Future of Steroid-Refractory Chronic GVHD Treatment

Yi-Bin Chen, MD: Hannah, what do you think we should do about chronic GVHD [graft-vs-host disease] trials going forward? We have 3 new approvals in steroid-refractory disease. What should we do for newly diagnosed patients? What are the strategies to try to advance the field?

Hannah Choe, MD: Corticosteroids remain. Even though they’re the gold standard, they clearly have many adverse effects, so we have to find a better agent. There has to be something better than corticosteroids, and we’re going see that in the future. These agents are going to be moved up earlier in use, either for first line or even prophylaxis of chronic GVHD. Once Sophie develops these biomarkers, we’re going to be able to determine whether these patients are going to develop chronic graft-vs-host disease and then risk stratify and start them on prophylactic ruxolitinib or belumosudil or whatever other agent might be emerging. Cutting out steroids completely is the goal—to avoid the bone density loss, hyperglycemia, hypertension, and long-term adverse effects of corticosteroids that we don’t think we’re going to see with ruxolitinib or belumosudil. Hopefully that’s the future.

Nelson J. Chao, MD, MBA: This is going to date me, but in 1990, we tried a prophylaxis trial for chronic GVHD with thalidomide. It was a bust, probably because there were too many relapses. In the back of our minds, we have to remember that as much as we want to get rid of GVHD—and we do—there’s still a beneficial effect, especially in chronic GVHD with the antileukemia effect, so we need to be careful not to forget that.

Yi-Bin Chen, MD: In transplant history—you can validate this, Nelson, given your long standing in the field—anything that we’ve done that has successfully lowered GVHD has usually resulted in a corresponding higher rate of relapse. Things may be changing a little with post-transplant cyclophosphamide. We don’t know that yet. We need readouts of trials. But you’re right: that’s the fear.

Nelson J. Chao, MD, MBA: At least with pharmacological ways. As we get better in understanding the biology, we’ll probably get there.

Yi-Bin Chen, MD: We’re doing more trials to more effectively prevent acute and chronic graft-vs-host disease, because those things appear to be linked on some level. Hannah, you touched on being able to give preemptive interventions for chronic GVHD. There are some data with anti B-cell agents, like rituximab. Part of that is, are we treating everybody? Will we have biomarkers for risk stratification to be able to treat a higher-risk population and so forth? Sophie, do you think we’re going to get away from steroids soon?

Sophie Paczesny, MD, PhD: In first line, I’m not sure. There’s an NIH [National Institutes of Health] study that says that the risk for worse outcome is not having steroids in the first place, so we’ll still be careful. If we can categorize the patient as high risk and low risk or standard risk, we may be focused on the standard or low risk. But for the high risk, I’ll go away from it.

Yi-Bin Chen, MD: You mean at least being able to get away from steroids for a subset of patients, maybe not all, depending on how they present and so forth.

Sophie Paczesny, MD, PhD: That’s right. And then as Nelson was saying, maybe adapting to the biology. There are new drugs where targeting the macrophages are important in chronic GVHD, like CSF1R. Why not? It will be interesting. CSF1R was 1 of the biomarkers that didn’t pan out in the larger group. But maybe there’s a subset in which we need it.

Yi-Bin Chen, MD: Let’s touch on that. That’s an exciting new therapy that’s in ongoing trials, a monoclonal antibody targeting the CSF1R receptor, which is on activated macrophages, which are thought to play a role in fibrosis. It goes along the trend of targeting fibrosis, not cumulative immunosuppression. This agent is in active trials right now that may be open at our respective centers for steroid-refractory chronic graft-vs-host disease. Are you excited about this pathway targeting?

Sophie Paczesny, MD, PhD: Macrophage is important, and we can also eventually present cells, so I’m excited about this pathway. It’s a different pathway from the T cells, avoiding so much immunosuppression on the T-cells and probably avoiding the loss of GVL [graft-vs-leukemia], as Nelson was mentioning. That’s an interesting approach.

Yi-Bin Chen, MD: Are there any other therapies in trials that are promising for people in chronic graft-vs-host disease?

Nelson J. Chao, MD, MBA: There are a couple. MSCs [mesenchymal stem cells] have been around for a while. People are interested in that. Glasdegib, a Notch inhibitor, is also in trials. Notch signaling is probably important through both T cells and B cells in chronic graft-vs-host disease. As I was saying earlier, as we understand some of the biology of this better, we’ll get to a point where we figure out the holy grail of transplant, which is to have no GVH but preserve GVL.

Yi-Bin Chen, MD: Do you think there are any applications for cellular therapy for chronic graft-vs-host disease?

Hannah Choe, MD: Beyond the MSCs, the role of the T regulatory cell is becoming so important for prevention of chronic graft-vs-host disease, so it wouldn’t be surprising if that enters as a role for treatment as well in the future, especially as we’re becoming more familiar with using cellular therapies. That would be very welcome in a high-risk population. I don’t know that any are in design. I don’t know any off the top of my head, but patients and physicians would be willing to entertain that.

Sophie Paczesny, MD, PhD: Correct. MSCs and regulatory T cells.

Yi-Bin Chen, MD: They appear to be the most promising subsets. We talked about the changing patterns of acute GVHD. Nelson, since you’ve been doing this the longest, can you reflect on chronic graft-vs-host disease when you started and chronic graft-vs-host disease now? Is there a difference? We talked about the difference in acute. Do you think there’s a difference in chronic in terms of presentation or severity or anything like that?

Nelson J. Chao, MD, MBA: No. What changes is—you can be a lumper or a splitter, and as we get more patients surviving longer, all of us have a broader experience of what chronic graft-vs-host disease could be. The onset is probably more insidious than it used to be because when we started, it was all ablative matched and you could pick the day that that was going to start happening. Today that’s not true, partly because of prep regimen. It’s so different now, and you don’t have the same level of toxicities that establish this. But I’d remind everybody that probably the best prophylaxis for chronic GVHD is not getting acute. That’s probably the highest risk factor for developing chronic. As we get better in preventing acute, hopefully we’ll see less chronic.

Yi-Bin Chen, MD: It could be reflected in the chronic.

Transcript Edited for Clarity