Treatment Strategies for Chronic Graft-Versus-Host Disease in Later Settings

My name is Ben Watkins. I'm the Division Chief of Pediatric Hematology and Oncology at Tulane University, and I'm the Director of Stem Cell Transplant Cell and Gene Therapy at Manning Family Children's in New Orleans. I believe early treatment is really paramount in changing the trajectory of chronic graft-versus-host disease and waiting too long may allow continued damage and later, fibrosis. So, steroids have been the mainstay of the first-line therapy for chronic GVHD; however, they're associated with a lot of toxicity. So, one of the main goals of therapy is really to reduce that steroid exposure. So typically, steroids are started at a half to one-mg per kg per day. Increasing the dose of steroids over that one-mg per kg doesn't tend to be beneficial in chronic GVHD, but can add significantly to the toxicity. So, second-line therapy is indicated with any worsening of chronic GVHD or lack of improvement or steroid dependence.& 3006 amp 3006 ;nbsp; 

There's no universally accepted second-line therapy for chronic GVHD and there tends to be a lot of provider variability. And so, decisions on second-line therapy should take into account a variety of factors: That includes organ involvement, toxicity, age of the patient, frequency and ease of administration, costs, compliance, things like that. And so, the standard that I use for second-line therapy in the vast majority of patients is ruxolitinib. And I think a lot of providers are using this much more frequently as second-line therapy in the situation of needing to advance treatment. And so, ruxolitinib is a JAK1/2 inhibitor that is used in the treatment of both acute and chronic GVHD. Ruxolitinib appears to be most effective in the treatment of skin, mouth, GI, and liver chronic GVHD. It does have some toxicities though, as all of these drugs do. The toxicity I most frequently see with ruxolitinib is cytopenias.  

This tends to occur most commonly when used kind of early and early post-transplant period, more for acute, or if you use it for an extended period of time. The cytopenias can result in holding or reducing doses and in some cases, discontinuation. As with any additional immunosuppression, infections can also occur with prolonged exposure. I tend to get pretty good responses with ruxolitinib and sometimes as early as within a couple of weeks. And, in my experience, in patients particularly with liver and skin graft-versus-host disease, I'd expect some response within those first few weeks. And once I get response, I'm going to be more apt to wean off the steroids a little bit more quickly to avoid some of those complications. Some of the other second-line therapies we sometimes use include ibrutinib, which was the first therapy that was FDA-approved for chronic GVHD. Ibrutinib is an inhibitor of Bruton's tyrosine kinase, which is involved in both T- and B-cell activity.  

And so while ibrutinib has shown some responses primarily in the inflammatory forms of chronic GVHD, real-world experience doesn't seem to be as promising, in my opinion. And I think it's been also associated with significant side effects like fatigue, muscle cramps, diarrhea, and others. I do still occasionally use it in my practice, but typically more as fourth- or fifth-line therapy. And I think that's changed over the last couple of years. Belumosudil is also a drug that have used for second- and sometimes third-line therapy. This is a ROCK2 inhibitor. It is where I typically use that drug is it seems to be most effective in the treatment of lung graft-versus-host disease, which can be really problematic and lead to really significant morbidity and mortality. And then the latest drug on the market that's really just come on in the last year or so is axatilimab.  

Axatilimab a little bit unique in that it targets different…it has a different target. So, ruxolitinib is JAK STAT, mainly involved in T-cell inhibition as well as involved in T-cell trafficking. Ibrutinib works on B and T cells; however, the way the axatilimab works is it blocks the receptor for a colony-stimulating factor that monocytes and macrophages utilize. So, one of the latter phases of chronic graft-versus-host disease is really hallmarked by monocyte-macrophage activation, which leads to a lot of fibrosis and sclerotic features of chronic GVHD. This tends to be the hardest type of graft-versus-host disease to treat. It's really difficult to get responses once you develop this type of GVHD. However, axatilimab works by specifically targeting that monocyte and macrophage activation. So, in clinical trials it's shown promise in both the inflammatory, but I think where the most promise for me is, more in the fibrotic forms of chronic GDHD. So, thank you for listening to this. I hope this helps when you consider treating patients with chronic graft-versus-host disease. And I appreciate you listening.