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Hematologic Cancer after Gene Therapy for Cerebral Adrenoleukodystrophy
Open accessAbstract
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.)
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TL;DR
In two completed phase 2–3 studies and long-term follow-up, 7 of 67 patients treated with elivaldogene autotemcel (eli-cel) for cerebral adrenoleukodystrophy developed hematologic cancer, associated with clonal lentiviral vector insertions in MECOM or PRDM16 and acquired somatic defects. The authors conclude that this oncogenic risk must be weighed against the severity of cerebral adrenoleukodystrophy and that monitoring and future vector design should be informed by these cases.
Key findings
- Hematologic cancer developed in 7 of 67 eli-cel recipients (10%) over 338 person-years: incidence rate 2.1 per 100 person-years (95% CI, 0.8 to 4.2); 1 of 32 patients in ALD-102 (0.5 per 100 person-years; 95% CI, 0 to 2.5) and 6 of 35 in ALD-104 (5.2 per 100 person-years; 95% CI, 1.9 to 10.9).
- Diagnoses were MDS with unilineage dysplasia in 2 patients at 14 and 26 months; MDS with excess blasts in 3 at 28, 42, and 92 months; MDS in 1 at 36 months; and AML in 1 at 57 months.
- In the 6 patients with available data, predominant clones contained lentiviral vector insertions at multiple loci, including MECOM–EVI1 in 5 patients and PRDM16 in 1; 6 of 7 patients also had somatic mutations (KRAS, NRAS, WT1, CDKN2A or CDKN2B, or RUNX1), and 1 of 7 had monosomy 7.
- Of 5 patients with MDS who underwent allogeneic HSCT, 4 remain free of MDS without recurrence of cerebral adrenoleukodystrophy symptoms, and 1 died from presumed graft-versus-host disease 20 months after HSCT (49 months after eli-cel); the AML patient is alive with full donor chimerism, and the most recent MDS patient is alive awaiting HSCT.
Methods
- Integration-site analysis, genetic studies, flow cytometry, and morphologic studies were performed on peripheral-blood and bone marrow samples from patients who received eli-cel in two completed phase 2–3 studies (ALD-102 and ALD-104) and an ongoing follow-up study (LTF-304).
- A total of 67 patients received eli-cel infusion (32 in ALD-102 and 35 in ALD-104); analyses included integration-site analysis, vector copy number, targeted sequencing with the Rapid Heme Panel, gene expression studies, chromosome analysis, fluorescence in situ hybridization, and flow cytometry.
- The main analysis characterized clinicopathological and genetic features of hematologic cancer cases as of April 25, 2024, with incidence rates and event-free survival reported.
Limitations
- The paper states that whether differences in mobilization and chemotherapy regimens played a role remains unclear, that additional unknown factors appeared to play a role in cancer development, and that persistent oligoclonality testing was not reliably predictive of transformation.
- The paper states that ongoing follow-up is critical to understanding longer-term safety and efficacy.
- Evident from the text: only 7 cancer cases were available, there was no randomized comparator, follow-up duration differed between ALD-102 and ALD-104, the seventh case had limited available data and was undergoing more-detailed investigation, and incidence estimates had wide confidence intervals.
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“Hematologic cancer developed in 7 of 67 patients after the receipt of eli-cel”
- Also stated in: § PATIENTS · plain
“Hematologic cancer developed in 7 patients (incidence rate, 2.1 per 100 person-years [95% CI, 0.8 to 4.2]; 338 person-years of total follow-up)”
- Also stated in: § DISCUSSION · plain
“among the 67 patients treated with eli-cel, 7 patients (10%) have received a diagnosis of hematologic cancer”
§ Hematologic Cancer after Gene Therapy for Cerebral Adrenoleukodystrophy > Abstract > RESULTS
plainn = 7- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- Also stated in: § PATIENTS · plain
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In the paper
“As of April 25, 2024, the probability of event-free survival (survival without major functional disabilities, hematologic cancer, or rescue-cell administration or allogeneic hematopoietic stem-cell transplantation) at 4 years was 81.0% (95% confidence interval [CI], 68.8 to 88.8)”
§ Hematologic Cancer after Gene Therapy for Cerebral Adrenoleukodystrophy > RESULTS > PATIENTS
plainn = 67- Asserted: passes — The authors put it forward as true.
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In the paper
“All seven patients, as compared with 35% of patients without hematologic cancer, had current oligoclonality.”
§ Hematologic Cancer after Gene Therapy for Cerebral Adrenoleukodystrophy > RESULTS > INTEGRATION-SITE ANALYSIS AND CLONAL ANALYSES
plainstates an associationn = 7- Asserted: passes — The authors put it forward as true.
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In the paper
“1 who had been treated in the ALD-102 study (incidence rate, 0.5 per 100 person-years [95% CI, 0 to 2.5]; 222 person-years of follow-up)”
§ Hematologic Cancer after Gene Therapy for Cerebral Adrenoleukodystrophy > RESULTS > PATIENTS
plainSingle case- Asserted: passes — The authors put it forward as true.
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In the paper
“Hematologic cancer developed in 7 patients (incidence rate, 2.1 per 100 person-years [95% CI, 0.8 to 4.2]; 338 person-years of total follow-up)”
- Also stated in: § DISCUSSION · plain
“incidence rate, 2.1 per 100 person-years; 95% CI, 0.8 to 4.2”
§ Hematologic Cancer after Gene Therapy for Cerebral Adrenoleukodystrophy > RESULTS > PATIENTS
plainn = 7- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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- Also stated in: § DISCUSSION · plain
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In the citing paper
“As reported by Duncan et al., in ALD-104, six cases of hematologic cancer have been recorded in either the 24-month or the long-term follow-up study (five cases of MDS and one case of acute myeloid leukemia).”
From Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy (2024) · cites this paper as [20]
In the citing paper
“On the other hand, it is useful to note that no other studies using LVVs across multiple disease applications have to date reported mutagenic events and that none of these have used LTR regulatory sequences to regulate transgene expression, rather using cellular or derivative cellular elements.59”
From Ex vivo modification of hematopoietic stem and progenitor cells for gene therapy (2025) · cites this paper as [59]
Citations
Cites
Hematopoietic Stem Cell Gene Therapy with a Lentiviral Vector in X-Linked Adrenoleukodystrophy
Cartier, N., Hacein-Bey-Abina, S., Bartholomae, C. C., Veres, G., Schmidt, M., Kutschera, I., Vidaud, M., Abel, U., Dal-Cortivo, L., Caccavelli, L., et al. (2009) · Science · doi:10.1126/science.1171242 · Cited by 1,508
Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia
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Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia
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Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy
Eichler, F., Duncan, C., Musolino, P. L., Orchard, P. J., De Oliveira, S., Thrasher, A. J., Armant, M., Dansereau, C., Lund, T. C., Miller, W. P., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1700554 · Cited by 604
Self-citationClonal analysis of lineage fate in native haematopoiesis
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The clinical landscape of CAR NK cells
Jørgensen, L. V., Christensen, E. B., Barnkob, M. B., & Barington, T. (2025) · Experimental Hematology and Oncology · doi:10.1186/s40164-025-00633-8 · Cited by 156
Viral and non-viral vectors in gene therapy: current state and clinical perspectives
Geng, G., Xu, Y., Hu, Z., Wang, H., Chen, X., Yuan, W., & Shu, Y. (2025) · EBioMedicine · doi:10.1016/j.ebiom.2025.105834 · Cited by 140
Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy
Eichler, F., Duncan, C. N., Musolino, P. L., Lund, T. C., Gupta, A. O., De Oliveira, S., Thrasher, A. J., Aubourg, P., Kühl, J.-S., Loes, D. J., et al. (2024) · New England Journal of Medicine · doi:10.1056/nejmoa2400442 · Cited by 107
Self-citationGreco, R., Ruggeri, A., McLornan, D. P., Snowden, J. A., Alexander, T., Angelucci, E., Averbuch, D., Bazarbachi, A. A., Hazenberg, M. D., Kałwak, K., et al. (2025) · Bone Marrow Transplantation · doi:10.1038/s41409-025-02701-3 · Cited by 72
Ottaviano, G., & Qasim, W. (2025) · Leukemia · doi:10.1038/s41375-025-02585-8 · Cited by 46
Metadata
- Authors
- Duncan, C. N., Bledsoe, J. R., Grzywacz, B., Beckman, A., Bonner, M., Eichler, F. S., Kühl, J.-S., Harris, M. H., Slauson, S., Colvin, R. A., Prasad, V. K., Downey, G. F., Pierciey, F. J., Kinney, M. A., Foos, M., Lodaya, A., Floro, N., Parsons, G., Dietz, A. C., Gupta, A. O., Orchard, P. J., Thakar, H. L., & Williams, D. A.
- Affiliations
- Boston Children's Hospital (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2024-10-10
- Volume
- 391
- Issue
- 14
- Pages
- 1287-1301
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC11846662
- OpenAlex
- W4403262140
- Cited by
- 164
- References
- 36
- Citations by year
- 2026: 76 · 2025: 72 · 2024: 15
- FWCI
- 32.80
- Type
- journal article
- Language
- en
- Open access
- green
- pmc.ncbi.nlm.nih.gov
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- Funders
- Bluebird Bio
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Keywords
- cerebral adrenoleukodystrophy, gene therapy, hematologic malignancies, myelodysplastic syndrome, acute myeloid leukemia, EVI1, MECOM, PRDM16, somatic mutations, monosomy 7, allogeneic hematopoietic stem cell transplantation
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily D, Member 1, Adolescent, Adrenoleukodystrophy, Child, Female, Follow-Up Studies, Genetic Vectors, Humans, Male, Myelodysplastic Syndromes, Genetic Therapy, Lentivirus, Hematologic Neoplasms, Clonal Evolution
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