From Bluebird Bio, Cambridge, MA (S.G., D.W., H.B., P.D.G., G.P., M.F., A.Y., M.G., S.B.V., A.M., J.L., R.A.C., M.B.); the Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute-National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD (J.T.); GeneWerk, Heidelberg, Germany (M.S.); the University of Alabama at Birmingham, Birmingham (J.K.); and the Division of Pediatric Hematology-Oncology, Medical University of South Carolina, Charleston (J.J.).
N Engl J Med. 2022 Jan 13;386(2):138-147. doi: 10.1056/NEJMoa2109167. Epub 2021 Dec 12.
Gene therapy with LentiGlobin for sickle cell disease (bb1111, lovotibeglogene autotemcel) consists of autologous transplantation of a patient's hematopoietic stem cells transduced with the BB305 lentiviral vector that encodes the β-globin gene. Acute myeloid leukemia developed in a woman approximately 5.5 years after she had received LentiGlobin for sickle cell disease as part of the initial cohort (Group A) of the HGB-206 study. An analysis of peripheral-blood samples revealed that blast cells contained a BB305 lentiviral vector insertion site. The results of an investigation of causality indicated that the leukemia was unlikely to be related to vector insertion, given the location of the insertion site, the very low transgene expression in blast cells, and the lack of an effect on expression of surrounding genes. Several somatic mutations predisposing to acute myeloid leukemia were present after diagnosis, which suggests that patients with sickle cell disease are at increased risk for hematologic malignant conditions after transplantation, most likely because of a combination of risks associated with underlying sickle cell disease, transplantation procedure, and inadequate disease control after treatment. (Funded by Bluebird Bio.).
用 LentiGlobin 治疗镰状细胞病（bb1111，lovotibeglogene autotemcel）包括用 BB305 慢病毒载体转导患者自身造血干细胞的自体移植，该载体编码β-珠蛋白基因。在接受 LentiGlobin 治疗镰状细胞病约 5.5 年后，一名女性患者发展为急性髓系白血病，她是 HGB-206 研究的初始队列（A 组）的一部分。对外周血样本的分析显示，母细胞中含有 BB305 慢病毒载体插入位点。因果关系调查的结果表明，鉴于插入位点的位置、母细胞中转基因的极低表达以及对周围基因表达没有影响，该白血病不太可能与载体插入有关。诊断后存在几种导致急性髓系白血病的体细胞突变，这表明镰状细胞病患者在移植后发生血液恶性疾病的风险增加，这很可能是由于基础镰状细胞病、移植程序以及治疗后疾病控制不足相关风险的综合作用。（由蓝鸟生物资助）。
