The first-in-class erythroid maturation agent luspatercept (Reblozyl) is already approved for the treatment of anemia in adult patients with beta thalassemia who require red blood cell (RBC) transfusions.
Now it has also shown to be beneficial for patients with beta thalassemia who are not dependent on transfusions. There is no drug specifically indicated as yet for this patient population, who often develop chronic anemia and iron overload.
The new results come from the phase 2 BEYOND trial, and were presented at the European Hematology Association 2021 annual meeting, held virtually because of the ongoing pandemic.
"We now have a new agent that showed benefit in improving anemia with non-transfusion-dependent thalassemia," lead author Ali T. Taher, MD, PhD, told Medscape Medical News.
"With the rising body of evidence on the detrimental impact of anemia in these patients, this presents a landmark achievement for a patient population who do not have many treatment options," said Taher, director of the Basile Cancer Institute at the American University of Beirut Medical Center, Beirut, Lebanon.
In commenting on the study, Kevin H.M. Kuo, MD, an assistant professor in the Division of Hematology at the University of Toronto, Canada, said the findings are encouraging in addressing the non-transfusion subgroup's treatment needs.
"I think luspatercept is an exciting addition to the armamentarium in the treatment of beta thalassemia," he told Medscape Medical News. "I think this is something we have always looked forward to because these non-transfusion-dependent patients have been a very neglected subgroup of patients."
"This is mainly because there is a perception that they tend to do better than their transfusion-dependent counterparts, but we realize that's not the case because these patients have complications stemming from both hemolysis and ineffective erythropoiesis," Kuo said.
"So, I'm pleased that we may be seeing a better treatment option for these patients."
Results From the BEYOND Trial
For the multicenter, double-blind, phase 2 BEYOND trial, 145 patients with non-transfusion-dependent beta thalassemia, who received no more than 5 RBC units in the 24 weeks prior to randomization, were randomly assigned to treatment with luspatercept 1 mg/kg, with titration up to 1.25 mg/kg (n = 96) or placebo (n = 49) subcutaneously every 3 weeks for at least 48 weeks. The patients had a median age of 40, and 41.7% were male
Throughout the trial, both groups received the best supportive care, with sporadic RBC transfusions when needed and iron chelation therapy.
Twenty patients (13.8%) received RBC transfusions (maximum 5 units) in the 24 weeks prior to treatment. The median baseline hemoglobin level was 8.2 g/dL (range 5.3-10.1).
The primary endpoint was an increase of at least 1.0 g/dL in hemoglobin from baseline to weeks 13 through 24 in the absence of RBC transfusions. This was achieved by as many as 74 of the 96 luspatercept patients (77.1%), compared with none in the placebo group (P < .0001).
Of the 55 patients with mean baseline hemoglobin levels of less than 8.5 g/dL in the luspatercept group, 40 (72.7%) achieved the primary endpoint vs none in the placebo group (P < .0001).
And of 41 with a mean baseline hemoglobin of 8.5 g/dL or higher in the luspatercept group, 34 (82.9%) achieved the primary endpoint vs none in the placebo group (P < .0001).
Overall, 52.1% of patients in the luspatercept arm achieved the secondary endpoint of an increase of 1.5 g/dL hemoglobin or more at weeks 13 through 24, vs none in the placebo arm (P < .0001).
The need for transfusions also declined with luspatercept, with most treated patients (89.6%) not requiring RBC transfusions at weeks 1 through 24, compared with 67.3% in the placebo group (P = .0013).
There were no significant differences in patient-reported scores of tiredness and weakness among the patient groups at weeks 13 through 24 and the scores were marginally improved in the luspatercept group at weeks 37 through 48 (P = .051).
The differences were similar in patients with a baseline hemoglobin of less than 8.5 g/dL. However, the improvement in scores correlated with the level of hemoglobin increase, Taher noted.
"When we actually look at patients who had an increase in hemoglobin levels, we see a clearer benefit in the tiredness and weakness score," he told Medscape Medical News.
"And for me as a clinician, this is what matters and what I expect, as we don't expect patients who did not have hemoglobin improvement to have better quality of life," he added.
Luspatercept was well-tolerated, with the most common treatment-emergent adverse events of any grade as follows: bone pain, in 36.5% of luspatercept patients and 6.1% of placebo patients; headache, 30.2% vs 20.4%; and arthralgia, 20.2% vs 14.3%.
The rates of treatment-emergent adverse events of grade 3 or higher were similar in the luspatercept vs placebo groups. There were no deaths or thromboembolic or thrombophlebitis events in either group.
Kuo noted that a key factor to be looked at in further studies is how the hemoglobin improvements relate to clinically meaningful patient-reported outcomes.
"An important question is how much does the hemoglobin increase [with luspatercept] correlate with changes in patient-reported outcomes," he said.
"This was only up to 48 weeks, so we will have to see if there is more of a long-term benefit."
An "Understudied" Population
EHA president John G. Gribben, DSc, agreed that the study importantly addresses an "understudied population" of beta thalassemia.
"Being classified as non-transfusion-dependent does not mean that these patients never need transfusion and indeed the decreased transfusion requirement was one of the positive aspects of the study," he told Medscape Medical News.
"But there were also decreases in other factors like decreased iron overload, etc, which means that we could expect decreased long-term morbidities for these patients," said Gribben, director of the Experimental Cancer Medicine Centre, University of London, UK,.
"As always, the number of patients was relatively small in this study and there is a need for longer term follow-up, but we were excited to see these data presented at this year's EHA congress," he said.
The study was supported by Celgene, a Bristol-Myers Squibb Company. Taher disclosed research and/or consultancy relationships with Agios, Celgene, Ionis Pharmaceuticals, Novartis Pharmaceuticals, and Vifor Pharma. Kuo was an investigator on the BELIEVE Trial, involving luspatercept in transfusion-dependent thalassemia patients. He has been a consultant for Agios, Celgene/BMS, and Forma and has taken part in research collaboration with Phoenicia Biosciences.
European Hematology Association (EHA) 2021 Annual Meeting: Abstract S101. Presented June 11, 2021.
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Cite this: Luspatercept Benefit Also in Non-Transfusion-Dependent Thalassemia - Medscape - Jun 13, 2021.