Advances in Treatment of Steroid-Refractory Chronic Graft-versus-Host Disease (GvHD) - Episode 8

Future Directions for the Treatment of GvHD

Yi-Bin Chen, MD, shares insight on unmet needs and the future treatment landscape for patients with chronic GVHD and steroid-refractory GVHD.

Matt Fowler: What are some of the remaining unmet needs for patients with chronic GVHD [graft-vs-host disease] and steroid-refractory chronic GVHD?

Yi-Bin Chen, MD: It’s useful to think about what the accomplishments in the field of chronic graft-vs-host disease have been over the last couple of decades. There’s been a lot of literature on disease manifestations of the multiple organs involved. These are well characterized from classic chronic graft-vs-host disease to manifestations of a dysregulated immune system as well. The NIH [National Institutes of Health] consortium has done an excellent job developing tools for standardized assessments of not only organ involvement but also the severity, and that has allowed us to communicate and conduct clinical trials. We understand pathophysiology better. We’re not close to elucidating at all, but we at least understand it better, understand that more pathways are involved and elucidating these pathways ultimately yields more targets for intervention or therapy.

We’ve managed to generate investment by industry and interest. We have 3 approved agents, and hopefully many more are on the way with ongoing clinical trials, which we hope will ultimately make the outcomes better. Our work is not done. There’s a lot of room for improvement, even in the accomplishments I just mentioned. The NIH tool is the best we have, but it’s also filled with subjectivity. It’s also inconsistent and a bit cumbersome to use in everyday practice. It takes training, and it’s an acquired tool to be able to use accurately.

Looking at all the trials that got these agents approved, one can see that the majority of clinical responses are partial responses and not complete responses. I touched on this before in discussing the REACH3 trial data. Partial responses can be life changing or can be of no difference. Do we have the wrong agents, or are we just intervening at the wrong time? Are we focusing at the wrong stage? In terms of steroid refractory, we should be focusing earlier because ultimately what we’re trying to do is prevent that end-organ damage and improve quality of life. We could use more tools to understand what these partial responses are, and that ultimately gets down to better patient-reported outcome tools to understand what’s important and what’s not, so there’s ongoing research in that realm.

When we see a patient with chronic graft-vs-host disease, we need to be able to somehow understand their prognosis, and that gets to some biomarker or measurement that can biologically stratify these patients. The state of acute graft-vs-host disease biomarkers is a bit more mature with commercially available assays that have allowed us to do biologically risk-stratified trials, but chronic graft-vs-host disease biomarker development is a bit behind that. Trying to figure out if we can develop such tools would be helpful and help us conduct better trials with more homogeneous patients. Understanding these biomarkers for this population can obviously also yield newer targets and newer agents for intervention. Those are some of the areas that we need to move forward with.

Obviously, focusing on treatment, there are obvious needs in prevention as well, and maybe even preemptive. That means we should start doing trials that focus after transplant on finding population that we think in real time are at high risk of chronic graft-vs-host disease with earlier intervention to prevent that fixed organ damage. I’m excited that in the next 10 years, this will be a really active area of research that will definitely help our patients going forward.

Matt Fowler: To wrap up our discussion, are there any therapies in development or ongoing clinical trials that you see that could address some of these unmet needs that you’re excited for?

Yi-Bin Chen, MD: The agent that’s maybe the closest to a pivotal trial would be a monoclonal antibody called axatilimab. This targets the CSF1R receptor, which is present on activated macrophages. It’s thought that these activated macrophages are very active in the fibrotic cascade, targeting that whole process of fibrosis. There’s an ongoing pivotal trial with this agent that we have open, as do many others, in hopes of seeing if targeting this novel pathway can have efficacy.

The other efforts in developing biomarkers and focusing on preemptive or better prevention of chronic GVHD would be worth an investment by the community. Most of the traditional trials that we’ve done have focused on prevention of acute GVHD partly because acute graft-vs-host disease cause the bulk of morbidity and mortality and partly because we thought acute would lead to chronic. By preventing acute, we can prevent chronic. But as you target more specific pathways, that may not be true, so developing specific interventions to specifically prevent chronic graft-vs-host disease will be something we do in the near future as well.

Matt Fowler: Perfect. Thank you all for watching this Cancer Network® OncView program from MJH Life Sciences®. We hope you found this to be valuable to your clinical practice.

Transcript Edited for Clarity