Beta-Thalassemia Gene Therapy Continues to Show Efficacy in Longer-Term Follow-up

Updated results from the phase I/II HGB-204 and HGB-207 trials indicated that several patients with severe, transfusion-dependent beta-thalassemia have remained transfusion-free up to four years after treatment with LentiGlobin gene therapy. Usanarat Anurathapan, MD, from Ramathibodi Hospital and Mahidol University in Bangkok, Thailand presented the results at the 2019 Transplantation & Cellular Therapy Meetings of the American Society for Blood and Marrow Transplantation and the Center for International Blood & Marrow Transplant Research.

The LentiGlobin gene-therapy product is designed to overcome a key limitation of allogeneic hematopoietic cell transplantation – lack of a compatible donor – for patients who require long-term red blood cell (RBC) transfusions, Dr. Anurathapan explained. To manufacture this gene therapy, investigators obtained mobilized autologous CD34-positive cells from patients, then transduced the cells ex vivo with the LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino-acid substitution (HbAT87Q). Patients underwent conditioning with busulfan prior to the modified cells being re-infused.

Earlier results from 22 patients enrolled in the two companion trials were published in the New England Journal of Medicine, and data from the HGB trials were recently used to support the E.U. regulatory review of LentiGlobin for transfusion-dependent thalassemia.

During his presentation, Dr. Anurathapan shared longer-term follow-up from each study. As of September 14, 2018, 18 patients (median age = 20 years; range = 12-35 years) had been treated in the HGB-204 trial and 16 patients (median age = 19 years; range = 8-34 years) had been treated in HGB-207.

HGB-204 included patients with either non-β0/β0 or β0/β0 genotypes, while HGB-207 included those with only non-β0/β0 genotypes. All participants were transfusion dependent at the time of enrollment (defined as the receipt of ≥8 transfusions or ≥100 mL/kg of packed RBCs per year in the 2 years before enrollment).

In both studies, participants were treated with a median of 8.0×106 cells/kg (median = 5.0-19.4×106 cells/kg).

Two-thirds of patients (n=23/34) experienced an any-grade bleeding-related adverse event (AE) within two years of infusion.

“The safety profile was generally consistent with a myeloablative conditioning regimen,” Dr. Anurathapan noted. Most treatment-related AEs were grade 1 (including abdominal pain, dyspnea, and dysplasia), but two patients in HGB-204 and one patient in HGB-207 experienced serious AEs (1 thrombosis and 2 instances of veno-occlusive liver disease [VOD]).

After a median follow-up of 38.9 months (range = 29.3-48.1 months), 16 of 18 patients in HGB-204 (89%) achieved the study’s primary endpoint of Hb improvement (defined as ≥2 g/dL of HbAT87Q between 18 and 24 months after infusion). Hb levels were stable in all patients, ranging from 9.1 g/dL to 12.5 g/dL at the last study visit.

Eleven patients achieved transfusion independence, which ranged from 22.8 to 46.3 months at last follow-up. A greater proportion of patients with non-β0/β0 genotypes achieved transfusion independence (n=8/10; 80%), compared with patients with β0/β0 genotype (n=3/8; 37.5%).

After a median follow-up of 9.3 months (range = 0.7-20.4 months), 11 patients in HGB-207 had at least three months of follow-up and were evaluable. Ten of these patients (91%) had stopped RBC transfusions, with all achieving Hb levels of at least 11 g/dL at last study visit.

Three patients had at least 12 months of follow-up and were evaluable for the primary endpoint analysis; two patients met the criteria for the primary endpoint (Hb ≥9 g/dL without RBC transfusions for ≥12 months post-infusion).

These data suggest that patients can achieve “near-normal” Hb levels without transfusions or any additional safety signals compared with myeloablative transplant conditioning, Dr. Anurathapan concluded.

The patient population in each trial was small, which limits the broad applicability of the studies’ results. Dr. Anurathapan added that the small number of enrolled patients limits the investigators’ ability to identify potential factors that caused delayed platelet engraftment in some patients.

The authors report relationships with Bluebird Bio, the manufacturer of LentiGlobin and the sponsor of this trial.


Anurathapan U, Locatelli F, Kwiatkowski JL, et al. Lentiglobin gene therapy for transfusion-dependent ß-thalassemia: outcomes from the phase 1/2 Northstar and phase 3 Northstar-2 studies. Abstract #84. Presented at the Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, February 23, 2019; Houston, TX.