Gene therapy in patients with transfusion-dependent β-thalassemia

Alexis 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. Brousse & 27 others C. 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, Morris 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

96 Citations (Scopus)

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 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
Volume378
Issue number16
DOIs
StatePublished - Apr 19 2018

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Thalassemia
Genetic Therapy
Hemoglobins
Genotype
Busulfan
Lentivirus
Globins
Cell Transplantation
Stem Cell Transplantation
Amino Acid Substitution
Genes
Reference Values
Transplantation
Biomarkers
Tissue Donors
Safety
Mutation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Thompson, A. A., Walters, M. C., Kwiatkowski, J., Rasko, J. E. J., Ribeil, J. A., Hongeng, S., ... Cavazzana, M. (2018). Gene therapy in patients with transfusion-dependent β-thalassemia. New England Journal of Medicine, 378(16), 1479-1493. https://doi.org/10.1056/NEJMoa1705342
Thompson, Alexis 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. ; Brousse, V. ; Poirot, C. ; Brouzes, C. ; Meritet, J. F. ; Pondarré, C. ; Beuzard, Y. ; Chrétien, S. ; Lefebvre, T. ; Teachey, D. T. ; Anurathapan, U. ; Ho, P. J. ; Von Kalle, C. ; Kletzel, Morris ; Vichinsky, E. ; Soni, S. ; Veres, G. ; Negre, O. ; Ross, R. W. ; Davidson, D. ; Petrusich, A. ; Sandler, L. ; Asmal, M. ; Hermine, O. ; De Montalembert, M. ; Hacein-Bey-Abina, S. ; Blanche, S. ; Leboulch, P. ; Cavazzana, M. / Gene therapy in patients with transfusion-dependent β-thalassemia. In: New England Journal of Medicine. 2018 ; Vol. 378, No. 16. pp. 1479-1493.
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author = "Thompson, {Alexis A} and Walters, {M. C.} and J. Kwiatkowski and Rasko, {J. E.J.} and Ribeil, {J. A.} and S. Hongeng and E. Magrin and Schiller, {G. J.} and E. Payen and M. Semeraro and D. Moshous and F. Lefrere and H. Puy and P. Bourget and A. Magnani and L. Caccavelli and Diana, {J. S.} and F. Suarez and F. Monpoux and V. Brousse and C. Poirot and C. Brouzes and Meritet, {J. F.} and C. Pondarr{\'e} and Y. Beuzard and S. Chr{\'e}tien and T. Lefebvre and Teachey, {D. T.} and U. Anurathapan and Ho, {P. J.} and {Von Kalle}, C. and Morris Kletzel and E. Vichinsky and S. Soni and G. Veres and O. Negre and Ross, {R. W.} and D. Davidson and A. Petrusich and L. Sandler and M. Asmal and O. Hermine and {De Montalembert}, M. and S. Hacein-Bey-Abina and S. Blanche and P. Leboulch and M. Cavazzana",
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month = "4",
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Thompson, AA, Walters, MC, Kwiatkowski, J, Rasko, JEJ, Ribeil, JA, Hongeng, S, Magrin, E, Schiller, GJ, Payen, E, Semeraro, M, Moshous, D, Lefrere, F, Puy, H, Bourget, P, Magnani, A, Caccavelli, L, Diana, JS, Suarez, F, Monpoux, F, Brousse, V, Poirot, C, Brouzes, C, Meritet, JF, Pondarré, C, Beuzard, Y, Chrétien, S, Lefebvre, T, Teachey, DT, Anurathapan, U, Ho, PJ, Von Kalle, C, Kletzel, M, Vichinsky, E, Soni, S, Veres, G, Negre, O, Ross, RW, Davidson, D, Petrusich, A, Sandler, L, Asmal, M, Hermine, O, De Montalembert, M, Hacein-Bey-Abina, S, Blanche, S, Leboulch, P & Cavazzana, M 2018, 'Gene therapy in patients with transfusion-dependent β-thalassemia', New England Journal of Medicine, vol. 378, no. 16, pp. 1479-1493. https://doi.org/10.1056/NEJMoa1705342

Gene therapy in patients with transfusion-dependent β-thalassemia. / Thompson, Alexis 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.; Brousse, V.; Poirot, C.; Brouzes, C.; Meritet, J. F.; Pondarré, C.; Beuzard, Y.; Chrétien, S.; Lefebvre, T.; Teachey, D. T.; Anurathapan, U.; Ho, P. J.; Von Kalle, C.; Kletzel, Morris; Vichinsky, E.; Soni, S.; Veres, G.; Negre, O.; Ross, R. W.; Davidson, D.; Petrusich, A.; Sandler, L.; Asmal, M.; Hermine, O.; De Montalembert, M.; Hacein-Bey-Abina, S.; Blanche, S.; Leboulch, P.; Cavazzana, M.

In: New England Journal of Medicine, Vol. 378, No. 16, 19.04.2018, p. 1479-1493.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Gene therapy in patients with transfusion-dependent β-thalassemia

AU - Thompson, Alexis A

AU - Walters, M. C.

AU - Kwiatkowski, J.

AU - Rasko, J. E.J.

AU - Ribeil, J. A.

AU - Hongeng, S.

AU - Magrin, E.

AU - Schiller, G. J.

AU - Payen, E.

AU - Semeraro, M.

AU - Moshous, D.

AU - Lefrere, F.

AU - Puy, H.

AU - Bourget, P.

AU - Magnani, A.

AU - Caccavelli, L.

AU - Diana, J. S.

AU - Suarez, F.

AU - Monpoux, F.

AU - Brousse, V.

AU - Poirot, C.

AU - Brouzes, C.

AU - Meritet, J. F.

AU - Pondarré, C.

AU - Beuzard, Y.

AU - Chrétien, S.

AU - Lefebvre, T.

AU - Teachey, D. T.

AU - Anurathapan, U.

AU - Ho, P. J.

AU - Von Kalle, C.

AU - Kletzel, Morris

AU - Vichinsky, E.

AU - Soni, S.

AU - Veres, G.

AU - Negre, O.

AU - Ross, R. W.

AU - Davidson, D.

AU - Petrusich, A.

AU - Sandler, L.

AU - Asmal, M.

AU - Hermine, O.

AU - De Montalembert, M.

AU - Hacein-Bey-Abina, S.

AU - Blanche, S.

AU - Leboulch, P.

AU - Cavazzana, M.

PY - 2018/4/19

Y1 - 2018/4/19

N2 - 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.

AB - 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.

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U2 - 10.1056/NEJMoa1705342

DO - 10.1056/NEJMoa1705342

M3 - Article

VL - 378

SP - 1479

EP - 1493

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 16

ER -

Thompson AA, Walters MC, Kwiatkowski J, Rasko JEJ, Ribeil JA, Hongeng S et al. Gene therapy in patients with transfusion-dependent β-thalassemia. New England Journal of Medicine. 2018 Apr 19;378(16):1479-1493. https://doi.org/10.1056/NEJMoa1705342