Thompson AA, et al. - Experts gauged the safety and efficacy of a marked β-globin (βA-T87Q) gene therapy in patients with transfusion-dependent β-thalassemia. The need for long-term red-cell transfusions in 22 patients with severe β-thalassemia was reduced or eliminated by gene therapy with autologous CD34+ cells transduced with the BB305 vector. No serious adverse events were associated with the drug product.

Methods

• Mobilized autologous CD34+ cells were extracted from 22 patients (12 to 35 years of age) with transfusion-dependent β-thalassemia and were then transduced ex vivo with LentiGlobin BB305 vector, which encoded adult hemoglobin (HbA) with a T87Q amino acid substitution (HbAT87Q) in two phase 1-2 studies.
• After the patients had undergone myeloablative busulfan conditioning, the cells were then reinfused.
• This was followed by monitoring of adverse events, vector integration, and levels of replication-competent lentivirus.
• Efficacy assessments involved levels of total hemoglobin and HbAT87Q, transfusion requirements, and average vector copy number.

Results

• All but 1 of the 13 patients who had a non-β0/β0 genotype had stopped receiving red-cell transfusions at a median of 26 months (range, 15 to 42) after infusion of the gene-modified cells.
• The levels of HbAT87Q ranged from 3.4 to 10.0 g per deciliter and the levels of total hemoglobin ranged from 8.2 to 13.7 g per deciliter.
• Correction of biologic markers of dyserythropoiesis was noted in evaluated patients with hemoglobin levels near normal ranges.
• A decrease of 73% was seen in the median annualized transfusion volume, and red-cell transfusions were discontinued in 3 out of 9 patients with a β0/β0 genotype or two copies of the IVS1-110 mutation.
• Treatment-related adverse events were typical of those linked with autologous stem-cell transplantation.
• Results did not reveal any clonal dominance related to vector integration.