Gene therapy in patients with transfusion-dependent β-thalassemia

A. A. Thompson*, M. C. Walters, J. Kwiatkowski, J. E.J. Rasko, J. A. Ribeil, S. Hongeng, E. Magrin, G. J. Schiller, E. Payen, M. Semeraro, D. Moshous, F. Lefrere, H. Puy, P. Bourget, A. Magnani, L. Caccavelli, J. S. Diana, F. Suarez, F. Monpoux, V. BrousseC. Poirot, C. Brouzes, J. F. Meritet, C. Pondarré, Y. Beuzard, S. Chrétien, T. Lefebvre, D. T. Teachey, U. Anurathapan, P. J. Ho, C. Von Kalle, M. Kletzel, E. Vichinsky, S. Soni, G. Veres, O. Negre, R. W. Ross, D. Davidson, A. Petrusich, L. Sandler, M. Asmal, O. Hermine, M. De Montalembert, S. Hacein-Bey-Abina, S. Blanche, P. Leboulch, M. Cavazzana

*Corresponding author for this work

Research output: Contribution to journalArticle

160 Scopus citations


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 patien with β-thalassemia, we wanted to evaluate the safety and efficacy of such gene therapy in patients with transfusiondependent β-thalassemia. METHODS: In two phase 1-2 studies, we obtained mobilized autologos 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 replicatin-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/β 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 witout serious adverse events related to the drug product.

Original languageEnglish (US)
Pages (from-to)1479-1493
Number of pages15
JournalNew England Journal of Medicine
Issue number16
StatePublished - Apr 19 2018

ASJC Scopus subject areas

  • Medicine(all)

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    Thompson, A. A., Walters, M. C., Kwiatkowski, J., Rasko, J. E. J., Ribeil, J. A., Hongeng, S., Magrin, E., Schiller, G. J., Payen, E., Semeraro, M., Moshous, D., Lefrere, F., Puy, H., Bourget, P., Magnani, A., Caccavelli, L., Diana, J. S., Suarez, F., Monpoux, F., ... Cavazzana, M. (2018). Gene therapy in patients with transfusion-dependent β-thalassemia. New England Journal of Medicine, 378(16), 1479-1493.