{"doi":"10.1056/nejmoa2405541","title":"Hematologic Cancer after Gene Therapy for Cerebral Adrenoleukodystrophy","abstract":null,"journal":"New England Journal of Medicine","year":2024,"id":622111,"datarank":0.7357912167657645,"base_score":4.90527477843843,"endowment":4.90527477843843,"self_citation_contribution":0.7357912167657645,"citation_network_contribution":0.0,"self_endowment_contribution":0.7357912167657645,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":134,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":271709,"name":"Jacob R. Bledsoe","orcid":"0000-0002-2387-5462","position":1,"is_corresponding":false},{"id":1033226,"name":"Bartosz Grzywacz","orcid":"0000-0003-0075-688X","position":2,"is_corresponding":false},{"id":1422276,"name":"Amy Beckman","orcid":"0000-0001-7127-6889","position":3,"is_corresponding":false},{"id":1050797,"name":"Melissa Bonner","orcid":"0000-0001-5043-1907","position":4,"is_corresponding":false},{"id":1606767,"name":"Florian S. Eichler","orcid":null,"position":5,"is_corresponding":false},{"id":1606768,"name":"Jörn-Sven Kühl","orcid":null,"position":6,"is_corresponding":false},{"id":321123,"name":"Marian H. Harris","orcid":"0000-0002-9956-664X","position":7,"is_corresponding":false},{"id":1606769,"name":"Sarah Slauson","orcid":null,"position":8,"is_corresponding":false},{"id":1606770,"name":"Richard A. Colvin","orcid":null,"position":9,"is_corresponding":false},{"id":569006,"name":"Vinod K. Prasad","orcid":"0000-0001-8151-8212","position":10,"is_corresponding":false},{"id":1606771,"name":"Gerald F. Downey","orcid":null,"position":11,"is_corresponding":false},{"id":1606772,"name":"Francis J. Pierciey","orcid":null,"position":12,"is_corresponding":false},{"id":763263,"name":"Melissa A. Kinney","orcid":"0000-0003-1528-6163","position":13,"is_corresponding":false},{"id":1606773,"name":"Marianna Foos","orcid":null,"position":14,"is_corresponding":false},{"id":1606774,"name":"Ankit Lodaya","orcid":null,"position":15,"is_corresponding":false},{"id":1606775,"name":"Nicole Floro","orcid":null,"position":16,"is_corresponding":false},{"id":1606776,"name":"Geoffrey Parsons","orcid":null,"position":17,"is_corresponding":false},{"id":1254731,"name":"Andrew C. Dietz","orcid":"0000-0003-2810-2466","position":18,"is_corresponding":false},{"id":735927,"name":"Ashish O. Gupta","orcid":"0000-0001-5679-5533","position":19,"is_corresponding":false},{"id":213483,"name":"Paul J. Orchard","orcid":"0000-0001-9426-1292","position":20,"is_corresponding":false},{"id":1606777,"name":"Himal L. Thakar","orcid":null,"position":21,"is_corresponding":false},{"id":3665,"name":"David A. Williams","orcid":"0000-0001-7057-6863","position":22,"is_corresponding":false},{"id":1606766,"name":"Christine N. Duncan","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Hematologic Cancer after Gene Therapy for Cerebral Adrenoleukodystrophy","abstract":"Background Gene 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. 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 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 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. 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.)","is_dataset_classified":null,"base_score":4.867534450455582,"endowment":4.867534450455582,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"39383458","pmcid":"PMC11846662","openalex_id":"https://openalex.org/W4403262140","authors":[],"funders":[{"funder_name":"NINDS NIH HHS","grant_id":"U54 NS115052","title":null},{"funder_name":"Bluebird Bio","grant_id":"","title":null}],"total_grants":2,"fwci":20.68,"citation_percentile":0.99762868,"influential_citations":0,"citation_trend":[{"year":2013,"count":1},{"year":2024,"count":16},{"year":2025,"count":70},{"year":2026,"count":42}],"oa_status":"green","license":"http://www.nejmgroup.org/legal/terms-of-use.htm","oa_locations":[{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11846662/pdf/nihms-2054235.pdf","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11846662/pdf/nihms-2054235.pdf","host_type":"repository"},{"url":"http://www.nejm.org/doi/pdf/10.1056/NEJMoa2405541","host_type":"publisher"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/11846662","host_type":"repository"},{"url":"https://doi.org/10.1056/nejmoa2405541","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/39383458","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11846662/","host_type":"repository"}],"fields_of_study":["Peroxisome Proliferator-Activated Receptors","Neuroblastoma Research and Treatments","Pituitary Gland Disorders and Treatments"],"mesh_terms":["ATP Binding Cassette Transporter, Subfamily D, Member 1","Adolescent","Adrenoleukodystrophy","Adult","Child","Female","Follow-Up Studies","Genetic Vectors","Humans","Male","Myelodysplastic Syndromes","Genetic Therapy","Lentivirus","Antigens, CD34","Hematologic Neoplasms","Young Adult","Clonal Evolution"],"keywords":["Adrenoleukodystrophy","Cancer","Genetic enhancement","Medicine","Gene","Oncology","Genetics","Internal medicine","Biology"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"nct"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-03T18:15:57.714421Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}