Gene Therapy Alleviates Transfusion Burden in Patients With Beta-Thalassemia

Treatment with gene therapy reduced or eliminated the need for long-term red blood–cell (RBC) transfusions in some patients with severe, transfusion-dependent beta-thalassemia, according to results of two companion phase I/II trials (HGB-204 and HGB-205) published in The New England Journal of Medicine.

“We found that gene therapy with LentiGlobin drug product succeeded in overcoming a principal limitation of allogeneic hematopoietic-cell transplantation, which is a lack of a histocompatible donor,” wrote the authors, led by Alexis A. Thompson, MD, MPH, from Ann & Robert H. Lurie Children’s Hospital of Chicago and 2018 president of the American Society of Hematology. Their results, though early, suggest that gene therapy may be an alternative treatment option for people who lack a suitable donor for allogeneic hematopoietic-cell transplantation.

The trials expand on an earlier single-patient, proof-of-concept study in which investigators established the feasibility of adding a gene to autologous hematopoietic cells using a lentiviral vector. The patient was able to safely discontinue transfusions for more than six years.

“Gene therapy with LentiGlobin drug product succeeded in overcoming a principal limitation of allogeneic hematopoietic-cell transplantation, which is a lack of a histocompatible donor.”

In the recently published phase I/II trials, the researchers evaluated the safety and efficacy of such gene therapy (BB305 vector) in 22 patients (18 in HGB-204 and 4 in HGB-205) with beta-thalassemia of any genotype who were transfusion dependent. Transfusion dependence was defined as the receipt of at least eight transfusions or at least 100 mL/kg of packed RBCs per year in the two years before enrollment.

The trial population included nine patients with a β0/β0 genotype (the most severe form of beta-thalassemia), nine with a βE/β0 genotype, and four patients with other genotypes.

The investigators obtained mobilized, autologous CD34-positive cells from participants and transduced the cells ex vivo with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino-acid substitution (HbAT87Q). After undergoing conditioning with single-agent, intravenous busulfan, modified cells were then re-infused at median doses of:

  • 0 million CD34-positive cells/kg (range = 6.1 million to 18.1 million cells/kg) in people with a β0/β0 genotype
  • 1 million CD34-positive cells/kg (range = 5.2 million to 13.0 million cells/kg) in those with other genotypes

Participants started receiving transfusions at an early age (median = 3.5 years in HGB-204 and 1.8 years in HGB-205 [range = 0-26 years and 0-14 years, respectively]). Median age at the time of trial enrollment was 20 years in HGB-204 (range = 12-35 years) and 18 years in HGB-205 (range = 16-19 years).

After a median of 26 months of follow-up (range = 15-42 months) after infusion, the authors reported no serious adverse events (AEs) related to the BB305 vector in either study. In HGB-204, five grade 1 AEs were characterized as related or possibly related to the drug product; the nine serious AEs reported in this study were attributed to busulfan conditioning. In HGB-205, no serious AEs were considered related to the drug product.

Following the infusion of the LentiGlobin drug product, seven of the 22 treated patients expressed at least 8 g/dL of HbAT87Q at the last visit, including three patients with a β0/β0 genotype. In addition, all have been free from transfusion for more than one year.

“Although the studies were not designed to test specific hypotheses about differences in the characteristics of the patients or the drug products, clinical outcomes appeared to vary according to the underlying genotype,” the authors noted.

All but one of the 13 patients with a non–β0/β0 genotype stopped receiving red-cell transfusions after gene therapy. At the last study visit (12 to 36 months after infusion), the median HbAT87Q level was 6.0 g/dL (range = 3.4-10.0 g/dL), and the median total hemoglobin level was 11.2 g/dL (range = 8.2-13.7 g/dL) in these patients.

Of the nine patients with a β0/β0 genotype, six had a median HbAT87Q level of 4.2 g/dL (range = 0.4-8.7 g/dL) and continued to receive transfusions. However, they experienced a 74 percent reduction in their annual number of transfusions and a 73 percent reduction in their annual transfusion volume (which ranged from 124 to 161 mL/kg in both trials), compared with the transfusion needs two years before enrollment (p values not reported).

The remaining three patients with a β0/β0 genotype had not received transfusions for 14 to 20 months, the investigators added.

While not all patients were able to stop receiving RBC transfusions, the investigators noted that “even the partial reduction in transfusion requirements that we observed in these patients may result in a reduction in iron load (and thereby long-term damage to target organs) and an increased life expectancy.

The findings from these early-phase studies are limited by the small number of patients enrolled, and the investigators noted that extended follow-up is necessary to establish the durability of transduction hematopoietic stem cells and progenitor cells after a single infusion. “Long-term surveillance of treatment-related toxicity related to the transfer of genes into hematopoietic stem cells and progenitor cells, busulfan conditioning, or both will also be necessary to define the therapeutic profile of this new treatment approach,” they concluded.

The corresponding authors report financial relationships with Bluebird Bio, which also supported this study.


Thompson AA, Walters MC, Kwiatkowski J, et al. Gene therapy in patients with transfusion-dependent β-thalassemia. N Engl J Med. 2018;378:1479-93.