The pediatric patients, with a rare neurodegenerative disease, were treated with bluebird bio’s Skysona to slow the progression of neurologic dysfunction. Six patients developed myelodysplastic syndrome and one patient developed acute myeloid leukemia.
Seven children treated with bluebird bio’s gene therapy Skysona for cerebral adrenoleukodystrophy, a rare and progressive neurodegenerative disease, developed blood cancers, according to a study published Wednesday in The New England Journal of Medicine.
Six of the seven cases of hematological malignancies 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.
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.
Skysona is a gene therapy that works by delivering functional copies of the ABCD1 gene into patients’ hematopoietic stem cells, which promotes the production of mature monocytes that can express functional ALDP proteins. ALDP plays an important role in the breakdown of very long chain fatty acids.
In September 2022, the FDA granted Skysona accelerated approval to the slow the progression neurologic dysfunction in boys four to 17 years of age with cerebral adrenoleukodystrophy (CALD), a rare and neurodegenerative disorder caused by a dysfunctional ABCD1 gene and which leads to severe functional decline. In the Phase II/III Starbeam trial, which formed the basis of its regulatory win, Skysona demonstrated strong major functional disability-free survival over 24 months.
In terms of safety, Starbeam detected cases of nausea, vomiting and febrile neutropenia, among other mild toxicities. Adverse events of grade 3 or 4 included lymphopenia, thrombocytopenia and hypokalemia.
Skysona’s label carries a boxed warning for hematologic malignancies, including “life-threatening cases” of MDS. These complications appear to be the result of the Skysona lentiviral vector that becomes integrated in proto-oncogenes—similar to what had been documented in the NEJM study.
The concerns about secondary blood cancers are not new. In August 2021, about a year before Skysona’s approval, the FDA hit its development program with a clinical hold after one patient developed MDS following treatment. In an advisory committee meeting in June 2022, however, a panel of external experts unanimously backed bluebird, agreeing that Skysona’s benefits outweigh its risks.
Wednesday’s study results come less than a month after news broke that patients had finally started receiving infusions of another bluebird gene therapy, Lyfgenia, for sickle cell disease. It is not yet clear whether the new safety signals will have far-reaching implications for bluebird’s portfolio.
In an emailed statement to BioSpace, a bluebird spokesperson clarified that the NEJM study “does not outline any new safety risks,” pointing out that blood cancer is a “known risk of Skysona and was included on the label as a boxed warning.”
“Lyfgenia and Zynteglo utilize a different vector and as such the safety profile of Skysona is distinct; these cases have no bearing on the safety profile of bluebird’s other therapies,” the spokesperson added.
Correction (October 14): This story was updated with clarifications from bluebird, highlighting the known risks of hematologic malignancy associated with Skysona and the safety profile of the biotech’s other assets.
