The gene therapy elivaldogene autotemcel (eli-cel; Skysona) has shown promising long-term efficacy in treating cerebral adrenoleukodystrophy (CALD), a rare and debilitating brain disease primarily affecting young boys. However, recent studies have revealed a significant risk of hematologic cancers associated with this treatment.
Hematologic Cancer Risk
In a study published in the New England Journal of Medicine, researchers reported that among 67 boys with CALD treated with eli-cel, seven developed hematologic cancers, including six cases of myelodysplastic syndrome (MDS) and one case of acute myeloid leukemia (AML). These cancers were diagnosed between 14 and 92 months after treatment. The study, led by David A. Williams, MD, from Dana-Farber Cancer Institute and Harvard Medical School, highlights the critical need for long-term monitoring of patients receiving this gene therapy.
The incidence rate of hematologic cancer was notably higher in the ALD-104 study (5.2 per 100 person-years) compared to the ALD-102 study (0.5 per 100 person-years). Researchers suggest that the conditioning agents used in these studies—busulfan-cyclophosphamide in ALD-102 versus busulfan-fludarabine in ALD-104—may account for the difference in cancer risk.
Long-Term Efficacy
Despite the cancer risk, a separate report in NEJM focusing on the ALD-102 study showed that 94% of 32 boys treated with eli-cel before age 17 were alive at 24 months, maintained stable neurologic function scores, and 81% experienced no major functional disabilities after up to 8.9 years of follow-up. These findings underscore the potential of eli-cel to stabilize neurologic function and extend life in patients with early-stage CALD.
Weighing Risks and Benefits
The decision to use eli-cel should involve a careful assessment of the risks and benefits, considering the severity of CALD, the availability of alternative treatments like allogeneic hematopoietic stem cell transplant (HSCT), and their associated risks. According to an accompanying editorial by Cynthia E. Dunbar, MD, of the National Heart, Lung, and Blood Institute, advances in haploidentical transplantation may make allogeneic HSCT more broadly applicable for CALD.
Mechanism of Action and Genetic Insights
CALD results from mutations in the ABCD1 gene, leading to an accumulation of very-long-chain fatty acids in the brain and spinal cord. Eli-cel introduces functional copies of the ABCD1 gene into a patient's hematopoietic stem cells via ex vivo transduction using the Lenti-D lentiviral vector. This enables patients to produce the ALD protein necessary for breaking down these fatty acids.
Further investigation revealed that the hematologic cancers observed in the trials were likely mediated by Lenti-D lentiviral vector insertion. In six cases with available data, the cancers were associated with the expansion of a clone containing an insertion site in a known proto-oncogene, MECOM (five cases) or PRDM16 (one case).
Future Directions
Ongoing research is focused on understanding and mitigating the cancer risks associated with eli-cel. Strategies include refining conditioning regimens and improving vector safety. As Dr. Christine Duncan, medical director of Clinical Research and Clinical Development in the Gene Therapy Program at Boston Children’s Hospital, stated, research aims to provide families with more information and options when facing this devastating disease. Continued follow-up is essential to fully understand the long-term safety and efficacy of eli-cel and similar gene therapies.
