NEW YORK – About 10 percent of the nearly 70 patients who received Bluebird Bio's gene therapy for cerebral adrenoleukodystrophy within clinical trials later developed blood cancer, according to results published in the New England Journal of Medicine on Thursday.
Most cases of hematologic cancer — which researchers believe is related to the particular lentiviral vector used to deliver the gene therapy — resolved after treatment.
While it remains unclear why some patients develop cancer, the study underscores another risk that patients and physicians must contend with when evaluating the risk-benefit profile of advanced therapies. The US Food and Drug Administration, for example, has been investigating the risk of T-cell malignancy in patients treated with certain autologous CAR T-cell immunotherapies.
In cerebral adrenoleukodystrophy, the research team is continuing to study why a proportion of patients treated with this gene therapy, Bluebird's Skysona (elivaldogene autotemcel), developed blood cancer while others didn't, even when patients had vector insertions near the same gene, said David Williams, senior author on the paper and chief of the hematology/oncology division at Boston Children's Hospital.
Still, he emphasized that after a median follow-up of six years since receiving the gene therapy, the treatment was effective for the majority of patients.
"Gene therapy works in this condition to stop the advance of the disease," Williams said.
Skysona has been on the market in the US with a list price of $3 million since receiving accelerated approval in 2022 for certain boys with early-stage cerebral adrenoleukodystrophy, a rare metabolic disorder caused by mutations in the ABCD1 gene. Only about 1 in 20,000 boys have the condition.
Skysona is designed as a treatment to slow the progression of this childhood-onset adrenoleukodystrophy by adding functional copies of the ABCD1 gene to patients' cells. Specifically, Skysona uses a Lenti-D lentiviral vector that encodes ABCD1 complementary DNA to transduce autologous CD34-positive hematopoietic stem cells, which are modified ex vivo and administered back into the body.
Lentiviral vectors are among the most common delivery methods being tested within gene therapies, alongside adeno-associated viruses, adenoviruses, and retroviruses. Some researchers have also been testing nonviral vectors such as liposomes and lipid nanoparticles.
When the FDA approved Skysona, it required a boxed warning for hematologic malignancy on the gene therapy's label, which urged physicians to "carefully consider alternative therapies prior to the decision to treat a child" with Skysona and close lifelong monitoring for patients who receive the product.
Williams and colleagues in the paper stressed weighing the risk of blood cancer alongside the severity of the condition and availability of other treatments, which also carry risks.
In a separate NEJM paper published Thursday, another research team, also led by Williams, reported positive outcomes for Skysona on cerebral adrenoleukodystrophy disease progression, including disability-free survival for most of the seven patients who developed blood cancer.
Bluebird, which funded both studies, did not respond to a request for comment on the studies' findings.
Weighing the 'big risk'
There aren't very many treatment options available for cerebral adrenoleukodystrophy, and treatment decisions need to be made quickly, before the disease progresses too far, Williams said. A standard treatment option is allogeneic hematopoietic stem cell transplantation (HSCT), which can halt disease progression if performed early.
But many patients don't have access to a closely matched donor, which can improve chances of longer survival and reduce likelihood of serious complications like graft rejection.
For those patients who don't have a closely matched donor, HSCT with a less compatible donor and gene therapy become two key treatment options, both of which carry their own risks.
"This is a really devastating disease," Williams said. "The big risk is that the disease progresses. Once you have damage to the central nervous system, that's not reversible."
But the gene therapy has proven a promising treatment for the rare brain disorder. In the second paper published in the NEJM, Williams and colleagues reported on functional outcomes from the open-label, global Phase II/III ALD-102 trial, in which 32 boys with early-stage but active cerebral adrenoleukodystrophy received Skysona. None of the patients had major functional disabilities at baseline. The earliest patient was treated in 2013.
Twenty-nine of the 32 patients had not experienced major functional disabilities — such as loss of communication, loss of voluntary movement, or wheelchair dependence — when the study ended at the two-year mark, and those 29 patients subsequently enrolled in a 13-year long-term follow-up study that remains ongoing.
However, three patients experienced treatment failure. One patient experienced major functional disabilities beginning nine months after treatment and died during the study. Two patients, one of whom later died, withdrew from the study to undergo allogeneic HSCT due to disease progression.
As of the most recent follow-up assessment, 26 of the patients continued to report no major functional disabilities. The probability of survival without major functional disabilities, hematologic cancer, or referral for HSCT four years after receiving the gene therapy was around 81 percent.
By contrast, in a matched cohort study, the overall survival for patients who had undergone allogeneic HSCT after four years was 77.8 percent and just 63.2 percent for disability-free survival, Williams and colleagues said in the paper.
"The probability and magnitude of benefit that gene therapy can offer in patients who do not have an appropriate donor must be considered," the study authors wrote in the paper on hematologic cancer risk. If left untreated, patients with the progressive neurodegenerative disease experience a loss of neurologic function and various disabilities, culminating in early death.
Who develops cancer?
To tease out why some patients developed hematologic cancer, investigators conducted integration-site analysis, genetic studies, flow cytometry, and morphologic studies using peripheral-blood and bone marrow samples from 67 patients who received Skysona within a Phase II/III trial, a Phase III trial, and the ongoing follow-up study of those two clinical trials.
They found that, of the 67 patients who received the gene therapy, seven patients — or about 10 percent — developed blood cancer.
That includes six patients who developed myelodysplastic syndrome (MDS) and a patient with acute myeloid leukemia (AML). The seven patients all received the gene therapy between 5 and 13 years of age and did not have histories of blood disorders, and the cancers developed between 14 months and more than seven years after treatment with Skysona.
These findings on hematologic cancer risk should "raise the bar" for offering Skysona as a treatment for cerebral adrenoleukodystrophy, noted Cynthia Dunbar, chief of the translational stem cell biology branch within the US National Institutes of Health's National Heart, Lung, and Blood Institute, in an editorial accompanying the NEJM paper. She was not involved in the studies.
In their paper, Williams and colleagues hypothesized that particular features of the Lenti-D lentiviral vector design, such as the presence of enhancer sequences and overexpression of the ABCD1 transgene, could play a role in some patients developing hematologic cancer. The conditioning regimens or other aspects of the gene therapy's preparation could also be involved.
Most of the patients who developed blood cancer had vector insertions within multiple genes that have been linked with cancer. Six patients had somatic genetic defects in the KRAS, NRAS, WT1, CDKN2A or CDKN2B, or RUNX1 genes, and in one patient, the cancer was associated with monosomy 7.
All of the patients had clonal lentiviral insertions in tumor cells in or near the MECOM or PRDM16 genes, which help cells function normally but can become an oncogene. However, nearly all patients who received Skysona within these studies had MECOM insertions, most of whom did not develop cancer. It's unclear which integrations led to malignancy.
Though vector inserts in the MECOM gene were common, they "were not sufficient for the development of hematologic cancer," the study authors wrote in the paper.
"Clonal evolution with vector insertions into multiple genes, somatic abnormalities, or both were needed for progression to MDS or AML," they wrote. "However, no overt combinations of multiple integrations with MECOM appeared to confer a predisposition to the development of hematologic cancer."
Dunbar said the high hematological cancer risk appears to be related to the gene therapy's use of a modified viral promoter, MNDU3, to control expression of the ABCD1 transgene in the lentivirus. There are no cases of blood cancer linked to insertional genotoxicity from lentiviral vectors in 250-plus patients who have received other treatments that incorporate lentivirus vectors.
These findings "do not raise any additional concerns in my opinion," in terms of hematologic cancer risk for other gene therapies using lentiviral vectors, she told Precision Medicine Online.
As part of an international collaboration, Williams is working on research to design and test safer vectors for delivering gene therapies for cerebral adrenoleukodystrophy using insights from patients who developed cancer within the Skysona trials. He said the group has applied for grant funding to advance their work.
"The vector needs to be made safer," he said, "but still needs to have efficacy in treating the disease."
Dunbar said it's likely researchers will identify additional blood cancer cases over time in patients treated with this specific gene therapy, given the long time frame it can take for cases to arise and findings of oligoclonal expansions in other patients who received the product, but so far have not presented with hematological cancer.
"Unfortunately, the results from the published trial show that it is hard to detect a problem very far in advance of overt MDS/AML," Dunbar said. She hopes to see advancements in the field that enable a vector that only expresses the therapeutic gene in macrophages and microglial cells, instead of constitutively, like in this gene therapy.
Still, after treatment, most patients in the clinical trials had positive outcomes, including those who developed cancer.
Five patients with MDS with unilineage dysplasia or excess blasts underwent allogeneic HSCT as treatment, four of whom remain free of MDS and have not had recurrent cerebral adrenoleukodystrophy symptoms. One patient died, likely from graft-versus-host disease, 20 months after HSCT and 49 months after gene therapy.
The patient with the most recent case of MDS is awaiting HSCT. The patient with AML has responded well to HSCT so far.
Of these six patients who developed cancer following gene therapy and remain alive, five continue to be free of major functional disabilities that are commonly seen in cerebral adrenoleukodystrophy at their most recent follow-up assessment. A single patient reported one functional disability, total incontinence, 18 months after treatment, which was before their MDS developed.
Investigators noted that the two clinical trials used different conditioning regimens. The Phase II/III trial used busulfan-cyclophosphamide while the Phase III trial used busulfan-fludarabine. Six of the seven patients who developed blood cancer were in the Phase III trial, suggesting a conditioning regimen of busulfan-cyclophosphamide might be preferable.
The study authors emphasized the need for additional research into the choice of promoter used to control expression of the transgene, as well as studies into how to optimize expression of the transgene so that it's high enough to inhibit disease progression while low enough to reduce likelihood of risks related to genotoxicity and genomic instability.
"The way these factors individually, in combination, or with other unidentified variables interact with one another to lead to genotoxicity is unclear," the study authors wrote.
In the meantime, since it's unclear which patients are most likely to develop hematologic cancer after this gene therapy, researchers recommended close monitoring of all patients.
Williams said "aggressive" surveillance of patients is needed. He said he uses molecular analysis to identify potential abnormalities near oncogenes in patients, who then get more frequent blood counts.
"The molecular analysis we do, as good as it is, doesn't predict who's going to develop MDS or leukemia," he said. "It only tells us to pay closer attention to a particular patient."