β-thalassemia is a blood disorder associated with ineffective erythropoiesis and peripheral hemolysis that lead to chronic anemia.¹ Transfusion-dependent β-thalassemia (TDT) patients would require lifelong and routine transfusions for survival, while those with non–transfusion-dependent β-thalassemia (NTDT) would require frequent transfusions for a limited period, or in the event of a specific occasion such as surgery or acute infection.1 Not only that iron overload is typically associated with frequent transfusions, NTDT patients may also experience significantly elevated liver iron concentration due to ineffective erythropoiesis and hypoxia that lead to increased intestinal iron absorption.¹ To reduce iron burden and improve anemia management, luspatercept, a recombinant fusion protein that enhances late-stage erythropoiesis was previously shown to significantly reduce the transfusion burden by at least 50%, when compared with placebo during any 12-week interval of the phase 3 BELIEVE study (40.2% vs. 6.3%; OR=9.95; 95% CI: 3.33-22.33).² To evaluate whether the ef ficacy and safety of luspatercept can be extended to the NTDT set ting, Professor Ali Taher, Professor of Medicine, Haematology & Oncology in the American University of Beirut Medical Centre, and his colleagues carried out the phase 2 placebo-controlled study with NTDT patients.³

A total of 145 patients with β-thalassemia or hemoglobin E/β-thalassemia who received less than or equal to 5 red blood cell units in the past 24 weeks were randomized 2:1 ratio to receive either 1mg/kg luspatercept (Titrate up to 1.25mg/kg; n=96) or placebo (n=49) subcutaneously.³ Both treatments were given to the patients every 3 weeks, lasting for at least 48 weeks.³ Supportive care was provided to all the patients, including transfusions and iron chelation therapy when needed.³ After the 48-week double-blind treatment period, the study was unblinded into a 15-month open-label treatment period per recommendation from the data monitoring committee, followed by a 3-year post-treatment follow-up.³ The primary endpoint was the achievement of greater than or equal to 1.0g/dL mean hemoglobin increase from the baseline over a continuous 12-week interval during week 13 to 24, in the absence of transfusions.³ A greater than or equal to 1.5g/dL mean hemoglobin increase in the same period was noted, and the NTDT patient’s reported outcomes of tiredness and weakness (NTDT-PRO T/W) were assessed as the secondary endpoints.³

During the study period, 74 out of 96 patients (77.1%) in the luspatercept group versus none in the placebo group achieved the primary outcome (p<0.0001).³ Similarly, 50 out of 94 patients (53.1%) in the luspatercept group achieved greater than or equal to 1.5g/dL increase in mean hemoglobin level versus none in the placebo group during week 13 to 24 (p<0.0001).³ Moreover, patients in the luspatercept group achieved an improved NTDTPRO T/W score when compared with placebo group at week 13 to 24 (-0.92 vs. -0.47; least squares mean difference [LSMD]=-0.48; p=0.0924) and week 37 to 48 (-1.00 vs. -0.16; LSMD=-0.79; p=0.051).³ In terms of safety, luspatercept had a lower rate of treatment-emergent adverse events including bone pain (36.5% vs. 6.1%), headache (30.2% vs. 20.4%) and arthralgia (29.2% vs. 14.3%) when compared with placebo.³ Two malignant events (4.1%) were reported in the placebo group, whereas no thromboembolic event was reported in either groups.³ “The treatment with luspatercept resulted not only in the increase in hemoglobin, but in a sustained elevation of hemoglobin levels in the patients with NTDT,” remarked Prof. Taher when highlighting the long-term clinical benefits of luspatercept for NTDT patients.³

Importantly, luspatercept successfully demonstrated a significant improvement in anemia of NTDT patients, also showing a positive correlation between hemoglobin and NTDT-PRO T/W. Prof. Taher thus concluded that the clinical benefits of luspatercept, which were previously observed with TDT, have now been demonstrated in NTDT patients with significant improvements in anemia, supporting the benefits of luspatercept in reducing transfusion burden in TDT or NTDT patients.³