The FDA is currently investigating reports of life-threatening blood cancers, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), in patients treated with Bluebird Bio's Skysona (elivaldogene autotemcel). This gene therapy is approved for early, active cerebral adrenoleukodystrophy (CALD) in boys aged 4-17. The agency is evaluating the need for further regulatory action to ensure patient safety.
Concerns Arise from Clinical Trial Data
Reports of these malignancies emerged from clinical trials, with diagnoses occurring between 14 and 92 months after Skysona treatment. Data published in The New England Journal of Medicine revealed that 7 out of 67 children treated with elivaldogene autotemcel developed hematologic malignancies. Specifically, in the ALD-102 trial, 1 out of 32 patients developed MDS, while in the ALD-104 trial, 6 out of 35 patients developed hematologic malignancies. These findings have prompted a thorough review of the therapy's safety profile.
FDA Recommendations and Monitoring
Given the potential risk of hematologic malignancies, the FDA recommends that healthcare providers carefully consider alternative treatments, such as allogeneic hematopoietic stem cell transplantation (HSCT) for patients with suitable, willing, and available human leukocyte antigen-matched donors, before opting for Skysona. The agency emphasizes the importance of lifelong monitoring for patients treated with Skysona, including regular complete blood counts every three months and assessments for clonal expansion at least twice in the first year post-treatment, followed by annual assessments. Bone marrow evaluations should also be considered as clinically indicated.
Skysona's Background and Mechanism
Skysona, approved in September 2022, addresses CALD, a rare neurodegenerative disease caused by mutations in the ABCD1 gene. This mutation leads to the accumulation of very long-chain fatty acids in the brain and spinal cord, resulting in neurological dysfunction. Skysona delivers functional copies of the ABCD1 gene into patients' stem cells, aiming to slow the progression of the disease. The prescribing information for Skysona includes a Boxed Warning about the risk of hematologic malignancies.
Bluebird Bio's Perspective
Bluebird Bio has acknowledged the reported cases and is collaborating with the FDA to investigate the potential link between Skysona and the development of blood cancers. The company has noted that Skysona utilizes a lentiviral vector, while their other gene therapies, Zynteglo and Lyfgenia, use self-inactivating gamma-retroviral vectors. Bluebird emphasizes the need for continued evaluation of the long-term safety of lentiviral vectors in gene therapy.
Broader Implications for Gene Therapy
This investigation highlights the ongoing safety challenges in the development of gene therapies. The FDA's scrutiny of Skysona follows other recent safety concerns with gene therapies, underscoring the importance of rigorous monitoring and risk assessment in this rapidly evolving field.
