Long-term efficacy and safety results of betibeglogene autotemcel gene therapy for transfusion-dependent β-thalassemia.

Clinical Snapshot

Key Findings

• P Value: Not provided in abstract

• Effect Size: Phase 3 participants achieved 90.2% transfusion independence vs 68.2% in phase 1/2

• Primary Outcome: Transfusion independence achieved in 52/63 (82.5%) participants overall

• Nnt Or Sensitivity: Sustained transfusion independence with median hemoglobin 11.2 g/dL in phase 3 participants

• Confidence Interval: Not provided in abstract

Clinical Application

Requires specialized gene therapy centers with stem cell processing capabilities and long-term follow-up infrastructure Would require TGA approval and PBS listing consideration. Relevant to Australian thalassemia population, particularly in multicultural communities. Would need integration with existing comprehensive care centers Patients with transfusion-dependent β-thalassemia suitable for gene therapy, particularly younger patients with adequate stem cell harvest potential

Abstract

Betibeglogene autotemcel (beti-cel) gene therapy for transfusion-dependent β-thalassemia (TDT) involves autologous transplantation of hematopoietic stem and progenitor cells transduced with a modified β-globin gene to produce functional adult hemoglobin (Hb) containing βA-T87Q-globin (HbAT87Q). Sixty-three participants with TDT (median age, 17 years [range, 4-35]) received beti-cel in phase 1/2 (n = 22) or phase 3 (n = 41) studies and enrolled in the long-term follow-up LTF-303 study (median follow-up, 5.9 years [range, 2.9-10.1]). Manufacturing refinements in phase 3 increased transduction efficiency, resulting in higher drug product vector copy number and HbAT87Q levels, which translated into higher Hb and transfusion independence (TI) rates than in phase 1/2. TI was achieved by 15 of 22 (68.2%) phase 1/2 participants (median weighted average Hb during TI, 10.2 g/dL) and 37 of 41 (90.2%) of phase 3 participants (median, 11.2 g/dL), and was sustained through last follow-up. Treatment efficacy was similar across ages and TDT genotypes. Among participants achieving TI, 38 of 52 (73%) had discontinued iron chelation at last follow-up, with no increase in liver iron concentration. Markers of ineffective erythropoiesis, including serum transferrin receptor and erythropoietin, improved with restoration of iron homeostasis. Health-related quality-of-life assessment scores showed durable improvements. No malignancies, insertional oncogenesis, or vector-derived replication-competent lentivirus were reported. These findings establish beti-cel as a durable, 1-time therapy that achieves TI, restores iron balance, and improves quality of life, offering a potentially curative treatment option for people with TDT. This trial was registered at www.clinicaltrials.gov as NCT02633943.

References

1. 1.Kwiatkowski, J. L., Thompson, A. A., Schneiderman, J., Thuret, I., Kulozik, A. E., Yannaki, E., Cavazzana, M., Hongeng, S., Olson, T. S., Sauer, M. G., Thrasher, A. J., Lal, A., Rasko, J. E. J., Kunz, J. B., Kinney, M. A., Chawla, A., Ali, S., Tao, G., Thakar, H. L., Paramore, C., Witthuhn, N., Walters, M. C., & Locatelli, F. (2026). Long-term efficacy and safety results of betibeglogene autotemcel gene therapy for transfusion-dependent β-thalassemia. Blood. https://doi.org/10.1182/blood.2025029196