Gene therapy benefits boys with rare brain disease, but hematologic cancer remains a risk
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Key takeaways:
- Most patients who received Skysona for cerebral adrenoleukodystrophy did not have major functional disabilities over a median follow-up period of 6 years.
- However, several patients developed hematologic cancer.
Bluebird Bio’s lentiviral vector gene therapy Skysona met its primary efficacy endpoint of survival without major functional disability in 81% of boys with early cerebral adrenoleukodystrophy, a recent analysis showed.
However, a second analysis revealed that seven patients who received Skysona (elivaldogene autotemceleli-cel, also known as eli-cel) developed hematologic cancer, highlighting the need for longer-term data, according to David A. Williams, MD, Leland Fikes Professor of Pediatrics at Harvard Medical School and chief of the division of hematology/oncology at Boston Children's Hospital, and colleagues.
Both analyses were simultaneously published in The New England Journal of Medicine.
“Gene therapy works in this disease to stop the progression of the disease based on [follow-up] of greater than 5 years for most patients,” Williams told Healio. “However, there is a significant risk of insertional mutagenesis leading to severe complications. To date, these have been successfully treated in most patients. We need to develop new, safer vectors for future use.”
As Healio previously reported, the FDA granted accelerated approval to eli-cel in September 2022 to slow the progression of neurologic dysfunction in boys aged 4 to 17 years with early, active cerebral adrenoleukodystrophy (CALD), a rare disease that leads to neurologic dysfunction and death in children, primarily young boys, according to Boston Children’s Hospital. As a condition of the accelerated approval, which includes a boxed warning for hematologic malignancy, Bluebird Bio agreed to provide confirmatory long-term clinical data to the FDA.
Primary efficacy endpoint
In the first analysis, Williams and colleagues examined the efficacy of eli-cel in 32 boys with early-stage CALD and MRI abnormalities who were enrolled in the phase 2/3 ALD-102 trial. Among them, 29 patients completed the 24-month study and are currently being monitored in the LTF-304 study.
The primary efficacy endpoint was survival at 24 months without any of the following major functional disabilities: complete loss of voluntary movement, cortical blindness, loss of communication, total incontinence, tube feeding and wheelchair dependence.
According to the researchers, there was a 94% survival rate at 24 months, and none of the 29 patients had a major functional disability at this time.
During the most recent assessment — a median follow-up period of 6 years — Williams and colleagues reported that 81% (n = 26) of patients did not have a major functional disability.
Twenty-two of the 32 patients experienced a serious adverse event, and four patients had adverse events that the researchers said were “directly related to eli-cel.” One patient developed myelodysplastic syndrome (MDS) with excess blasts and subsequently underwent allogeneic hematopoietic stem-cell transplantation (HSCT). The patient did not have evidence of MDS at his most recent follow-up assessment, according to the researchers.
Hematologic cancer risk
In the second analysis, Williams and colleagues examined the risk for oncogenesis with eli-cel among 67 patients with CALD who were enrolled in the ALD-102 trial, a companion trial called ALD-104 and the ongoing LTF-304 trial, which includes patients from both ALD-102 and ALD-104.
As of April 25 seven patients had been diagnosed with hematologic cancer over 338 person-years of follow up, which translates to an incidence rate of 2.1 per 100 person-years (95% CI, 0.8-4.2). This subgroup includes one patient from the ALD-102 trial and six patients from the ALD-104 trial.
The specific diagnoses were MDS in one patient, MDS with unilineage dysplasia in two patients, MDS with excess blasts in three patients, and acute myeloid leukemia (AML) in one patient.
The three patients with MDS with excess blasts and one patient with MDS with unilineage dysplasia underwent allogeneic HSCT. Four of these five patients are free of MDS recurrence, the researchers reported. The other patient likely died from graft-versus-host disease.
Meanwhile, the patient with AML had full donor chimerism following HSCT, and the most recently diagnosed patient with MDS is awaiting HSCT.
Williams and colleagues noted that eli-cel’s risk for oncogenesis “must be weighed against the severity and natural history of cerebral adrenoleukodystrophy as well as the availability of other treatments and their risks, including allogeneic HSCT.”
“This is a devasting disease which can rapidly progress after inflammation is seen in the CNS,” Williams said. “There are patients who do not have a highly matched unrelated donor. For those patients, gene therapy is a consideration, given the positive outcomes in [long-term follow up].”
He added that families must “have adequate and thorough explanation of the risk and show understanding of the risk.”
“It is an extremely difficult situation for these families,” Williams said.
References:
- Duncan CN, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa240554.
- Eichler F, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2400442.
- What is adrenoleukodystrophy? https://www.childrenshospital.org/conditions/adrenoleukodystrophy-ald. Accessed Oct. 11, 2024.