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Luspatercept effectively treats anemia in transfusion-dependent myelodysplastic syndrome
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SAN DIEGO — Luspatercept significantly reduced the transfusion burden compared with placebo among patients with anemia due to myelodysplastic syndrome, according to results of a randomized, double-blind, placebo-controlled phase 3 study presented during the plenary session of ASH Annual Meeting and Exposition.
Treatment with luspatercept (ACE-536; Acceleron Pharma, Celgene) enabled 38% of patients to avoid red blood cell transfusions for at least 8 weeks.
“Patients with lower-risk, red blood cell transfusion-dependent myelodysplastic syndrome have a worse prognosis owing to greater risk for progression to acute myeloid leukemia and inferior OS compared with transfusion-independent patients,” Alan F. List, MD, president and CEO of Moffitt Cancer Center, told HemOnc Today. “Complicating this is the fact that red blood cell transfusion-dependent lower-risk, non-del(5q) patients with myelodysplastic syndrome have a lower response rate to erythroid-stimulating agents, such as recombinant erythropoietin, that is generally not sustained, which accentuates risk for iron overload and secondary organ complications. We have few effective FDA-approved treatment options for patients with lower-risk myelodysplastic syndrome who are either refractory to or become unresponsive to erythroid-stimulating agents.”
Because myelodysplastic syndrome is associated with an erythroid maturation defect, patients often have anemia and are dependent upon red blood cell transfusions. Luspatercept is a first-in-class erythroid maturation agent that enhances late-stage erythropoiesis.
“Anemia and the chronic need for transfusions is a very big issue for these patients,” lead study author Pierre Fenaux, MD, PhD, professor of hematology at Hôpital Saint-Louis in Paris, said in a press release. “With low hemoglobin levels, patients are tired all the time and have an increased risk of falls and cardiovascular events. When you can improve hemoglobin levels, you really see a difference in quality of life.”
The analysis included 229 patients (median age, 71 years; range, 26-95; 62.9% men) with Revised International Prognostic Scoring System-defined very low-, low- or intermediate-risk myelodysplastic syndrome with ring sideroblasts. Ninety percent of patients harbored a SF3B1 mutation.
Patients were refractory to or intolerant of erythropoiesis-stimulating agents — 218 patients (95.2%) had previously received these agents — and required red blood cell transfusions. Patients had received a median of five (range, 1-20) red blood cell units transfused over 8 weeks during the 16 weeks prior to treatment. Within the 8-week period prior to treatment, 43.2% of patients had received six or more red blood cell units, 27.9% had received between four to six units, and 28.8% received fewer than four units.
At baseline, 138 patients (60.3%) had serum erythropoietin levels less than 200 IU/L, 58 patients (25.3%) had levels of 200 IU/L to 500 IU/L, and 32 patients (14%) had levels greater than 500 IU/L.
Median time from diagnosis was 41.8 months (range, 3-421).
Researchers randomly assigned patients 2:1 to receive a starting dose of 1 mg/kg luspatercept (n = 153) — with titration up to 1.75 mg/kg, if needed — or placebo (n = 76) subcutaneously every 3 weeks for at least 24 weeks.
Red blood cell transfusion independence for at least 8 weeks during the first 24 weeks served as the study’s primary endpoint.
Red blood cell transfusion independence for at least 12 weeks during the first 24 weeks served as a key secondary endpoint.
Overall, 58 patients (37.9%) assigned luspatercept achieved the primary endpoint compared with 10 patients (13.2%) assigned placebo (OR = 5.1; P < .0001).
“I might point out that patients in the placebo arm who responded had a very low transfusion burden at baseline, and they exceeded that 8-week threshold for response simply by virtue of changes in transfusion pattern compared with baseline,” List said during a press conference. “There was not a meaningful change in hemoglobin in the placebo arm like we see with the luspatercept arm.”
A greater proportion of patients assigned luspatercept also achieved red blood cell transfusion independence for at least 12 weeks (28.1% vs. 7.9%; OR = 5.1; P = .0002).
Further, 52.9% of patients assigned luspatercept achieved a modified hematologic improvement-erythroid response — defined as either a reduction in transfusion of four or more red blood cell units in an 8-week period or a mean hemoglobin increase of 1.5 g/dL or higher without transfusions in the first 24 weeks — compared with 11.8% of patients assigned placebo (P < .0001).
Among patients who achieved transfusion independence, the median rise in hemoglobin was 2.55 g/dL, reaching as high was 4.1 g/dL.
“An agent such as luspatercept that can restore effective erythropoiesis in a sizable proportion of lower-risk, transfusion-dependent patients with myelodysplastic syndrome and ring sideroblasts that leads to either transfusion independence, rise in hemoglobin or major reduction in transfusion burden has the potential to greatly improve the quality of life for this group of patients and reduce iron loading and associated complications over time,” List told HemOnc Today. “Indeed, ferritin levels declined in patients on the luspatercept treatment arm, whereas they continued to rise in placebo-treated patients.”
Researchers noted the safety profile appeared similar with previous reports. The most common adverse events associated with luspatercept included fatigue and muscle pain, although these also are symptoms of anemia.
“This was a very clean and safe drug,” List said during the press conference. “There were no differences in treatment-emergent adverse events, and absolutely no differences in severe adverse events or the frequency of progression to AML.”
Future research should aim to further understand the underlying disease biology, List said.
“This study shows that novel treatments born out of understanding the biology of disease can offer the greatest promise for patients with myelodysplastic syndrome,” he told HemOnc Today. “Further development of biologically rational agents firmly rooted in engaging the features driving the disease should be prioritized. In lower-risk myelodysplastic syndrome in particular, agents targeting innate immune signaling may be especially promising.” – by Alexandra Todak
Reference:
Fenaux P, et al. Abstract 1. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.
Disclosures: Fenaux reports honoraria and research funding from Celgene, Janssen, Jazz Pharmaceuticals and Otsuka. List reports research funding from Celgene. Please see the abstract for a list of all other authors’ relevant financial disclosures.
Perspective
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David Steensma, MD
The study — along with the FLYER trial, also presented at this meeting — indicate that the experimental drug luspatercept, a ligand trap, can help patients with anemia that is due to different diseases. The analysis included patients with myelodysplastic syndrome who had ring sideroblasts and either no response to or who were not eligible for treatment with an erythropoiesis-stimulating agent for their anemia.
The responses in the placebo arm highlight one of the challenges in formally measuring responses in myelodysplastic syndrome, given the course fluctuates a bit. There has just been a proposed revision for the International Working Group response criteria that will hopefully clarify that a bit in the future. It is a challenge in some of these patients to assess true response.
Luspatercept is clearly an active drug, and the safety profile really seems quite benign. This will be a useful therapy for us to have in myelodysplastic syndrome for our patients with ring sideroblasts, who represent about 25% of patients overall, but who are clearly overrepresented in the clinical population getting transfusions, because they have significant anemia. It will be helpful to have this new addition to our myelodysplastic syndrome treatment armamentarium; it’s been 12 years since we’ve had an FDA-approved drug in this disease, and we’ve had seven for AML in the last year and a half, so it’s our turn.
Reference:
Domencia Cappellini M, et al. Abstract 163. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.
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