The Expanding Field of GVHD - Episode 13

Treatment Advances on the Horizon for Chronic GVHD

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Expert panelists share their perspectives on ongoing treatment evolutions in the setting of chronic graft versus host disease.


Corey S. Cutler, MD, MPH, FRCPC: The past behind us, what are the exciting things that are coming in chronic GVHD [graft-vs-host disease]? Yi-Bin, what do you think is the future?

Yi-Bin Chen, MD: I think a couple of things. We had mentioned the state of biomarkers for acute GVHD and where that was. Certainly, our goal is to get there for chronic GVHD as well and there’s a lot of ongoing research to figure out if biomarkers exist for chronic GVHD. What I mean by this is not diagnostic biomarkers again, but more prognostic biomarkers in one way in terms of being able to, at diagnosis, separate high-risk and low-risk biology of chronic GVHD. But more importantly, I think what would be really useful are biomarkers that help us predict which patients will respond to which therapy.

Now, we have all these options and still it’s this empiric trial and error. Looking at a clinical phenotype and thinking, ‘Oh, well that patient will respond to this therapy,’ is probably incredibly primitive without understanding the actual immune pathway that’s at play. I think first, from a biomarker standpoint, is to pour a lot of resources into trying to figure that out, to send a panel off at diagnosis to help inform us which treatment would be the most helpful. Second, when thinking about treatment, we have to move away from steroids, right? I think certain biomarkers will help, but clinical trials where we test nonsteroid alternatives in certain forms of GVHD, even up front, have to be done, or short-course steroids followed by a rapid taper to get off have to be done as well. And I think what’s clear is that our patients suffer a tremendous burden of morbidity from steroids and they’re probably not useful, at some point, for the activity. For me, it’s about developing biomarkers to stratify patients, be it on risk or response to treatment, and then moving away from steroids in general.

I’ll add one more thing, which is if you look at the clinical trials for all these agents that we’ve mentioned, they have impressive overall response rates; they range from 50% to 75% in terms of what data set you look at. The vast majority of those responses are all partial responses; there’s a very small minority, often in the single-digit range, that are complete responses. And if that’s the case, we can either say OK, maybe that’s the disease, maybe that’s because we don’t have the right drugs, or maybe it’s just too late. Once it sets in, there’s an element of reversibility and organ damage that we’re not going to reverse. And if that’s the case, then we have to act earlier. Then that gets to the fact that there should be a focus on treatment, but also a focus more on specific trials to specifically prevent chronic GVHD in real time.

Corey S. Cutler, MD, MPH, FRCPC: I agree entirely. Better positioning of our active agents earlier on is probably going to be a big thing. Linda, what do you see as some of the important advances on the horizon for chronic GVHD or approaches?

Linda M. Perry, PA-C: One of the things I was going to mention is, with respect to combination therapy, we do have several of these approved drugs and they all have seemingly very different mechanisms of action, assuming that the adverse effects don’t overlap too much, which for ruxolitinib, for instance, and belumosudil shouldn’t overlap too much. Well how could you best use these drugs together? Along with some of the other more friendly therapies, such as ECP [extracorporeal photopheresis] and a low-dose methotrexate; that way, you’re targeting different pathways to hopefully maximize response. How do you use those and can there be clinical trials to address that issue?

Corey S. Cutler, MD, MPH, FRCPC: I think one of the big things is primary prevention of chronic GVHD. We and others have undertaken trials of things like B-cell depletion following transplant as a strategy to prevent the occurrence of chronic GVHD or clinical chronic GVHD before it happens. Of course, the approaches that include ATG [antithymocyte globulin] and perhaps PTCy [posttransplant cyclophosphamide] are associated with lower rates of chronic GVHD in the long term.

We don’t quite yet know how chronic GVHD associated with these regimens differs from the chronic GVHD that we’ve traditionally seen with tacrolimus-methotrexate. Is it going to be more or less resistant? Will it be more amenable to therapy, etc? But I think there’s a lot that needs to be done. I think what Yi-Bin said about finding the right drug for the right patient is critical. And employing large databases and machine learning, and both clinical and biochemical algorithms that will help point us in the right direction, certainly are things that we need to incorporate in the future.

Transcript edited for clarity.