Long-term outcomes of lentiviral gene therapy for the β-hemoglobinopathies: the HGB-205 trial

• Published in: Nature medicine Vol. 28; no. 1; pp. 81 - 88
• Main Authors: Magrin, Elisa, Semeraro, Michaela, Hebert, Nicolas, Joseph, Laure, Magnani, Alessandra, Chalumeau, Anne, Gabrion, Aurélie, Roudaut, Cécile, Marouene, Jouda, Lefrere, Francois, Diana, Jean-Sebastien, Denis, Adeline, Neven, Bénédicte, Funck-Brentano, Isabelle, Negre, Olivier, Renolleau, Sylvain, Brousse, Valentine, Kiger, Laurent, Touzot, Fabien, Poirot, Catherine, Bourget, Philippe, El Nemer, Wassim, Blanche, Stéphane, Tréluyer, Jean-Marc, Asmal, Mohammed, Walls, Courtney, Beuzard, Yves, Schmidt, Manfred, Hacein-Bey-Abina, Salima, Asnafi, Vahid, Guichard, Isabelle, Poirée, Maryline, Monpoux, Fabrice, Touraine, Philippe, Brouzes, Chantal, de Montalembert, Mariane, Payen, Emmanuel, Six, Emmanuelle, Ribeil, Jean-Antoine, Miccio, Annarita, Bartolucci, Pablo, Leboulch, Philippe, Cavazzana, Marina
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2022; Nature Publishing Group
• Subjects: 631/61/201; 692/308/153; 692/699/1541; Adolescent; Anemia, Sickle Cell - therapy; Autografts; beta-Thalassemia - therapy; Biomedical and Life Sciences; Biomedicine; Blood diseases; Busulfan; Cancer Research; CD34 antigen; DNA nucleotidylexotransferase; Female; Gene therapy; Genetic Therapy - adverse effects; Humans; Infectious Diseases; Lentivirus - genetics; Male; Metabolic Diseases; Molecular Medicine; Neurosciences; Patients; Remission; Sickle cell disease; Thalassemia; Transfusion; Transplantation; Treatment Outcome; Young Adult
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-021-01650-w

Sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT) are the most prevalent monogenic disorders worldwide. Trial HGB-205 ( NCT02151526 ) aimed at evaluating gene therapy by autologous CD34 + cells transduced ex vivo with lentiviral vector BB305 that encodes the anti-sickling β A-T87Q -globin expressed in the erythroid lineage. HGB-205 is a phase 1/2, open-label, single-arm, non-randomized interventional study of 2-year duration at a single center, followed by observation in long-term follow-up studies LTF-303 ( NCT02633943 ) and LTF-307 ( NCT04628585 ) for TDT and SCD, respectively. Inclusion and exclusion criteria were similar to those for allogeneic transplantation but restricted to patients lacking geno-identical, histocompatible donors. Four patients with TDT and three patients with SCD, ages 13–21 years, were treated after busulfan myeloablation 4.6–7.9 years ago, with a median follow-up of 4.5 years. Key primary endpoints included mortality, engraftment, replication-competent lentivirus and clonal dominance. No adverse events related to the drug product were observed. Clinical remission and remediation of biological hallmarks of the disease have been sustained in two of the three patients with SCD, and frequency of transfusions was reduced in the third. The patients with TDT are all transfusion free with improvement of dyserythropoiesis and iron overload. The final report of the phase 1/2 lentiviral gene therapy trial in severe β-hemoglobinopathies, HGB-205, shows a long-term safety profile and sustained reduction of transfusion requirements in patients with β-thalassemia and of sickle cell crises in patients with sickle cell disease.