• Sunita Goyal, John Tisdale, Manfred Schmidt, Julie Kanter, Jennifer Jaroscak, Dustin Whitney, Hans Bitter, Philip D Gregory, Geoffrey Parsons, Marianna Foos, Ashish Yeri, Maple Gioia, Sarah B Voytek, Alex Miller, Jessie Lynch, Richard A Colvin, and Melissa Bonner.
• 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.

AbstractGene 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.).Copyright © 2021 Massachusetts Medical Society.

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