Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia
Alexis A Thompson, Mark C Walters, Janet Kwiatkowski, John E J Rasko, Jean-Antoine Ribeil, Suradej Hongeng, Elisa Magrin, Gary J Schiller, Emmanuel Payen, Michaela Semeraro, Despina Moshous, Francois Lefrere, Hervé Puy, Philippe Bourget, Alessandra Magnani, Laure Caccavelli, Jean-Sébastien Diana, Felipe Suarez, Fabrice Monpoux, Valentine Brousse, Catherine Poirot, Chantal Brouzes, Jean-François Meritet, Corinne Pondarré, Yves Beuzard, Stany Chrétien, Thibaud Lefebvre, David T Teachey, Usanarat Anurathapan, P Joy Ho, Christof von Kalle, Morris Kletzel, Elliott Vichinsky, Sandeep Soni, Gabor Veres, Olivier Negre, Robert W Ross, David Davidson, Alexandria Petrusich, Laura Sandler, Mohammed Asmal, Olivier Hermine, Mariane De Montalembert, Salima Hacein-Bey-Abina, Stéphane Blanche, Philippe Leboulch, Marina Cavazzana, Alexis A Thompson, Mark C Walters, Janet Kwiatkowski, John E J Rasko, Jean-Antoine Ribeil, Suradej Hongeng, Elisa Magrin, Gary J Schiller, Emmanuel Payen, Michaela Semeraro, Despina Moshous, Francois Lefrere, Hervé Puy, Philippe Bourget, Alessandra Magnani, Laure Caccavelli, Jean-Sébastien Diana, Felipe Suarez, Fabrice Monpoux, Valentine Brousse, Catherine Poirot, Chantal Brouzes, Jean-François Meritet, Corinne Pondarré, Yves Beuzard, Stany Chrétien, Thibaud Lefebvre, David T Teachey, Usanarat Anurathapan, P Joy Ho, Christof von Kalle, Morris Kletzel, Elliott Vichinsky, Sandeep Soni, Gabor Veres, Olivier Negre, Robert W Ross, David Davidson, Alexandria Petrusich, Laura Sandler, Mohammed Asmal, Olivier Hermine, Mariane De Montalembert, Salima Hacein-Bey-Abina, Stéphane Blanche, Philippe Leboulch, Marina Cavazzana
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 .).
Source: PubMed