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.Mahidol University2026-04-142026-04-142026-01-01Blood (2026)00064971https://repository.li.mahidol.ac.th/handle/123456789/116212Abstract: 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.Biochemistry, Genetics and Molecular BiologyMedicineImmunology and MicrobiologyArticleSCOPUS10.1182/blood.20250291962-s2.0-1050352325671528002041525466