Inside the Clinic: Graft-versus-Host Disease Best Practices - Episode 13

The Future of GvHD: Promising Agents in Development

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Yi-Bin Chen, MD: In terms of research for graft-versus-host disease [GvHD] and trials moving forward, I think it helps to look back and ask ourselves why our trials of the past have failed. I think if you look at large trials in the past, we’ve always enrolled a high proportion of low-risk patients. We’ve treated grade 2, 3, and 4 the same, in the same population. And we’ve powered our large comparative studies on historical controls and watched in real time, as when we did a phase 3 trial, our contemporaneous control outperformed the historical one. We need to learn from this. We need to take lessons from that and be able to better design our trials. I think as you’ve heard me mention, developing biomarkers for graft-versus-host disease or any other system to better risk stratify patients, and this is important for trials moving forward.

For patients at diagnosis now who we deem to be high risk, either biologically or we think they’re going to be worse, the trials moving forward should probably include steroids plus an additional agent because these patients do not have satisfactory responses to initial steroids. For patients with biologically low-risk disease and those we think will respond quite well to steroids, we should think about other strategies. We should think about maybe not using steroids and just your novel drug.

Or we should start steroids at a dose and then think about doing aggressive tapers to spare patients the toxicity of steroids. Those are not novel ways to think about it, these trials are ongoing right now and are in the discussion at that level. But the ability to take what used to be 1 population of graft-versus-host disease and separate them into what we believe are biologically different populations will be very powerful and hopefully successful.

I think biologically we’ve seen that patients who do the worst with acute graft-versus-host disease are generally patients with lower GI [gastrointestinal] disease, and so targeting that subset of patients will hopefully lift the outcomes for all. And I think recent investigations in mouse models and others have suggested how important preservation of the intestinal stem cell initiative is, ultimately to helping our patients with intestinal graft-versus-host disease. Looking at that biology and the steps and learning more about intestinal stem cells may ultimately guide us into how we’re going to improve outcomes for that population.

Corey Cutler, MD: The field of acute graft-versus-host disease has really undergone a huge change in the last few years. Whereas, 5 to 8 years ago we had very few agents we were testing, we now have this embarrassment of riches where there are a number of agents being tested in steroid-refractory and even upfront management of acute graft-versus-host disease. We have other JAK inhibitors. We have alpha-1 antitrypsin, which is being tested broadly. There is therapy against CD6 and other targets that is being tested actively. And hopefully we’ll come up with better algorithms, both for the initial treatment of GvHD and for later on.

One thing I think that needs to be discussed is the use of biomarkers and how that might help us treat GvHD a little better. In my mind, they’re still a bit experimental, but they have become part of our clinical trial armamentarium in how to judge patients having lower- or higher-risk acute graft-versus-host disease. That’s going to make a big difference in the coming years if they’re truly validated in a number of other studies. I think the biggest push in acute graft-versus-host disease has to be prophylaxis. As we determine that the experimental agents that we have are effective for therapy of advanced disease, we’re going to move those agents into the preventive setting. Certainly, preventing acute graft-versus-host disease is a much better approach than trying to have more effective treatments for severe or steroid-resistant disease.

The REACH3 is a very large randomized trial looking at ruxolitinib versus best supportive care or best available care for steroid-resistant chronic graft-versus-host disease. This trial has completed accrual, although we do not yet have any results. Of course, the field is looking for anything that will help in this setting. There is 1 agent, that’s ibrutinib, that is approved in steroid-refractory chronic graft-versus-host disease. But there are lots of other agents that are being tested in that field, and the ROCK2 inhibitor KD025 is one of the more promising agents. But certainly, we are all anxiously awaiting the results of REACH3, and hopefully we’ll know those data soon.

Transcript Edited for Clarity