Gene Therapy Toxicities and Management


Biree Andemariam, MD: What are some of the sequelae that providers and families alike are concerned about? Julie, what are the common toxicities, both short and long term, focusing on gene therapy?

Julie Kanter, MD: The majority of gene therapies right now use myeloablative conditioning. In my opinion, looking at all the data, everyone who’s doing gene therapy right now should be using myeloablative conditioning. We know that’s going to cause infertility in about 90% to 100% of people. There’s some leeway because I’ve seen magic happen. I’ve seen individuals have post–gene therapy babies. But in general, we always say these individuals are at high risk, are likely going to be infertile, and we offer steps to mitigate that. The other thing is that they’re all going to have mucositis, which means nasty ulcers, and it’s going to be uncomfortable. We know that there’s an increased risk for infection, though we haven’t seen as high a risk for infection in gene therapies as we have with the stem cell transplants. We know that there’s a risk, although thankfully we haven’t seen it, of a liver problem called veno-occlusive disease of the liver. We haven’t seen that in the sickle cell population, but it’s been a big issue we’ve seen in thalassemia.

There are these risks. We’re very clear. This is a 10-hour conversation, but it’s also very limited by what’s available at your center and what your transplanters are comfortable with—especially in the adult world. Elliott mentioned this, but we have to have a network of transplant centers where there’s a hematologist and a transplanter who have relationships. We also need to make it so our patients can get there.

Michael DeBaun, MD, MPH: I just wanted to mention that we also have now come to realize that our patients’ postcurative therapy may have their first cancer. This is not trivial. In a group of around 110 individuals, approximately 6 or 7 had developed a myeloid malignancy. My understanding is that 1 of the patients who received gene therapy also developed a myeloid malignancy. There’s biology that we need to understand to better select or preselect individuals who are at lowest risk for having malignancy postcurative therapy. This goes to the broader picture of the importance of—I would hesitate to say registry because they are often passive—but formal late-effects studies funded by the NIH [National Institutes of Health] to understand what the implications of the biology of curative therapy are and how we can mitigate organ disease postcurative therapy as well as decrease the risk of first-time malignancy for individuals with this disease.

Julie Kanter, MD: That is interesting. It goes back to 1 of the things we’ve seen in some of those malignancies in haploidentical transplant. It’s very similar to what we saw in the individual who was in the Group A part of the LentiGlobin study. That individual also may have been underdosed in his chemotherapy—so not quite myeloablation. There is some concern that those cells that recover, if they don’t totally engraft on the haplo [haploidentical] side or if they recover some of their non–gene therapy–treated cells, have been chemotherapy-exposed cells and may be causative in these situations. So I totally agree. We need to be really firm in our commitment to following and funding to follow these patients long term.

Transcript Edited for Clarity

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