Gene therapy with elivaldogene autotemcel (BlueBird’s Skysona/eli-cel) has been a miracle for children with the rare disease cerebral adrenoleukodystrophy (CALD). Unfortunately, the treatment appears to have caused blood cancer in some patients. Now researchers from Massachusetts General Hospital, BlueBird, and their colleagues are sharing new data on this phenomenon.
Skysona comprises autologous CD34+ cells transduced with lentiviral vector containing ABCD1 complementary DNA (Lenti-D). The drug’s effects are unquestionable, as this report describes. Six years after treatment with the first gene therapy FDA approved (2022) for CALD, 94 percent of patients have had no decline in neurological functioning, with over 80 percent remaining free of major disability. The cancers were discussed here. Both articles are in the New England Journal of Medicine.
Six of the seven cases of hematological malignancies in children treated with Skysona were diagnosed as myelodysplastic syndrome (MDS), arising between 14 and 92 months after Skysona treatment. The other patient was diagnosed with acute myeloid leukemia (AML) at 57 months. Six patients were subsequently treated with stem cell transplantation, which led to one death due to graft-versus-host disease. The single AML patient remains alive and has shown good response to the transplant.
CALD, affects the brain, typically during childhood. It occurs in about 1 in 21,000 boys between ages 4 and 10, affecting about 35–40 percent of those with the ABCD1 mutation. Females with the ABCD1 mutation are at low risk of developing CALD.
Skysona delivers functional copies of the ABCD1 gene into patients’ hematopoietic stem cells. In September 2022, the FDA granted Skysona accelerated approval for boys four to 17 years of age with CALD.
“Cerebral adrenoleukodystrophy is a devastating brain disease that strikes children in the prime of their childhood and development,” said Florian Eichler, MD, director of the Leukodystrophy Clinic in the Department of Neurology at Massachusetts General Hospital, first author of the paper on long-term outcomes.
He added that, “When I initially began treating patients with CALD, 80 percent came into our clinic on death’s door, and now the ratio has flipped. 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.”
According to the researchers, the emergent blood cancers are linked with clonal vector insertions in cancer-related genes, and with the accumulation of somatic mutations in certain sites of interest, including in the KRAS, WT1 and CDKN2A genes.
“Our paper on leukemias in this condition serves as a key step to evaluate the risks associated with the eli-cel therapy and lentiviral vector technology,” said Christine Duncan, MD, medical director of clinical research and clinical development in the Gene Therapy Program at the Boston Children’s Hospital and first author of the second report. “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.”
The researchers say they will continue to study the potential causes of hematologic malignancy, which are complex and not yet fully elucidated. Improving lentiviral vectors and refining HSCT regimens for CALD are a high priority. With newborn screening for adrenoleukodystrophy improving the possibility of early detection of CALD, there may be expanded opportunities to identify patients who may benefit from gene therapy, especially those lacking matched donors for allogeneic HSCT.
