Journal Article

Hematologic Cancer after Gene Therapy for Cerebral Adrenoleukodystrophy

Floro, Nicole, Eichler, Florian S., Kühl, Jörn-Sven, Thakar, Himal L., Gupta, Ashish O., Dietz, Andrew C., Harris, Marian H., Kinney, Melissa A., Prasad, Vinod K., Parsons, Geoffrey, Bledsoe, Jacob R., Slauson, Sarah, Orchard, Paul J., Bonner, Melissa, Pierciey, Francis J., Grzywacz, Bartosz, Downey, Gerald F., Colvin, Richard A., Foos, Marianna, Lodaya, Ankit, Duncan, Christine N., Beckman, Amy, Williams, David A.

2024

Overview

Gene therapy with elivaldogene autotemcel (eli-cel) consisting of autologous CD34+ cells transduced with lentiviral vector containing 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. 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. Hematologic 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 (MDS and EVI1 complex protein EVI1 [ecotropic virus integration site 1], in 5 patients) or (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 ( , , , or , or ), 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. 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.).

• Publisher: Massachusetts Medical Society
• Subject: Acute myeloid leukemia / Adolescent / Adolescent Medicine / Adrenoleukodystrophy / Adrenoleukodystrophy - genetics / Adrenoleukodystrophy - therapy / Allergy / Allografts / ATP Binding Cassette Transporter, Subfamily D, Member 1 - genetics / Blood cancer / Blood platelets / Blood tests / Bone marrow / Bone Marrow Transplantation / Cancer / CD34 antigen / Child / Childhood Cancer / Childhood Diseases / Chimerism / Clonal Evolution - genetics / Dysplasia / Female / Flow cytometry / Follow-Up Studies / Gene Editing / Gene expression / Gene therapy / Genetic analysis / Genetic Therapy - adverse effects / Genetic Therapy - methods / Genetic Vectors - administration & dosage / Genetic Vectors - adverse effects / Genetics / Graft-versus-host reaction / Hematologic Neoplasms - epidemiology / Hematologic Neoplasms - genetics / Hematology / Hematopoietic stem cells / Humans / Immunology / Inflammatory Disease / Lentivirus - genetics / Leukemia / Lymphoma / Male / Monosomy / Mutation / Myelodysplastic syndrome / Myelodysplastic Syndromes - epidemiology / Myelodysplastic Syndromes - genetics / Neurology / Neuromuscular Disease / Neuroscience / Neurosurgery / Neurosurgery General / Oncology / Patients / Pediatrics / Pediatrics General / Peripheral blood / Runx1 protein / Stem cell transplantation / Stem Cells / Teenagers / Thrombocytopenia / Tumorigenesis / Zinc finger proteins