PracticeUpdate Conference Series ASH 2018

Luspatercept Reduces Need for BloodTransfusions Among PatientsWithBeta Thalassemia Treatment cut need for blood transfusions by at least a third over 12 weeks in amajority of patients. A dult patients with beta thalassemia experience a significantly reduced need for blood transfusions when their number of transfusion units by at least half compared with 0.9% of patients receiving placebo (P = .0017).

One limitation of the study was that the primary endpoint was perhaps poorly designed to capture patient response. During a press conference, Dr. Cappellini said that the secondary endpoints, which captured a rolling response over 12-week periods, were perhaps a better measure of efficacy in this patient population. “It is much better to follow patients with the rolling methodology because patients are [each] different [from one another] so they may respond at a different time, and not within a fixed period,” Dr. Cappellini said. Using this methodology to evaluate response, 70% of patients treated with luspatercept were able to reduce blood transfusions by at least a third over any con- secutive 12-week period. Comparatively, of those patients receiving placebo, less than 30%were able to achieve such a reduction (odds ratio 5.79, P < .0001). “The results of BELIEVE provide hope for a treatment improvement for beta-thal- assemia patients who require regular blood transfusions, significantly reduc- ing the transfusion burden by 33%, 50%, or more,” Dr. Cappellini told Elsevier’s PracticeUpdate . Dr. Cappellini believes that adoption of luspatercept in the therapeutic manage- ment of beta-thalassemia patients “will also impact the possibility of reducing the mul- timorbidities that patients experience due to iron toxicity. Iron accumulates by blood transfusions, and it causes organ damage if not removed by daily iron chelation.” “We have to keep in mind these are young adult patients transfusing 3 units every 3 weeks for all their life, so it is really a substantial impact” that treatment with lus- patercept has, Dr. Cappellini said during a press conference. Patients enrolled in the trial encountered adverse events such as bone pain and thrombotic events, including stroke; however, adverse event rates were not significantly different between the luspa- tercept and placebo groups. No deaths were reported among patients treated with luspatercept and adverse events were manageable without requiring dose modification or interruption.

sites in 15 countries who had beta-thal- assemia and who required regular red blood cell transfusions and randomized them to receive either luspatercept (n=224) or placebo (n=112), both adminis- tered by injection every 3 weeks. Patients who received luspatercept during the trial received a starting dose of 1.0 mg/ kg, titrated up to 1.25 mg/kg. Patients were followed over the course of 48 weeks in a double-blind format, with investigators tracking the number of units of blood that each study participant required. Prior to enrollment, participating patients required a median of 6 units of blood over a 12-week period. By the final quarter of the trial follow-up period (weeks 37–48), 19.6% of patients had reduced their number of transfusion units required by at least one-third com- pared with 3.6% of patients receiving placebo (P < .0001). By the same period, as many as 10.3% of patients had reduced

receiving the experimental drug luspater- cept, according to results of the phase III BELIEVE study. As described by presenter Maria Cappellini, MD, of the University of Milan in Italy, luspatercept is a “first-in-class erythroid maturation agent under devel- opment for the treatment of adult patients with beta thalassemia or MDS [myelodys- plastic syndrome]-associated anemia.” It is manufactured by Celgene and Acceleron Pharma, sponsors of the present study. The mechanism of action for luspatercept involves binding selectively to members of the TGF-beta superfamily of ligands, which has the downstream effect of enhancing late-stage erythropoiesis by attenuating dysregulated Smad2/3 signaling. The investigators enrolled 336 adult patients (median age 30 years) from 65

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ASH 2018 • PRACTICEUPDATE CONFERENCE SERIES 15