Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia.

N Engl J Med

From the Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago (A.A.T., M.K.); University of California, San Francisco, Benioff Children's Hospital, Oakland (M.C.W., E.V.), Lucile Salter Packard Children's Hospital at Stanford, Palo Alto (S.S.), and David Geffen School of Medicine, University of California, Los Angeles, Los Angeles (G.J.S.) - all in California; Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia (J.K., D.T.T.); Centenary Institute (J.E.J.R.), University of Sydney, Sydney Medical School (J.E.J.R., P.J.H.), and Royal Prince Alfred Hospital (J.E.J.R., P.J.H.), Camperdown, NSW, Australia; Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (J.-A.R., E.M., D.M., F.L., P.B., A.M., L.C., J.-S.D., F.S., F.M., V.B., C.B., O.H., M.D.M., S.B., M.C.), Groupe Hospitalier Universitaire Ouest (J.-A.R., A.M., L.C., M.C.), IMAGINE Institute (E.M., M.S., D.M., M.C.), Université Paris Descartes (M.S., C. Poirot, S.H.-B.-A.), Université Paris Diderot (H.P., T.L.), Pierre et Marie Curie University (C. Poirot), and Hôpital Cochin (J.-F.M.), Paris, CEA University Paris-Sud, Institute of Emerging Diseases and Innovative Therapies, Fontenay-aux-Roses (E.P., Y.B., S.C., P.L.), Hôpital Louis-Mourier, Colombes (H.P., T.L.), Centre Hospitalier Intercommunal de Créteil, Créteil (C. Pondarré), and Hôpital Bicêtre, Le Kremlin-Bicêtre (S.H.-B.-A.) - all in France; Bluebird Bio, Cambridge (J.-A.R., S.S., G.V., O.N., R.W.R., D.D., A.P., L.S., M.A.), and Harvard Medical School, Brigham and Women's Hospital, Boston (P.L.) - both in Massachusetts; Ramathibodi Hospital, Mahidol University, Bangkok, Thailand (S.H., U.A., P.L.); and the National Center for Tumor Diseases-German Cancer Research Center, Heidelberg, Germany (C.K.).

Published: April 2018

The study aims to assess the safety and effectiveness of gene therapy as an alternative to long-term red-cell transfusions for patients with transfusion-dependent β-thalassemia, focusing on the use of a lentiviral vector to modify patients' cells.
In two phase 1-2 trials involving 22 patients aged 12 to 35, researchers collected and modified the patients' own blood cells with a gene that encodes for adult hemoglobin, followed by reinfusing these cells after conditioning treatment.
Results showed significant improvements: 12 out of 13 patients with a non-β/β genotype stopped needing transfusions, while those with the β/β genotype experienced a

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 (β) 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 (HbA). 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, 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-β/β genotype had stopped receiving red-cell transfusions; the levels of HbA 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 β/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 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 .).

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