Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia.

Thompson AA1, Walters MC1, Kwiatkowski J1, Rasko JEJ1, Ribeil JA1, Hongeng S1, Magrin E1, Schiller GJ1, Payen E1, Semeraro M1, Moshous D1, Lefrere F1, Puy H1, Bourget P1, Magnani A1, Caccavelli L1, Diana JS1, Suarez F1, Monpoux F1, Brousse V1, Poirot C1, Brouzes C1, Meritet JF1, Pondarré C1, Beuzard Y1, Chrétien S1, Lefebvre T1, Teachey DT1, Anurathapan U1, Ho PJ1, von Kalle C1, Kletzel M1, Vichinsky E1, Soni S1, Veres G1, Negre O1, Ross RW1, Davidson D1, Petrusich A1, Sandler L1, Asmal M1, Hermine O1, De Montalembert M1, Hacein-Bey-Abina S1, Blanche S1, Leboulch P1, Cavazzana M1.

Author information

Abstract

BACKGROUND:

Donor availability and transplantation-related risks limit the broad use of allogeneic hematopoietic-cell transplantation in patients with transfusion-dependent β-thalassemia. After previously establishing that lentiviral transfer of a marked β-globin (βA-T87Q) gene could substitute for long-term red-cell transfusions in a patient with β-thalassemia, we wanted to evaluate the safety and efficacy of such gene therapy in patients with transfusion-dependent β-thalassemia.

METHODS:

In two phase 1-2 studies, we obtained mobilized autologous CD34+ cells from 22 patients (12 to 35 years of age) with transfusion-dependent β-thalassemia and transduced the cells ex vivo with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution (HbAT87Q). The cells were then reinfused after the patients had undergone myeloablative busulfan conditioning. We subsequently monitored adverse events, vector integration, and levels of replication-competent lentivirus. Efficacy assessments included levels of total hemoglobin and HbAT87Q, transfusion requirements, and average vector copy number.

RESULTS:

At a median of 26 months (range, 15 to 42) after infusion of the gene-modified cells, all but 1 of the 13 patients who had a non-β0/β0 genotype had stopped receiving red-cell transfusions; 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 achieved in evaluated patients with hemoglobin levels near normal ranges. In 9 patients with a β0/β0 genotype or two copies of the IVS1-110 mutation, the median annualized transfusion volume was decreased by 73%, and red-cell transfusions were discontinued in 3 patients. Treatment-related adverse events were typical of those associated with autologous stem-cell transplantation. No clonal dominance related to vector integration was observed.

CONCLUSIONS:

Gene therapy with autologous CD34+ cells transduced with the BB305 vector reduced or eliminated the need for long-term red-cell transfusions in 22 patients with severe β-thalassemia without serious adverse events related to the drug product. (Funded by Bluebird Bio and others; HGB-204 and HGB-205 ClinicalTrials.gov numbers, NCT01745120 and NCT02151526 .).