New data underline cancer risk of Bluebird therapy for brain disease

About two years ago, the Food and Drug Administration approved a personalized gene therapy for an ultra-rare childhood brain disorder despite concerns treatment might inadvertently trigger cancer.

Those concerns are now back in the spotlight, as new study data published Wednesday in The New England Journal of Medicine document seven cases of blood malignancies in young boys given the therapy, called Skysona.

The cases are among 67 boys with cerebral adrenoleukodystrophy, or CALD, who were enrolled in studies of Skysona. In the months and years after treatment, six developed myelodysplastic syndromes, or MDS, a form of bone marrow cancer, and one developed acute myeloid leukemia, according to the study authors.

All of the cases were previously disclosed by Skysona’s developer, Bluebird bio, to study investigators and to the FDA, which updated the treatment’s labeling in April. Bluebird has also shared details of some of the cases at medical meetings.

However, the paper is the fullest assessment yet of the safety of Skysona, which the FDA cleared in Sept. 2022 on the condition Bluebird confirm its benefit with additional data.

At the time of the approval, researchers had reported three of the MDS cases, which were discussed at length by a group of experts the FDA convened to advise it. The panel ultimately voted unanimously in favor of Skysona, citing what they saw as convincing evidence of its benefit treating CALD.

Before Skysona, there was no medicine specifically for CALD, which causes progressive degeneration in the brain and, if unaddressed, typically leads to death in a child’s second decade of life. The disease is linked to the X chromosome, so it affects boys.

Those past disclosures mean the cancer cases documented Wednesday won’t come as a major surprise to treating physicians or the patient community. Still, they give doctors a more complete sense of how Skysona’s risks balance against its benefit, which could inform treatment choices for CALD patients. (In some, stem cell transplants from a matched sibling donor can stabilize the disease.)

“These troubling events raise the bar for offering eli-cel autologous gene therapy for cerebral adrenoleukodystrophy,” wrote Cynthia Dunbar, chief of the translational stem cell biology branch at the National Heart Lung and Blood Institute, in an editorial also published Wednesday. Skysona was previously called eli-cel.

The main NEJM paper shows five of the six boys who developed MDS went on to receive a stem cell transplant, which is typical for treating MDS. Four remain free of MDS with any recurrence of CALD symptoms, while one died from apparent graft-versus-host disease nearly two years after his transplant. The sixth boy with MDS is awaiting a transplant, researchers said.

The boy who had leukemia is also alive following a stem cell transplant.

In all seven cases, researchers determined the cancers were “probably mediated” by the engineered virus Bluebird used to construct Skysona, which is built from patient stem cells.

There are a number of ways researchers can insert helpful new genes into such cells; the way Bluebird chose involves a lentivirus that semirandomly integrates into the stem cells’ genome. Malignant cells in six of the patients had lentiviral DNA within two genes linked to the development of cancer. The seventh case is still being investigated.

When Skysona development began, scientists weren’t sure which cells in the brain needed to express the helpful gene the therapy would deliver. So they added genetic components to their lentivirus shuttle that ensured subsequent gene expression would be strong across the variety of cell types that arise from the transplanted stem cells.

In her editorial, Dunbar hypothesizes that these components, known as a “promoter,” could be to blame, citing a meta-analysis of several hundred patients treated with other lentiviral gene therapies that found no cases of blood cancer.