Treatment for Steroid-Refractory Chronic GVHD

Yi-Bin Chen, MD: If we look at the patients who undergo transplant overall, probably more than 60% of patients develop some form of chronic graft-vs-host disease [GVHD]. As we talked about before, there’s a broad biological spectrum, from mild to moderate to severe, in how we classify it. We tend to not think mild disease is so significant, nor do we think mild disease requires systemic therapy for the most part. About 40% of our patients probably require some systemic therapy for chronic graft-vs-host disease at some point.

The prognosis for these patients is varied. It obviously depends on the severity of the symptoms, which organs are involved, and the severity of that organ involvement. Our classification systems don’t capture all of that. If you take a patient with scleroderma disease and you're just grading it by body surface area, they may have localized scleroderma that doesn’t look so severe on our grading systems, but if it’s on a certain part of their body, like over their anterior abdominal wall, it may make breathing very difficult as their diaphragm contracts. The quality of life in terms of what our patients experience may be different than what’s reflected in the actual classification.

The overall prognosis for these patients depends on if their disease responds to the treatments that we employ. Obviously, patients with more severe disease have a worse prognosis than those with mild disease. As we develop newer and hopefully better therapies, the prognosis will be much more dependent on how their disease responds to such therapies.

Corey S. Cutler, MD, MPH, FRCPC: When patients become steroid-resistant, steroid-refractory, or even steroid-intolerant, we have a number of agents that we use in the second line. Ibrutinib is the only drug that’s approved in the second line for steroid-refractory chronic GVHD. It was approved based on a 42-patient study that demonstrated a response rate of about two-thirds of subjects with steroid-resistant GVHD.

Very importantly, the REACH3 trial, which has now been presented publicly, demonstrated an improvement in steroid-refractory chronic GVHD outcomes when we compared ruxolitinib to best available therapy according to investigator choice. We expect that agent to be approved by the agency and have a label expansion later in the year. And then the ROCK2 inhibitor belumosudil has similarly demonstrated very impressive results, with approximately a 75% response rate in subjects treated with 2 to 5 prior lines of therapy. We similarly expect that belumosudil will be approved by the agency later this year. While we only have 1 agent now, by the end of 2021, we suspect that we will have 3 approved agents for the therapy of steroid-refractory chronic GVHD.

Also importantly, there are many other agents being developed in that space. We’re going to learn how to treat chronic GVHD better in the coming years, understanding which patients need which agent based on biomarkers and other clinical factors. We’re going to see a nice improvement in chronic GVHD treatment outcomes in the years to come.

Haris Ali, MD: The REACH3 study compared ruxolitinib with best available therapy for steroid-refractory chronic GVHD and showed about twice as much response with ruxolitinib compared to other treatment. A number of patients actually crossed over from the best available therapy to the ruxolitinib arm, and they continued to have responses. Ruxolitinib was used even before the study for chronic GVHD. There have been multiple reports, including one that we reported from City of Hope on the 42 patients in which we showed patients were having responses on this treatment. This also confirms the finding that it is an effective and active treatment for steroid-refractory chronic GVHD.

Yi-Bin Chen, MD: Based on the published work in the last few years, we had already started using ruxolitinib for steroid-refractory chronic graft-vs-host disease in our practice. We had found it quite tolerable, and a high percentage of patients had a meaningful benefit in terms of classification systems but also by subjective quality of life. REACH3 was a really important study. It was one of the only large phase 3 studies in steroid-refractory chronic graft-vs-host disease. Ruxolitinib showed a benefit in terms of overall response rate as well as multiple secondary end points compared to best available control. Even though the critique would be that the control arm was heterogeneous, there’s no other way to do the trial because there was no internationally accepted standard that could serve as a control. The results were certainly validating for our practice and reassuring that this was a standard of care that could be used.

We look forward to, hopefully, approval of this agent to allow more of our patients to gain access. Ruxolitinib for chronic graft-vs-host disease has been quite tolerable. It’s rare that you run into a toxicity where you have to stop the drug. Just like in acute graft-vs-host disease, there are cytopenias that can develop. They’re a bit less common than in the early post-transplant study. Usually with dose reductions, you’re able to get by and still continue the drug itself.

Transcript Edited for Clarity