Elivaldogene Autotemcel (Bluebird Bio)

Seven young boys treated with bluebird bio’s gene therapy for a rare neurological disease have been diagnosed with blood cancer months or years after treatment, according to data published on Wednesday in the New England Journal of Medicine . Researchers have long known that therapies developed with lentiviral vectors could, in some cases, cause cancer, but they have been seeking to understand why Skysona comes with a seemingly greater risk. The cases may relate to the design of the lentiviral vector used in the treatment, scientists hypothesize. Bluebird’s eli-cel was approved in 2022 under the brand name Skysona to treat cerebral adrenoleukodystrophy, also known as CALD. The condition mostly affects young boys and progresses rapidly without treatment, leading to neurological decline or death. Skysona was approved in 2022 with a black box warning for hematologic malignancy, and the FDA updated its label in April to disclose that there had been six cases of the cancer out of 67 patients dosed in clinical studies. An additional case has been diagnosed since then, according to new data published in NEJM. The patients received Skysona when they were between 5 and 13 years old, with the cancer diagnoses occurring 14 to 92 months later, according to the data. In an editorial published alongside the data, Cynthia Dunbar, a hematologist at the NIH’s National Heart, Lung and Blood Institute, wrote that more cases may appear over time. “Unfortunately, I think she’s right,” Christine Duncan, lead author of the NEJM study and Boston Children’s Hospital senior physician, told Endpoints News. “ Patients are being followed very closely. The families are being very educated. They all know about all of these cases.” Duncan and her team hypothesized that the cases may have been driven by the design of the lentiviral vector used in Skysona. CALD is caused by a mutation in a gene called ABCD1. Skysona works by using a lentivirus to insert a functioning form of the ABCD1 gene. Skysona’s lentiviral vector was designed with the use of a viral promoter, intended to help drive strong expression of the gene. But a risk of that type of promoter is oncogenesis, or driving the development of cancer, Duncan explained. “We’re relatively confident that that promoter in the design of the vector is driving this,” she said. “The question then is, in my mind, is it driving it alone, or are there other factors that contribute?” Duncan noted that patients in one study, ALD-102, which has reported only one case of hematologic cancer, received a stronger chemotherapy regimen as part of preparation for treatment than another study, ALD-104, which reported the other six cases. But at this time, it remains unclear whether that made a difference, or whether other factors were involved. “Is it a combination of conditioning regimen and the vector?” she asked. “We can’t know for certain.” Duncan added that the risk-benefit analysis for Skysona may vary from patient to patient. Some patients may be eligible for allogeneic stem cell transplant, but that process comes with its own risks — and just 20% of CALD patients have an available matched donor, according to the NEJM editorial. “We recognize that families of children diagnosed with CALD face urgent treatment decisions, and bluebird is committed to ensuring that treating physicians have access to the most up-to-date safety information to support informed decision making,” bluebird said in a statement. Leaving CALD untreated is the greatest risk, Duncan said. “Both allogeneic stem cell transplant, so the traditional therapy, and gene therapy, they both have things that are good about them, they both have things that are bad about them. And for any individual patient, it’s not the same scale,” Duncan said. “At the end of the day, I think it is very valuable, very important that families have choices that they can personalize with their caregivers and their providers.” Researchers noted there have been no cases of lentivirus-caused cancer reported with bluebird’s sickle cell and beta thalassemia therapy, which used a different lentiviral vector called BB305, and none with Orchard Therapeutics’ metachromatic leukodystrophy therapy Lenmeldy. Lei Lei Wu contributed reporting.