What's Next in the Management of GVHD?

Bart L. Scott, MD:What’s next for the treatment of graft-versus-host disease [GVHD] associated with stem-cell transplant? In particular, in regards to ruxolitinib, there are 2 coming phase III randomized trials known as REACH2 and REACH3. REACH2 is a phase III randomized multicenter trial comparing ruxolitinib to best available therapy for patients with steroid-refractory acute graft-versus-host disease. And REACH3 is also a multicenter phase III randomized trial comparing ruxolitinib to best available therapy, but for steroid-refractory chronic graft-versus-host disease. Both of these could potentially prove that ruxolitinib is better than best available therapy for treating steroid-refractory GVHD in both the acute and chronic setting.

What are the unmet needs following the trials with ruxolitinib? There’s still an issue with acute graft-versus-host disease, and there are certainly patients who don’t respond to ruxolitinib in that setting. And they really have very few treatment options available to them. Particularly when you have GI [gastrointestinal] involvement with steroid-refractory GVHD, that historically has a very poor prognosis and generally has a dismal outcome with a multitude of symptoms that leads to a patient’s slow decline. And then with chronic GVHD, I think the most important concern is lung involvement. That typically saps patients of their ability to breathe well and is typically slowly progressive, with more shortness of breath over a long period. And patients can have a lot of [adverse] effects from that.

Are there any other coming agents that are of interest for treatment of GVHD? Fedratinib is a JAK inhibitor that was actually just approved last month, which would be in August of 2019, for myelofibrosis. It also, like ruxolitinib, inhibits the JAK/STAT pathway and could be potentially useful in treating graft-versus-host disease. Unfortunately, one of its major adverse effects from a GI perspective is diarrhea. So there’s a lot of potential overlap with symptoms of acute GVHD. Another drug that’s of interest is alpha-1 antitrypsin, and there is some early phase results that are promising, particularly in patients with steroid-refractory GI graft-versus-host disease. Those are 2 agents that are of potential interest in the future.

In regard to what future clinical trials should address, there’s always this balance of GVHD and relapse. And I think we need to look at overall survival as principal endpoints of future clinical trials. I also would like to see trials that detect patients who are at risk for serious GVHD at an earlier time point, so that you can intervene earlier before they develop significant sequelae related to the graft-versus-host disease. I would apply this in both the acute and chronic setting.

Transcript edited for clarity.