FDA Updates Labeling for bluebird's Active Cerebral Adrenoleukodystrophy Gene Therapy Eli-Cel to Reflect Risk of Hematologic Malignancy

The FDA is requiring updated labeling for bluebird bio's elivaldogene autotemcel (eli-cel; marketed as Skysona), a gene therapy product comprised of engineered autologous CD34+ hematopoietic stem cells intended to treat early, active cerebral adrenoleukodystrophy (CALD), to reflect an increased risk of hematologic malignancy following treatment with the product.¹

Specifically, the agency is requiring updates to the Boxed Warning, Indications and Usage, Warnings and Precautions, and Adverse Reactions – Clinical Trials Experience sections of eli-cel's prescribing information and Medication Guide. With regard to the revised Indications and Usage section, only patients without an available human leukocyte antigen (HLA)-matched donor for allogeneic hematopoietic stem cell (allo-HSC) are eligible to receive eli-cel.

“...Skysona should only be used in CALD patients without suitable alternative treatment options, given the increased risk of hematologic malignancy,” the FDA said in a press release announcing the required labeling changes.¹ “The Limitations of Use section retains language emphasizing careful consideration of appropriateness and timing of treatment.”

The changes are to be made in relation to new safety information regarding the risk of hematologic malignancies that has become available following a probe by the FDA announced in November of last year.² The FDA stated that as of July 2025, 10 of 67 patients (15%) treated in clinical trials for eli-cel have developed hematologic malignancies.¹ At the time of eli-cel's approval by the FDA in September 2022, only 3 of the 67 patients (4%) had developed known hematologic malignancies.

“Current reports suggest that the time to diagnosis of hematologic malignancy ranges from 14 months to 10 years after Skysona administration,” the FDA also stated.¹ “Nine of the 10 patients have been treated with allo-HSCT (with or without chemotherapy) for the hematologic malignancy. The malignancies are life-threatening conditions, and 1 death related to treatment for malignancy has occurred. One patient developed recurrence of myelodysplastic syndrome (MDS) after initial treatment, which required retreatment. Importantly, some patients developed malignancy before Skysona had time to potentially provide therapeutic benefit for their CALD.”

According to results reported in The New England Journal of Medicine in October 2024, the aforementioned patient who died had received allo-HSCT for the treatment of their MDS.³ The patient’s death, which occurred 20 months after receiving the allo-HSCT, was attributed to presumed graft-versus-host disease (GvHD). At the time of the paper’s writing, only 7 of the 67 patients had been diagnosed with hematologic malignancies. The 67 patients were treated across the phase 2/3 ALD-102 (NCT01896102), phase 2/3 ALD-104 (NCT03852498), and LTF-304 (NCT02698579) clinical trials, with LTF-304 being an ongoing long-term follow-up study for patients treated in ALD-102 and ALD-104.

"The risk of oncogenesis with eli-cel must be weighed against the severity and natural history of CALD as well as the availability of other treatments and their risks, including allogeneic HSCT,” first author Christine N. Duncan, MD, the medical director of clinical research and clinical development for the Gene Therapy Program at Boston Children’s Hospital, and colleagues, wrote in the paper.³ “Overall survival was 77.8% among patients who had undergone allogeneic HSCT 4 years previously in a matched cohort study; the cumulative incidence estimate for acute grade 2to 4 GvHD was 11.1%, and the estimate for GvHD overall was 17.2%. Moreover, the availability of HLA highly matched donors is limited and is a crucial determinant of outcomes in patients undergoing allogeneic HSCT. Most patients who received eli-cel in the ALD-102 and ALD-104 studies benefitted clinically, with 81% 4-year survival free of major functional disabilities and hematologic cancer, and without referral for allogeneic HSCT. Therefore, the probability and magnitude of benefit that gene therapy can offer in patients who do not have an appropriate donor must be considered. Because gene therapy is an evolving field, ongoing follow-up is critical to understanding the longer-term safety and efficacy of novel treatments like eli-cel.”

REFERENCES
1. FDA approves required labeling changes for increased risk of hematologic malignancy following treatment with Skysona (elivaldogene autotemcel). News release. FDA. August 7, 2025. Accessed August 11, 2025. https://www.fda.gov/vaccines-blood-biologics/fda-approves-required-labeling-changes-increased-risk-hematologic-malignancy-following-treatment
2. FDA investigating serious risk of hematologic malignancy following Skysona (elivaldogene autotemcel). News release. FDA. November 27, 2025. Accessed August 11, 2025.https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-serious-risk-hematologic-malignancy-following-skysona-elivaldogene-autotemcel
3. Duncan CN, Bledsoe JR, Grzywacz B, et al. Hematologic cancer after gene therapy for cerebral adrenoleukodystrophy. N Engl J Med. 2024;391(14):1287-1301. doi: 10.1056/NEJMoa2405541