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Gene Therapy in Patients with Transfusion-Dependent [beta]-Thalassemia.
Thompson, Alexis A. M.D., M.P.H.; Walters, Mark C. M.D.; Kwiatkowski, Janet M.D.; Rasko, John E.J. M.B., B.S., Ph.D.; Ribeil, Jean-Antoine M.D., Ph.D.; Hongeng, Suradej M.D.; Magrin, Elisa Ph.D.; Schiller, Gary J. M.D.; Payen, Emmanuel Ph.D.; Semeraro, Michaela M.D., Ph.D.; Moshous, Despina M.D., Ph.D.; Lefrere, Francois M.D.; Puy, Herve M.D., Ph.D.; Bourget, Philippe Pharm.D., Ph.D.; Magnani, Alessandra M.D., Ph.D.; Caccavelli, Laure Ph.D.; Diana, Jean-Sebastien M.D.; Suarez, Felipe M.D., Ph.D.; Monpoux, Fabrice M.D.; Brousse, Valentine M.D.; Poirot, Catherine M.D., Ph.D.; Brouzes, Chantal M.D.; Meritet, Jean-Francois Ph.D.; Pondarre, Corinne M.D., Ph.D.; Beuzard, Yves M.D.; Chretien, Stany Ph.D.; Lefebvre, Thibaud M.D.; Teachey, David T. M.D.; Anurathapan, Usanarat M.D.; Ho, Joy P. M.B., B.S., D.Phil.; von Kalle, Christof M.D., Ph.D.; Kletzel, Morris M.D.; Vichinsky, Elliott M.D.; Soni, Sandeep M.D.; Veres, Gabor Ph.D.; Negre, Olivier Ph.D.; Ross, Robert W. M.D.; Davidson, David M.D.; Petrusich, Alexandria B.S.; Sandler, Laura M.P.H.; Asmal, Mohammed M.D., Ph.D.; Hermine, Olivier M.D., Ph.D.; De Montalembert, Mariane M.D., Ph.D.; Hacein-Bey-Abina, Salima Pharm.D., Ph.D.; Blanche, Stephane M.D., Ph.D.; Leboulch, Philippe M.D.; Cavazzana, Marina M.D., Ph.D.
[Article] New England Journal of Medicine. 378(16):1479-1493, April 19, 2018.

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Background: Donor availability and transplantation-related risks limit the broad use of allogeneic hematopoietic-cell transplantation in patients with transfusion-dependent [beta]-thalassemia. After previously establishing that lentiviral transfer of a marked [beta]-globin ([beta]A-T87Q) gene could substitute for long-term red-cell transfusions in a patient with [beta]-thalassemia, we wanted to evaluate the safety and efficacy of such gene therapy in patients with transfusion-dependent [beta]-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 [beta]-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-[beta]0/[beta]0 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 [beta]0/[beta]0 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 [beta]-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.)