Hematologic Cancer after Gene Therapy for Cerebral Adrenoleukodystrophy
Christine Duncan, Jacob R. Bledsoe, Bartosz Grzywacz, Amy Beckman, Melissa Bonner, Florian Eichler, Jörn‐Sven Kühl, Marian H. Harris, Sarah Slauson, Richard A. Colvin, Vinod K. Prasad, Gerald 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, David A. Williams
Abstract
BACKGROUND: 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. METHODS: We 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. RESULTS: ), 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. CONCLUSIONS: Hematologic 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.).