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Journal Articles New England Journal of Medicine Year : 2018

Gene Therapy in Patients with Transfusion-Dependent beta-Thalassemia

A. A. Thompson
  • Function : Author
M. C. Walters
  • Function : Author
J. Kwiatkowski
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J. E. J. Rasko
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J. -A. Ribeil
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S. Hongeng
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E. Magrin
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G. J. Schiller
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E. Payen
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M. Semeraro
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D. Moshous
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F. Lefrere
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H. Puy
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P. Bourget
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A. Magnani
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L. Caccavelli
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J. -S. Diana
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F. Suarez
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F. Monpoux
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V. Brousse
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C. Poirot
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C. Brouzes
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J. -F. Meritet
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C. Pondarre
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Y. Beuzard
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S. Chretien
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T. Lefebvre
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D. T. Teachey
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U. Anurathapan
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P. J. Ho
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C. von Kalle
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M. Kletzel
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E. Vichinsky
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S. Soni
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G. Veres
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O. Negre
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R. W. Ross
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D. Davidson
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A. Petrusich
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L. Sandler
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M. Asmal
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O. Hermine
M. de Montalembert
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S. Blanche
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P. Leboulch
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M. Cavazzana
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Abstract

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 (HbA(T87Q)). 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 HbA(T87Q), 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 HbA(T87Q) 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.)

Dates and versions

hal-03295931 , version 1 (22-07-2021)

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Cite

A. A. Thompson, M. C. Walters, J. Kwiatkowski, J. E. J. Rasko, J. -A. Ribeil, et al.. Gene Therapy in Patients with Transfusion-Dependent beta-Thalassemia. New England Journal of Medicine, 2018, 378 (16), pp.1479-1493. ⟨10.1056/NEJMoa1705342⟩. ⟨hal-03295931⟩
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