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Concerns Linger After Gene Therapy Shows Long-Term Benefit for Cerebral Adrenoleukodystrophy
A median 6 years after treatment with elivaldogene autotemcel (eli-cel) gene therapy for cerebral adrenoleukodystrophy (CALD), 94% of patients showed no decline in neurological functioning and 81% remained free of major functional disabilities. Nevertheless, reports of hematologic malignancies in some patients have raised concern, according to a pair of studies published in the New England Journal of Medicine.
CALD is a rare, progressive, genetic white-matter disease that primarily occurs in boys and causes loss of neurological function and early death. In 2022, the US Food and Drug Administration (FDA) approved eli-cel for the treatment of CALD, establishing it as the first gene therapy for the disease.
“When I initially began treating patients with CALD, 80% came into our clinic on death’s door, and now the ratio has flipped,” said Florian Eichler, MD, director of the leukodystrophy clinic at Massachusetts General Hospital, Boston, Massachusetts, and first author of one of the studies. “We cautiously celebrate that we have been able to stabilize this neurologic disease and give these boys back a fulfilling life, but that jubilation is dampened by the fact that we see malignancy in a subset of these patients. This is something that we are actively trying to understand and address.”
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As part of the ALD-102 trial, 32 boys with early-stage CALD received eli-cel. The therapy uses a Lenti-D lentiviral vector to add a healthy copy of the ABCD1 gene to blood stem cells that have been removed from the patient. The stem cells are later reintroduced to the patient in an autologous hematopoietic stem cell transplant (HSCT).
One patient in ALD-102 developed myelodysplastic syndrome (MDS) with excess blasts, which the Lenti-D lentiviral vector appears to have triggered. In the more recent ALD-104 trial 6 of 35 patients developed a hematologic malignancy (MDS in 5 and acute myeloid leukemia in 1) that also may have been vector-caused. However, the protocol for ALD-104 differed from ALD-102 in the chemotherapy drug used during HSCT (fludarabine instead of cyclophosphamide) and other areas that may have contributed to the apparent increased risk of leukemia, the research team explained.
“Our paper on leukemias in this condition serves as a key step to evaluate the risks associated with the eli-cell therapy and lentiviral vector technology,” said Christine Duncan, MD, first author of the paper and medical director of clinical research and clinical development in the gene therapy program at Boston Children’s Hospital, Boston, Massachusetts. “Although the overall trial results are optimistic, we hope to expand our research to inform future follow-up to provide families facing a devastating disease with more information and options.”
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