Treating Chronic Graft-Versus-Host Disease

Brian Watkins, MD, Tulane University & Manning Family Children’s, New Orleans, Louisiana , discusses the treatment course of an 18-year-old patient with chronic graft-versus-host disease (GVHD) after receipt of an allogeneic stem cell transplant for relapsed acute myeloid leukemia (AML).

Transcript:

Hello, 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 and Cell and Gene Therapy at Manning Family Children's in New Orleans.

This patient has had a mixed response to his initial treatment. His mouth and eye chronic GVHD has resolved and his skin chronic GVHD has improved. However, despite that improvement in some of the organs, he's had worsening of his liver GVHD. His liver GVHD is now a score of 3, putting it into the severe category. The changes in the skin coloration also make me somewhat concerned that the skin is possibly evolving and becoming more lichenoid, less inflammatory in appearance and more chronic inflammatory.

And so considering he has worsening of his liver, GVHD, I would recommend adding additional therapy. I believe early treatment is really paramount in changing the trajectory of chronic GVHD and waiting too long may allow continued damage and later fibrosis.

Steroids have been the mainstay of the first-line therapy for chronic GVHD. However, they're associated with a lot of toxicity. One of the main goals of therapy is really to reduce that steroid exposure. Typically, steroids are started at a half to 1 mg/kg per day. Increasing the dose of steroids over that 1 mg/kg doesn't tend to be beneficial in chronic GVHD, but can add significantly to the toxicity.

Second-line therapy is indicated with any worsening of chronic GVHD or lack of improvement or steroid dependence, but 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.

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 in the 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 GVHD, 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 evolved 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.

Belamosudil is also a drug that have used for second- and sometimes third-line therapy. This is a ROCK2 inhibitor. Where I typically use that drug is it seems to be most effective in the treatment of lung GVHD, 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 is a little bit unique in that 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 colony stimulating factor that monocytes and macrophages utilize.

So one of the latter phases of chronic GVHD 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 GVHD 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 inflammatory, but I think where the most promise for me is more in the fibrotic forms of chronic GVHD.

So in this patient specifically, I worry about his skin. It has changed from this color of being more red maculopapular, very inflammatory, to kind of this darker coloration. When I see that happening, sometimes over time, what we notice is the skin will start to thicken, we'll develop more sclerotic forms of skin, GVHD. And that's where things like axatilimab can be beneficial in the third-line treatment.

Also, this patient doesn't have lung GVHD. I've had several patients who have started similar to this patient and upfront did not have any lung and involvement, but over time we see a drop in the FEV1 and some of the symptoms of chronic lung GVHD. It's important to get PFDs very frequently and ask a lot about the symptoms of lung GVHD and to start treatment as early as possible. Once you see that there's some signs there because it can be associated with really a lot of morbidity and mortality.

So thank you for listening to this. I hope this helps when you consider treating patients with chronic GVHD. And I appreciate you listening, so thank you.