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Luspatercept increases hemoglobin levels, reduces transfusion burden in myelodysplastic syndromes
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ORLANDO, Fla. — The fusion protein luspatercept led to a sustained increase in hemoglobin levels and reduced the transfusion requirement among patients with low- or intermediate-risk myelodysplastic syndromes, according to preliminary data from a phase 2 study presented at the ASH Annual Meeting and Exposition.
Patients with myelodysplastic syndromes have increased Smad 2/3 signaling in the bone marrow, resulting in ineffective erythropoiesis, according to study background. Luspatercept (ACE-536; Acceleron, Celgene) inhibits Smad 2/3 signaling and promotes erythropoiesis differentiation and is under investigation for the treatment of anemias with ineffective erythropoiesis.
Aristoteles Giagounidis, MD, PhD, head of the department of oncology, hematology, and palliative care at Marien Hospital Düsseldorf in Germany, and colleagues conducted this ongoing, 24-month extension study to evaluate longer-term effects of luspatercept treatment on anemia in patients with low- or intermediate-1–risk myelodysplastic syndromes.
“Erythropoiesis is highly proliferative but it is also subject to negative regulation, which acts on both maturation and survival,” Giagounidis said in his presentation. “Most of this happens through certain molecules which belong to the transforming growth factor-beta [TGF-β] super family.
“TGF-β super family doesn’t only inhibit erythropoiesis but it also inhibits a number of tissues in the human body… so we thought to use luspatercept in lower-risk myelodysplastic syndromes thinking that a rising hemoglobin could happen with this drug,” Giagounidis added.
Primary outcomes included the erythroid response of increased hemoglobin among patients with a low transfusion-burden (less than four red blood cell units every 8 weeks), reduced transfusions among high transfusion-burden patients (four or more red blood cell units every 8 weeks), transfusion independence, safety, and pharmacokinetic and pharmacodynamic biomarkers.
The investigators enrolled 32 patients; preliminary safety and efficacy data were available for 22 of the patients (median age, 70.5 years) as of April 17, 2015 (low transfusion burden, n = 9; high transfusion burden, n = 13). Sixty-four percent of patients had received prior erythropoietin-stimulating agent therapy, 18% had prior lenalidomide (Revlimid, Celgene) and all patients had 15% or greater ring sideroblasts in bone marrow.
Patients received luspatercept at a starting dose of 1 mg/kg for a median of 8 cycles (range, 5-12).
In the low transfusion-burden group, eight (89%) of the patients achieved an erythroid response for hemoglobin increase, or 1.5 g/dL or greater for 8 or more weeks. The mean change in hemoglobin exceeded 1.5 g/dL for a median of 17 weeks (range, 5-22) in this cohort.
Ten (77%) patients in the high transfusion-burden cohort achieved an erythroid response, or reduction of four or more red blood cell units transfused over 8 weeks.
Six of 14 patients (43%) who received 2 or more red blood cell units transfused over the 8 weeks prior to treatment achieved transfusion independence for at least 8 weeks (median, 23 weeks; range, 10-30 weeks as of data cutoff). All of these patients continued treatment after the cutoff.
“Patients demonstrated robust hematologic improvement for erythroid and reduced transfusion burden,” Giagounidis said. “Luspatercept was generally safe and well tolerated and treatment has lasted for up to a year and demonstrated sustained increases of hemoglobin and reduced transfusion dependence.” – by Anthony SanFilippo
Reference:
Giagounidis A, et al. Abstract 92. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.
Disclosure: The researchers report research funding and honoraria from and consultant/advisory roles and employment with Acceleron, Boehringer Ingelheim, Bristol-Meyers Squibb, Celgene and Novartis.
Perspective
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Rami S. Komrokji, MD
The TGF-β pathway is over-activated and over-expressed in MDS. The over-activation of this pathway contributes to myelosuppression.
There are 2 drugs in this class that can target active interceptors which are part of this super family of TGF-β. There are also small molecules that can target the tyrosine kinase component of it.
But, sotatercept and luspatercept are two drugs that are ligand fusion proteins. Luspatercept was developed by the researchers on this study from Germany. I was part of the sotatercept study in the United States. Both of the studies looked at the lower-risk MDS population.
In this study by Giagounidis, et al, there was a selection for patients who had ringed sideroblasts. By nature those patients usually are only transfusion dependent and don’t progress. Early on they started to notice a signaling of response in those patients so the study became enriched with this population. They saw encouraging responses.
They looked at 2 cohorts – those with a high transfusion burden (more than 4 units of blood every 8 weeks) and those with low transfusion burden. There was an absolute hemoglobin increase of more than 1.5 g which is an objective sign of response in the low transfusion burden, which was approximately more than 60% response in that group. This was especially noticeable for those patients with ring sideroblasts, who were more likely to respond to this treatment. Treatment also was very well tolerated.
This is one of the most exciting drugs in development in MDS and the studies are moving forward. The next study, known as MEDALIST, will be a phase 3 study where patients will be randomly assigned to get luspatercept compared with standard care and it will target only patients with ring sideroblasts.
If the signal that was observed by Giagounidis and colleagues is there again, then this will be a drug that will be approved for MDS. We’re very excited about this. We have not seen this good signal of response in many of the studies recently presented. This one has very high potential and hopefully, moving forward, provides a new option for patients.Click Here to Manage Email Alerts