• Christine N Duncan, Jacob R Bledsoe, Bartosz Grzywacz, Amy Beckman, Melissa Bonner, Florian S Eichler, Jörn-Sven Kühl, Marian H Harris, Sarah Slauson, Richard A Colvin, Vinod K Prasad, Gerald F Downey, Francis J Pierciey, Melissa A Kinney, Marianna Foos, Ankit Lodaya, Nicole Floro, Geoffrey Parsons, Andrew C Dietz, Ashish O Gupta, Paul J Orchard, Himal L Thakar, and David A Williams.
• From Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School (C.N.D., D.A.W.), the Department of Pathology, Boston Children's Hospital (J.R.B., M.H.H.), and Massachusetts General Hospital and Harvard Medical School (F.S.E.) - all in Boston; the Department of Laboratory Medicine and Pathology, University of Minnesota Medical Center (B.G., A.B.), and the Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota (A.O.G., P.J.O.) - both in Minneapolis; Bluebird Bio, Somerville, MA (M.B., S.S., R.A.C., V.K.P., G.F.D., F.J.P., M.A.K., M.F., A.L., N.F., G.P., A.C.D., H.L.T.); the Department of Pediatric Oncology, Hematology and Hemostaseology, Leipzig University Hospital, Leipzig, Germany (J.-S.K.); and the Division of Pediatric Transplant and Cellular Therapy, Duke University School of Medicine, Durham, NC (V.K.P.).
• N. Engl. J. Med. 2024 Oct 10; 391 (14): 128713011287-1301.

BackgroundGene therapy with elivaldogene autotemcel (eli-cel) consisting of autologous CD34+ cells transduced with lentiviral vector containing ABCD1 complementary DNA (Lenti-D) has shown efficacy in clinical studies for the treatment of cerebral adrenoleukodystrophy. However, the risk of oncogenesis with eli-cel is unclear.MethodsWe performed integration-site analysis, genetic studies, flow cytometry, and morphologic studies in peripheral-blood and bone marrow samples from patients who received eli-cel therapy in two completed phase 2-3 studies (ALD-102 and ALD-104) and an ongoing follow-up study (LTF-304) involving the patients in both ALD-102 and ALD-104.ResultsHematologic cancer developed in 7 of 67 patients after the receipt of eli-cel (1 of 32 patients in the ALD-102 study and 6 of 35 patients in the ALD-104 study): myelodysplastic syndrome (MDS) with unilineage dysplasia in 2 patients at 14 and 26 months; MDS with excess blasts in 3 patients at 28, 42, and 92 months; MDS in 1 patient at 36 months; and acute myeloid leukemia (AML) in 1 patient at 57 months. In the 6 patients with available data, predominant clones contained lentiviral vector insertions at multiple loci, including at either MECOM-EVI1 (MDS and EVI1 complex protein EVI1 [ecotropic virus integration site 1], in 5 patients) or PRDM16 (positive regulatory domain zinc finger protein 16, in 1 patient). Several patients had cytopenias, and most had vector insertions in multiple genes within the same clone; 6 of the 7 patients also had somatic mutations (KRAS, NRAS, WT1, CDKN2A or CDKN2B, or RUNX1), and 1 of the 7 patients had monosomy 7. Of the 5 patients with MDS with excess blasts or MDS with unilineage dysplasia who underwent allogeneic hematopoietic stem-cell transplantation (HSCT), 4 patients remain free of MDS without recurrence of symptoms of cerebral adrenoleukodystrophy, and 1 patient died from presumed graft-versus-host disease 20 months after HSCT (49 months after receiving eli-cel). The patient with AML is alive and had full donor chimerism after HSCT; the patient with the most recent case of MDS is alive and awaiting HSCT.ConclusionsHematologic cancer developed in a subgroup of patients who were treated with eli-cel; the cases are associated with clonal vector insertions within oncogenes and clonal evolution with acquisition of somatic genetic defects. (Funded by Bluebird Bio; ALD-102, ALD-104, and LTF-304 ClinicalTrials.gov numbers, NCT01896102, NCT03852498, and NCT02698579, respectively.).Copyright © 2024 Massachusetts Medical Society.

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