Fecal Microbiota Transplantation for Acute GVHD

Transcript:

Yi-Bin A. Chen, MD: I think as I mentioned before and as all of us are experiencing, the approval of ruxolitinib and the experience and the trial have been a tremendous step forward in treating patients with acute graft-versus-host disease [GVHD]. There’s no doubt about that. It certainly is another standard agent in our armamentarium that we hope to continue to improve.

But it’s also not a home run. I think we need to acknowledge this. As you mentioned, the day 28 overall response rate was 55%. That means a little less than half of the patients required another agent or didn’t have a satisfactory response. It illustrates the work that has to be done. And so, I want to touch bit on research in acute graft-versus-host disease—where the field is going, what trials we’re doing. I had touched on the challenges experienced in previous clinical trials and how tough a population it is to do research on, especially the steroid-refractory population, not only because of the competing risks and how sick these patients are, but also that they’re likely different in terms of why they have graft-versus-host disease. They won’t all respond the same to 1 treatment, so it’s not about finding a magic bullet here.

So how do we move forward? How do we improve outcomes in graft-versus-host disease? I think the first thing is what Zack touched on already, the different ways of risk stratification. Certainly in the past, we lumped all acute GVHD together and treated everyone the same. That meant that the lower-risk patients all responded and probably diluted any effect that you wanted to see. And so, for agents that might have worked we weren’t able to figure out if they did. We treated the higher-risk patients, yet they were so sick that they suffered complications and stopped the experimental drug before we were able to even see if these drugs worked.

For both of these reasons, it’s been a fairly challenging field to try to make advances in. One question has always been, “Hey, guys, you give medicines to prevent graft-versus-host disease, so why don’t you focus more of your time on prevention rather than treatment?” There’s credence to that. It’s just that the majority of our patients will not develop severe, acute GVHD. You heard me say that only about 30% of our patients overall developed any acute graft-versus-host disease that requires treatment, and only about 10% develop severe graft-versus-host disease in our practice. But yes, we probably could prevent it more.

I think the debate there depends on what agent you’re studying. Inherently, as you’re preventing a complication, you are overtreating patients. And so your appetite for overtreatment really depends on what the toxicity of your agent is. If your agent is great, and it works and it prevents disease and has 0 [adverse] effects, sure, it totally makes sense to prevent. I think it depends on the severity of your [adverse] effects. That will determine your appetite for how many patients you can overtreat to prevent.

I think these are complicated discussions. It depends on what agent you have and what your practice is. One big area of graft-versus-host disease research that has recently emerged, not only in transplanted GVHD but in other areas of health, is the microbiome. Zack, you’ve done work in microbiome-related research in graft-versus-host disease. Can you discuss what’s going on in that area?

Zachariah M. DeFilipp, MD: Sure. In recent years, we’ve learned a lot about the changes in the intestinal microbiome of our patients around the time of transplant. Analyses of fecal specimens collected from patients early on after transplant have shown that if the diversity of their microbiome is low at that time early after transplant, this is associated with worse outcomes after the transplant—worse survival outcomes. In addition to that, changes in the microbiota composition have also been associated with specific clinical outcomes such as relapse, but also GVHD.

Although these associations do not demonstrate causality, they do give the initial data that we need to further investigate whether we could influence patient outcomes with microbiome-directed interventions. There are a number of studies that are looking at microbiome-directed interventions to either prevent or treat acute graft-versus-host disease. One of the more prominent ones is fecal microbiota transplantation [FMT], which refers to taking fecal matter from a healthy donor and transferring this to the transplant recipient with the intention of improving upon or further diversifying the recipient’s microbiome.

There have been case reports and small series that have reported the resolution of steroid-refractory acute graft-versus-host disease following the administration of FMT. At Massachusetts General Hospital, we conducted a pilot study to preemptively administer FMT to transplant recipients early after transplant. We found this approach to be safe and to be associated with improvements in the transplant recipient’s microbiome diversity, which was associated with engraftment of the donor stool species.

Yi-Bin A. Chen, MD: So we took third-party stool and transplanted that into transplant patients after their cells engrafted?

Zachariah M. DeFilipp, MD: Correct.

Yi-Bin A. Chen, MD: And we restored diversity to their microbiome, right?

Zachariah M. DeFilipp, MD: Correct.

Yi-Bin A. Chen, MD: Do you think that is an approach that could become an intervention in the future?

Zachariah M. DeFilipp, MD: As you were just discussing, I think that there is a balance between the prevention of graft-versus-host disease and the treatment of graft-versus-host disease. Sometimes it is easier to prevent graft-versus-host disease, but we always have to make sure that these interventions are both feasible and safe. Based on our pilot data, it seems that the approach of giving FMT early after transplant when a patient’s gastrointestinal tract is not inflamed due to graft-versus-host disease complications may be an ideal or safer time to administer an FMT to try to reset the microbiome and decrease the risk to develop graft-versus-host disease in the future. There are a number of ongoing studies that are looking at microbiome-directed interventions, such as FMT, to either treat or prevent acute graft-versus-host disease.

Yi-Bin A. Chen, MD: I think it’s a really exciting field. Many other areas of medicine are researching microbiome interventions as well, and we really look forward to the results of not only our own study but those of our colleagues around the country who are doing similar studies to figure out if there’s a role for microbiome interventions.

Transcript Edited for Clarity