لخّصلي

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 ?A-T87Q-globin gene.The phase 1-2 HGB-206 study is evaluating the efficacy and safety of LentiGlobin for sickle cell disease, and an unprespecified interim analysis of the results is now reported in the Journal.8 Here, we report a case of acute myeloid leukemia that developed in a female patient approximately 5.5 years after she had received gene therapy with LentiGlobin as part of the initial cohort (Group A) of the HGB-206 study, as well as the results of investigations to determine whether the development of acute myeloid leukemia was vector-mediated.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.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.

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 βA-T87Q-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.)
Sickle cell disease is a progressive, genetic disease caused by a point mutation in the β-globin gene and is associated with substantial morbidity and early mortality.1,2 Sickle hemoglobin production and subsequent polymerization leads to red-cell sickling, clinically manifesting as chronic hemolytic anemia, vasculopathy, and vaso-occlusion.1,2 Current management of sickle cell disease relies on lifelong use of palliative short-term and long-term therapies.1,2 Allogeneic hematopoietic stem-cell transplantation is the only accepted, potentially curative treatment option for patients with sickle cell disease; however, its use is limited by a paucity of matched donors, immunologic complications, and the inherent risks of transplantation-related morbidity and mortality.1,3,4
Gene therapy with LentiGlobin for sickle cell disease (bb1111, lovotibeglogene autotemcel) consists of autologous transplantation of the patients’ own hematopoietic stem cells (HSCs) transduced with the BB305 lentiviral vector encoding the βA-T87Q-globin gene, which is designed to produce antisickling hemoglobin (HbAT87Q).5-7 Through the use of autologous HSCs, gene therapy with LentiGlobin circumvents the need for a donor and may avoid the immunologic complications associated with allogeneic HSC transplantation. The phase 1–2 HGB-206 study is evaluating the efficacy and safety of LentiGlobin for sickle cell disease, and an unprespecified interim analysis of the results is now reported in the Journal.8 Here, we report a case of acute myeloid leukemia that developed in a female patient approximately 5.5 years after she had received gene therapy with LentiGlobin as part of the initial cohort (Group A) of the HGB-206 study, as well as the results of investigations to determine whether the development of acute myeloid leukemia was vector-mediated.