Abstract Introduction: β-thalassemia is characterized by ineffective erythropoiesis leading to chronic anemia. Although patients with non-transfusion-dependent (NTD) β-thalassemia usually require fewer red blood cell (RBC) transfusions than patients who are transfusion-dependent (TD), the underlying ineffective erythropoiesis and related anemia, bone marrow expansion, and iron overload lead to multiple complications. In pediatric patients who are NTD, RBC transfusions are typically needed only during specific circumstances, such as infections and to support growth. There remains an unmet need among pediatric patients with NTD β-thalassemia for treatments that maintain hemoglobin levels in order to optimize early treatment and prevent or reduce the risk of subsequent serious or irreversible morbidities as patients enter adulthood. Luspatercept has been shown to durably increase hemoglobin levels and reduce transfusion burden in adult patients with NTD and TD β-thalassemia, respectively. Results from a phase 2a study of the safety and pharmacokinetics of luspatercept in pediatric patients with β-thalassemia (NCT04143724; EudraCT 2022-502499-22-00) showed that the safety profile in pediatric patients who are TD is consistent with that observed in adults (Kattamis A., et al. HemaSphere 2024;8S1:2804–2805). Here we present safety data from the NTD dose-confirmation cohort of the study. Methods: This ongoing phase 2a study has a staggered design conducted in 2 parts for patients 12 to 18 years of age (part A) and 6 to 12 years of age (part B); both parts include separate NTD and TD cohorts. This analysis focused on the NTD dose-confirmation cohort of part A. The treatment of pediatric patients with NTD β-thalassemia is evaluated at sites outside of the United States; study locations include China, Germany, Greece, India, Italy, Thailand, and Türkiye. Patients eligible for inclusion in this cohort were 12 to 18 years of age with NTD β-thalassemia, defined as receiving 4 RBC transfusions in the 24 weeks pre-enrollment, not on a regular transfusion program, being RBC transfusion-free for ≥8 weeks pre-enrollment, and having a mean baseline hemoglobin level of ≤10 g/dL. Patients received luspatercept at 1.0 mg/kg subcutaneously once every 3 weeks for 4 cycles to confirm that the dose is safe and well tolerated in adolescent patients with NTD β-thalassemia. Results: As of June 9, 2025, 3 patients from Italy, China, and Thailand had been enrolled in the dose-confirmation cohort. Patients had a median age of 13 years (range, 12–17); 1 patient (33.3%) was female and 2 (66.7%) were male; and 1 patient (33.3%) was White and 2 (66.7%) were Asian. One patient (33.3%) had hemoglobin E/β-thalassemia combined with α-thalassemia and 2 had β-thalassemia (1 with an α-gene triplication). Median baseline hemoglobin level was 7.8 g/dL (range, 6.7–8.6); 2 patients had liver iron concentration (LIC) 3 mg/g dry weight (dw) and 1 had LIC 7 to ≤15 mg/g dw. No patients had received iron chelation therapy or had a splenectomy. Baseline performance status was evaluated using the Karnofsky (1 patient) and Lansky (2 patients) performance scales; performance status scores were 100, 90, and 100, respectively. Two patients had ≥1 comorbidity: 1 had splenomegaly and osteopenia and 1 had splenomegaly, iron overload, and growth retardation. Median treatment duration was 184 days (range, 127–237) and patients had received a median of 7 doses (range, 6–9) of luspatercept. One patient experienced a dose delay at day 84 due to a hemoglobin level of ≥11.5 g/dL. All 3 patients experienced at least 1 treatment-emergent adverse event (TEAE); reported TEAEs were upper respiratory tract infection, gastroenteritis, abdominal pain, toothache, oropharyngeal pain, influenza-like illness, hyperuricemia, and headache (each reported by 1 patient). One patient experienced a grade 3/4 TEAE of gastroenteritis. No serious TEAEs, grade 5 TEAEs, TEAEs leading to dose delay, or TEAEs suspected to be related to treatment were reported. Conclusions: Safety data from pediatric patients with NTD β-thalassemia who have received luspatercept 1.0 mg/kg indicate no new safety signals and no patients experiencing serious TEAEs or dose-limiting toxicities, consistent with previous results from the pediatric TD cohort at the same dose. TEAEs were generally non-hematologic in nature and considered not related to luspatercept treatment. Recruitment is ongoing for the part A NTD dose-expansion cohort.
Aydınok et al. (Mon,) studied this question.