• Julie Kanter, Mark C Walters, Lakshmanan Krishnamurti, Markus Y Mapara, Janet L Kwiatkowski, Stacey Rifkin-Zenenberg, Banu Aygun, Kimberly A Kasow, Francis J Pierciey, Melissa Bonner, Alex Miller, Xinyan Zhang, Jessie Lynch, Dennis Kim, Jean-Antoine Ribeil, Mohammed Asmal, Sunita Goyal, Alexis A Thompson, and John F Tisdale.
• From the University of Alabama Birmingham, Birmingham (J.K.); UCSF Benioff Children's Hospital, Oakland, CA (M.C.W.); Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Children's Healthcare of Atlanta, Emory University, Atlanta (L.K.); the Division of Hematology-Oncology, Columbia Center for Translational Immunology, Columbia University Medical Center, New York (M.Y.M.), the Division of Pediatric Hematology, Oncology and Cellular Therapy, Cohen Children's Medical Center, New Hyde Park (B.A.), and Zucker School of Medicine at Hofstra-Northwell, Hempstead (B.A.) - all in New York; the Division of Hematology, Children's Hospital of Philadelphia, and the Department of Pediatrics, University of Pennsylvania Perelman School of Medicine - both in Philadelphia (J.L.K.); Hackensack University Medical Center, Hackensack, NJ (S.R.-Z.); the University of North Carolina at Chapel Hill, Chapel Hill (K.A.K.); Bluebird Bio, Cambridge, MA (F.J.P., M.B., A.M., X.Z., J.L., D.K., J.-A.R., M.A., S.G.); Northwestern University Feinberg School of Medicine and Ann and Robert H. Lurie Children's Hospital - both in Chicago (A.A.T.); and the Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute and National Institute of Diabetes and Digestive and Kidney Diseases (NHLBI-NIDDK), National Institutes of Health, Bethesda, MD (J.F.T.).
• N. Engl. J. Med. 2022 Feb 17; 386 (7): 617-628.

BackgroundSickle cell disease is characterized by the painful recurrence of vaso-occlusive events. Gene therapy with the use of LentiGlobin for sickle cell disease (bb1111; lovotibeglogene autotemcel) consists of autologous transplantation of hematopoietic stem and progenitor cells transduced with the BB305 lentiviral vector encoding a modified β-globin gene, which produces an antisickling hemoglobin, HbAT87Q.MethodsIn this ongoing phase 1-2 study, we optimized the treatment process in the initial 7 patients in Group A and 2 patients in Group B with sickle cell disease. Group C was established for the pivotal evaluation of LentiGlobin for sickle cell disease, and we adopted a more stringent inclusion criterion that required a minimum of four severe vaso-occlusive events in the 24 months before enrollment. In this unprespecified interim analysis, we evaluated the safety and efficacy of LentiGlobin in 35 patients enrolled in Group C. Included in this analysis was the number of severe vaso-occlusive events after LentiGlobin infusion among patients with at least four vaso-occlusive events in the 24 months before enrollment and with at least 6 months of follow-up.ResultsAs of February 2021, cell collection had been initiated in 43 patients in Group C; 35 received a LentiGlobin infusion, with a median follow-up of 17.3 months (range, 3.7 to 37.6). Engraftment occurred in all 35 patients. The median total hemoglobin level increased from 8.5 g per deciliter at baseline to 11 g or more per deciliter from 6 months through 36 months after infusion. HbAT87Q contributed at least 40% of total hemoglobin and was distributed across a mean (±SD) of 85±8% of red cells. Hemolysis markers were reduced. Among the 25 patients who could be evaluated, all had resolution of severe vaso-occlusive events, as compared with a median of 3.5 events per year (range, 2.0 to 13.5) in the 24 months before enrollment. Three patients had a nonserious adverse event related or possibly related to LentiGlobin that resolved within 1 week after onset. No cases of hematologic cancer were observed during up to 37.6 months of follow-up.ConclusionsOne-time treatment with LentiGlobin resulted in sustained production of HbAT87Q in most red cells, leading to reduced hemolysis and complete resolution of severe vaso-occlusive events. (Funded by Bluebird Bio; HGB-206 ClinicalTrials.gov number, NCT02140554.).Copyright © 2021 Massachusetts Medical Society.

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