Betibeglogene autotemcel gene therapy in patients with transfusion-dependent, severe genotype β-thalassaemia (HGB-212): a non-randomised, multicentre, single-arm, open-label, single-dose, phase 3 trial.

Autor:	Kwiatkowski JL; Division of Hematology, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: kwiatkowski@chop.edu., Walters MC; University of California San Francisco Benioff Children's Hospital, Oakland, CA, USA., Hongeng S; Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand., Yannaki E; Gene and Cell Therapy Center of the Hematology Dept and Hematopoietic Cell Transplantation Unit, George Papanicolaou Hospital, Thessaloniki, Greece., Kulozik AE; Department of Paediatric Oncology, Haematology, Oncology and Immunology, University of Heidelberg, Heidelberg, Germany; Hopp Children's Cancer Centre, Heidelberg, Germany; Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany; Clinical Co-operation Unit, Paediatric Leukaemia, DKFZ, and Medical Faculty, University of Heidelberg, Heidelberg, Germany., Kunz JB; Department of Paediatric Oncology, Haematology, Oncology and Immunology, University of Heidelberg, Heidelberg, Germany; Hopp Children's Cancer Centre, Heidelberg, Germany., Sauer MG; Department of Pediatric Hematology and Oncology and Blood Stem Cell Transplantation, Hannover Medical School, Hannover, Germany., Thrasher AJ; UCL Great Ormond Street Institute of Child Health, Great Ormond Street Hospital NHS Trust, London, UK., Thuret I; Department of Pediatric Hematology and Oncology, Rare Disease Center for Thalassemia, Hôpital de la Timone, Marseille, France., Lal A; University of California San Francisco Benioff Children's Hospital, Oakland, CA, USA., Tao G; Bluebird Bio, Somerville, MA, USA., Ali S; Bluebird Bio, Somerville, MA, USA., Thakar HL; Bluebird Bio, Somerville, MA, USA., Elliot H; Bluebird Bio, Somerville, MA, USA., Lodaya A; Bluebird Bio, Somerville, MA, USA., Lee J; Bluebird Bio, Somerville, MA, USA., Colvin RA; Bluebird Bio, Somerville, MA, USA., Locatelli F; IRCCS Ospedale Pediatrico Bambino Gesù, Catholic University of the Sacred Heart, Rome, Italy., Thompson AA; Division of Hematology, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Jazyk:	angličtina
Zdroj:	Lancet (London, England) [Lancet] 2024 Nov 08. Date of Electronic Publication: 2024 Nov 08.
DOI:	10.1016/S0140-6736(24)01884-1
Abstrakt:	Background: Transfusion-dependent β-thalassaemia (TDT) is a severe disease, resulting in lifelong blood transfusions, iron overload, and associated complications. Betibeglogene autotemcel (beti-cel) gene therapy uses autologous haematopoietic stem and progenitor cells (HSPCs) transduced with BB305 lentiviral vector to enable transfusion independence. Methods: HGB-212 was a non-randomised, multicentre, single-arm, open-label, phase 3 study of beti-cel in patients with TDT conducted at eight centres in France, Germany, Greece, Italy, the UK, and the USA. Patients with β 0 /β 0 , β 0 /β +IVS-I-110 , or β +IVS-I-110 /β +IVS-I-110 genotypes, clinically stable TDT, and a transfusion history of at least 100 mL/kg per year of packed red blood cells (pRBCs) or at least eight transfusions of pRBCs per year in the 2 years before enrolment were eligible for participation. After undergoing HSPC mobilisation and busulfan-based, pharmacokinetic-adjusted myeloablative conditioning, patients were infused with beti-cel and followed up for 24 months. The primary efficacy outcome was transfusion independence, defined as weighted average haemoglobin level of 9 g/dL or above without pRBC transfusions for 12 or more months. The primary outcome was measured in all patients who received an infusion of beti-cel (transplant population); safety was evaluated in all patients who initiated study treatment (intention-to-treat population). Patients were eligible to enrol in the ongoing 13-year long-term follow-up study (for a total of 15 years), LTF-303 (registered at ClinicalTrials.gov, NCT02633943). This trial, HGB-212, was registered at ClinicalTrials.gov (NCT03207009), and is complete. Findings: From June 8, 2017, to March 12, 2020, 20 patients were screened for eligibility. One patient was ineligible and one withdrew consent before HSPC mobilisation and myeloablative conditioning. Of the 18 patients who received beti-cel, ten (56%) were male and eight (44%) were female; 13 (72%) were younger than 18 years at the time of informed consent, and five (28%) were older than 18 years. 12 (67%) patients had β 0 /β 0 genotypes, three (17%) had β 0 / β +IVS-I-110 , and three (17%) had β +IVS-I-110 /β +IVS-I-110 . As of Jan 30, 2023, all patients enrolled in the long-term follow-up study and the median follow-up was 47·9 months (range 23·8-59·0). All 18 patients were evaluable for transfusion independence, with 16 (89%) of 18 reaching and maintaining transfusion independence to last follow=up (estimated effect size 89·9% [95% CI 65·3-98·6]). All patients had at least one adverse event after beti-cel infusion. There were no serious adverse events considered to be related to beti-cel, and no deaths. Interpretation: These data demonstrate that beti-cel can allow patients with genotypes that cause severe β-thalassaemia (β 0 /β 0 , β 0 /β +IVS-I-110 , or β +IVS-I-110 /β +IVS-I-110 ) to reach transfusion independence. Beti-cel offers the potential to attain near-normal haemoglobin levels for those with severe forms of TDT, and a potentially curative option without the risks and limitations of allogeneic HSPC transplantation. Patients are being followed up for a total of 15 years to assess the durability of transfusion independence and long-term safety profile of beti-cel. Funding: Bluebird Bio, Somerville, MA, USA. Competing Interests: Declaration of interests JLK reports research funding from Bluebird Bio, Vertex Pharmaceuticals, Editas, Sangamo, Sanofi, Regeneron, Agios, Forma, and Imara; consultancy fees from Bluebird Bio, Vertex Pharmaceuticals, Forma, and Imara; and advisory board roles at Celgene (Bristol Myers Squibb), Silence Therapeutics, Chiesi, and Pfizer. IT reports advisory board roles from Bluebird Bio, Vertex Pharmaceuticals, Global Blood Therapeutics, and Pfizer. AAT reports research funding from Bluebird Bio, Vertex Pharmaceuticals, Beam, Editas, and Novartis; consultancy fees from Bluebird Bio, Beam, Editas, and Roche; and equity ownership in Global Blood Therapeutics. FL reports consultancy fees from Bluebird Bio and Vertex; and speaker bureau fees from Sanofi, AMGEN, BMS, Miltenyi, and Gilead. MCW reports consultancy from Vertex Pharmaceuticals and an advisory board role from Ensoma. AEK reports royalties and honoraria from Bluebird Bio. JBK reports consultancy fees from Bluebird Bio, Novartis, Vertex Pharmaceuticals, Global Blood Therapeutics, and Pfizer; research funding from Global Blood Therapeutics and Pfizer; advisory board roles at Global Blood Therapeutics and Novartis; and honoraria from Pfizer and Novartis. EY reports clinical research funding from Bluebird Bio. GT, HE, SA, HLT, ALo, JL, and RAC report employment at and stock in Bluebird Bio. All other authors declare no competing interests. (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu