12%) in the placebo group, and 90 patients (59%) vs. 13 patients (17%) during weeks 1 to 48.
Researchers reported a mean increase in hemoglobin level of at least 1 g/dL during weeks 1 to 24 among 54 patients (35%) who received luspatercept and six patients (8%) who received placebo, and 63 patients (41%) vs. eight patients (11%) during weeks 1 to 48.
Sixty-five patients who received luspatercept and 34 patients who received placebo experienced grade 3 or grade 4 adverse events. The most common adverse events among the luspatercept and placebo groups included fatigue (27% vs. 13%), diarrhea (22% vs. 9%), asthenia (20% vs. 12%), nausea (20% vs. 8%), dizziness (20% vs. 5%) and back pain (19% vs. 7%).
“Patients with lower-risk myelodysplastic [syndrome] with ring sideroblasts for whom erythropoiesis-stimulating agents are not effective or are not an option have limited treatment options available beyond continued transfusions,” Fenaux and colleagues wrote. “Luspatercept significantly reduced the transfusion burden in a substantial proportion of these patients and was associated with mainly low-grade toxic effects.” – by John DeRosier
Disclosures: Celgene and Acceleron Pharma funded the study. Fenaux reports a consultant role with Celgene. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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Ruben A. Mesa, MD, FACP
Patients with myelodysplastic syndrome face several challenges. For the sizeable percentage of patients who are low to intermediate risk, the main problems are anemia and being transfusion dependent. Because anemia can cause patients to be short of breath and have limited energy, the ability to improve anemia represents a major clinical benefit in terms of symptoms. On top of that, getting transfusions on a regular basis comes with some risks and takes a lot of time for the patient, and the hassle impacts quality of life.
Available therapies have improved myelodysplastic syndrome but have had limited activity when it comes to anemia. The hypomethylating agents azacitidine and decitabine — which have been approved for over 10 years — are helpful with more aggressive and advanced disease and in patients moving toward acute leukemia. They can improve anemia, but their effectiveness is more limited for that.
Additionally, lenalidomide is particularly effective for patients with deletion 5q mutation, but its benefits are more limited for patients without this mutation who are low to intermediate risk.
The last option, erythropoietin-stimulating agents, can help with anemia, but only for a minority of patients are they particularly helpful.
Thus, there has been a big unmet need for this group of individuals, who can sometimes live several years with the disease.
This study was well-done with an appropriate group of patients and clearly showed a benefit of luspatercept, a novel TGF-beta ligand trap, compared with placebo. Luspatercept appeared well-tolerated overall. The patients represented in this study clearly benefit from the treatment, and I believe it will become a standard of care for transfusion-dependent low-risk patients with myelodysplastic syndrome, especially if they are lacking deletion 5q or have failed an erythropoietin-stimulating agent.
Although these data answer a lot of questions when it comes to this particular subset of patients, questions remain regarding whether this is helpful for those who have anemia but don’t need transfusions. Second, for individuals who have myelodysplastic syndrome and are already receiving other therapies but still have anemia, should we consider adding this medicine as a combination? The answer is likely yes but would need to be confirmed in trials.
Finally, there are those who have transfusion-dependent anemia with other myeloid conditions that are cousins of myelodysplastic syndrome. I am currently an investigator on a study that is testing luspatercept in myelofibrosis (NCT03194542). We have seen that the drug is active there, too and hope to see a potential future similar approval.
Going forward, we have to see if patients with myeloproliferative neoplasm-myelodysplastic syndrome overlap syndromes may similarly benefit when anemia is problematic. There are several studies ongoing or planned for the future that may help answer these questions.
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