preheader BJH 1

High rates of sustained transfusion independence following gene transfer in patients with β-Thalassemia Major

Long-term results of an international study suggest that gene therapy with Betibeglogene autotemcel is a potentially curative gene therapy for patients with transfusion-dependent β-thalassemia (TDT), inducing durable transfusion independence (TI) in more than three quarters of patients. TDT patients who achieved TI after gene therapy also experienced significant reductions in iron overload following chelation therapy, and this iron control was maintained after chelation therapy was discontinued.

Transfusion-dependent β-thalassemia (TDT) is a severe genetic disease requiring lifelong, regular packed red blood cell (pRBC) transfusions and iron chelation treatment. Despite this iron chelation, many patients will eventually develop iron overload, which in turn can lead to chronic diseases including cardiovascular problems, diabetes, and osteoarthritis. Betibeglogene autotemcel (beti-cel) is a one-time ex vivo gene therapy that addresses the underlying cause of TDT to potentially facilitate a lifelong, stable production of modified adult hemoglobin (Hb) at a sufficient level to achieve transfusion independence (TI). The potential of beti-cel as a treatment for TDT was assessed in two completed phase I/II studies (HGB-204, HGB-205) and in two ongoing phase III studies (HGB-207, HGB-212). After 2 years of follow-up, patients from these studies could enroll in a long-term follow-up study (LTF-303 [NCT02633943]) for up to an additional 13 years. During ASH 2021, results from LTF-303 were presented with up to 7 years of follow-up.

Study design and main results

Patients included in this study underwent single-agent, pharmacokinetic-adjusted busulfan myeloablation after which they were infused with autologous CD34+ cells transduced with BB305 lentiviral vector. LTF-303 assessments included transfusion status, Hb, iron overload, and safety.

LTF-303 enrolled a total of 57 patients (22 from phase I/II studies, 35 from phase III trials), of whom 55% were female. The median age of study participants was 19 years old, ranging from 5 to 35 years. The rate of TI was 68.2% for patients treated in the phase I/II studies with a median duration of ongoing TI of 65.9 months. In the phase I/II group, the weighted average HB level during TI was 10.3 g/dL. Among patients who participated in the phase III trials the rate of TI was 88.6% with a median duration of TI of 32 months. In this cohort, the weighted average HB level during TI was 11.6 g/dL. In patients who achieved TI, several markers indicated an improved erythropoiesis together with significant reductions in iron burden. Overall, 74% of TI patients restarted iron chelation after beti-cel infusion with a median time to the start of chelation therapy of 8.1 months. Twenty of the 34 patients who restarted iron chelation have since stopped chelation therapy. The median duration of the iron chelation therapy for these patients was 25.7 months. Interestingly, subanalyses showed restoration of the iron homeostasis in response to iron chelation therapy with a stabilization of iron markers after chelation was stopped in patients with TI.

Serious AEs occurring after 2 y in LTF-303 were reported in 8 patients (diabetic ketoacidosis, gonadotropic insufficiency, ectopic pregnancy, fetal death, cholelithiasis, gallbladder wall thickening/polyp, bacteremia with neutropenia, pulmonary embolism, and major depression; each n=1). No beti-cel–related AEs were observed beyond 2 years after the infusion. No deaths, replication-competent lentivirus, insertional oncogenesis, or malignancies were reported. Insertion site analysis indicated sustained polyclonal hematopoiesis.


In summary, based on these long-term results it is safe to say that beti-cel is a potentially curative gene therapy for patients with TDT offering patients a chance to become transfusion independent with near-normal Hb levels. Furthermore, TDT patients who achieved TI after gene therapy experienced reductions in iron overload following chelation therapy, and this iron control was maintained after chelation was discontinued.


Thompson A, et al. Restoring Iron Homeostasis in Pts Who Achieved Transfusion Independence after Treatment with Betibeglogene Autotemcel Gene Therapy: Results from up to 7 Years of Follow-up. Presented at ASH 2021; Abstract 573.

Speaker Alexis A. Thompson

Alexis A. Thompson

Alexis A. Thompson, MD, MPH, Ann & Robert H. Lurie Children’s Hospital of Chicago, IL, USA


See: Keyslides


Back to Top