A phase 2 study of luspatercept in adults and adolescents with α-thalassemia: Findings from the dose-confirmation cohort in adolescents

Abstract Introduction: α-thalassemia hemoglobin H (HbH) disease occurs when ≥2 of a patient's 4 α-globin alleles are abnormally expressed, leading to ineffective erythropoiesis and chronic anemia. There remains a significant unmet need for treatments to alleviate anemia in patients with α-thalassemia HbH disease. Luspatercept is approved for the treatment of anemia in adult patients with β-thalassemia who require red blood cell (RBC) transfusions in the USA, China (patients requiring ≤15 RBC units/24 wk), and in the EU for the treatment of anemia associated with transfusion-dependent (TD) and non-transfusion-dependent (NTD) β-thalassemia. Here we present data from 6 adolescent patients enrolled in an open-label, dose-confirmation cohort of a phase 2, multicenter study to determine the safety and tolerability of luspatercept for the treatment of patients with TD or NTD α-thalassemia HbH disease (NCT05664737). Methods: Eligible adolescent patients (age 12 to <18 y) had a diagnosis of α-thalassemia HbH disease. TD was defined as requiring ≥4 RBC events during the 24 wk prior to enrollment, having no transfusion-free period >56 d during the 24 wk prior to enrollment, and a history of regular transfusions for ≥2 y. NTD was defined as requiring <4 RBC events during the 24 wk prior to enrollment, being RBC transfusion-free during ≥8 wk prior to enrollment, and having mean baseline hemoglobin (Hb) ≤10 g/dL based on 2 measurements ≥1 wk apart within 4 wk prior to enrollment. Patients also had Karnofsky (≥16 y) or Lansky (<16 y) performance status score ≥50 at screening. Adolescent patients were enrolled in TD and NTD dose-confirmation cohorts (n=3 each) where they received a single 21-d cycle of treatment (1 dose of luspatercept at the recommended dose [RD] of 1.0 mg/kg subcutaneously [SC]) and were evaluated for safety and tolerability; the RD was determined from the dose-escalation and dose-confirmation results of luspatercept in adolescent patients with β-thalassemia (ACE-536-B-THAL-004). Following dose confirmation, enrollment began for the dose-expansion phase (n=30 in each TD and NDT cohort), where patients receive luspatercept at the RD SC every 21 d for 48 wk; after completing the dose-confirmation or dose-expansion phases, patients can subsequently enter a long-term treatment phase (≤5 y) and post-treatment follow-up period. Results: As of March 3, 2025, 3 adolescent patients were enrolled in each of the TD and NTD dose-confirmation cohorts. Median (range) age was 14 y (13–17) and 17 y (16–17), respectively. In the TD cohort all patients were male, and in the NTD cohort all were female. Median (range) baseline transfusion burden was 6.0 RBC units/24 wk (4.0–6.0) in the TD cohort; in the NTD cohort 1 patient received transfusions at baseline (2.0 units). All patients in the TD cohort had baseline Hb ≥8.5 g/dL; in the NTD cohort, 2 (66.7%) patients had baseline Hb <8.5 g/dL and 1 (33.3%) had baseline Hb ≥8.5 g/dL. Across both cohorts, only 1 (33.3%) patient (TD) had prior splenectomy. Median (range) serum ferritin at baseline was 785.5 μg/L (426.5–1535.5) for the TD cohort and 106.0 µg/L (23.5–584.0) for the NTD cohort; median (range) baseline liver iron concentration as measured by MRI was 8.2 mg/g dry weight (dw) (4.3–27.0) and 1.7 mg/g dw (1.6–3.5) for TD and NTD cohorts, respectively. All patients in the TD cohort and none in the NTD cohort received prior iron chelation therapy. All patients had ≥1 comorbidity at baseline. During the dose-confirmation period, within the 21 d from their first dose of study therapy, treatment-emergent adverse events (TEAEs) were reported in 2/6 patients (TD: one grade 1 dizziness; one grade 2 upper respiratory infection). No grade 3/4 TEAEs, dose-limiting toxicities (DLTs; defined as grade ≥3 hemolytic crises or other grade ≥3 AEs outside the expected safety profile occurring within 21 d of the first dose), serious TEAEs, or AEs of special interest (thromboembolic events, malignancies or pre-malignancies, extramedullary masses, and bone fractures) were reported in either cohort. Conclusions: In this analysis from the dose-confirmation phase of luspatercept in adolescent patients with TD and NTD α-thalassemia HbH disease, no DLTs or new safety signals were reported, suggesting that the RD of 1.0 mg/kg is well-tolerated in these patients. Enrollment in the TD and NTD dose-expansion cohorts is ongoing.