EBMT 2025 | The risk of developing leukemia after lentiviral gene therapy

The risk of insertional mutagenesis causing leukemia has been around for many decades. Since we have started using viral vectors for gene addition, that risk has always remained there. About 20 years ago, when we were using gamma retroviral vectors, this risk was very common. Many patients who received gamma retroviral therapy for different genetic diseases developed leukemias afterwards. With the development of lentiviral vectors, fortunately, which are much, much safer, this risk had been almost non-existent until recently. And so there were two instances where this sort of risk re-emerged. 

One, when in the clinical trial that was being conducted by Bluebird Bio for their sickle cell disease gene addition technology. On that trial, two patients developed leukemia, and the trial had to be shut down, put on clinical hold for a brief duration while these two cases were investigated. Now, extensive investigations for those two patients revealed that the lentiviral integration actually did not cause leukemia in those patients. We don’t completely understand what might have caused the leukemia. It is likely that at least one of those patients might have been predisposed to develop leukemia anyway, and they just got unlucky and developed leukemia after they got gene therapy. And in the other patient, it is also possible that maybe exposure to myeloablative busulfan was what was responsible for causing leukemia. So at least in those sickle cell disease patients, leukemia was not caused because of the viral integration. 

However, there is another therapy for cerebral adrenoleukodystrophy. The trade name is Skysona. This therapy, also being marketed by Bluebird Bio, on their pivotal clinical trial for this gene addition therapy, several patients have developed leukemia after getting gene therapy and in these patients it is well documented that the lentiviral vector preferentially integrates near a proto-oncogene MECOM and then the MND promoter that is part of that lentiviral vector is responsible for the overexpression of the MECOM gene resulting in leukemia in those patients. So many patients, many children who have received this type of gene therapy have developed leukemia as a direct consequence of receiving the gene therapy and the integration of this lentiviral vector at that locus. And it is presumed that many other patients who are currently in follow-up might also develop leukemia. 

So this gives us a little bit of a pause. We hope that newer therapies, therapies that we have been developing and vetting for past several years, are better than the alternatives that we are trying to leave behind. In this case, we are trying to avoid all the complications that are associated with an allogeneic transplant with an alternative donor, graft-versus-host disease, graft rejection, the need for immunosuppression, and replacing them with a potentially better therapy. But as we have learned in the case of cerebral adrenoleukodystrophy, that newer therapy may not be better. That newer therapy may be worse than the alternative, that’s allogeneic transplantation, because it causes leukemia. 

So I think the scientific community really has to take a pause here, think about it, reevaluate our options. Because that risk of myelodysplasia and development of leukemia has resurfaced now, and we don’t want to push the community, push the scientific field backward. If we don’t pause and reassess what we are doing, how these therapies are affecting our patients, we may run the risk of losing the confidence of our patients, of the community that we serve, and we may end up completely pausing any development in this field. 

So my heart goes out to those patients and families that have developed leukemia. They volunteered to be part of these first in human clinical trials. So while I’m really appreciative of their altruism and their bravery for participating in these clinical trials, I’m heartbroken that these therapies have not helped them the way we would want to help them, that it might have brought them more harm than good and so as a medical community I feel like it is our responsibility, we owe it to these patients to study how these therapies are affecting our patients, both short-term as well as long-term. And if there are these adverse events that we can recognize, especially development of myelodysplasia, that we have to pause, think about it, fix those problems, and then move forward again.

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