Dr. Corey Cutler:
Welcome to The ASCO Post Roundtable Series on Treatment Sequencing Considerations for Chronic Graft-vs-Host Disease. I'm Dr. Corey Cutler. I'm the Director of the Stem Cell Transplant Program at the Dana-Farber Cancer Institute in Boston. And joining me today are two of my colleagues who I'll ask to introduce themselves.
Dr. Betty Hamilton:
Hi, I am Dr. Hamilton. I'm a transplant physician within the Blood and Marrow Transplant Program at the Cleveland Clinic. I'm Associate Professor of Medicine of the Lerner College of Medicine of Case Western University.
Dr. Hannah Choe:
Hi, I am Hannah Choe. I'm an Associate Professor at the Ohio State University Comprehensive Cancer Center in Columbus, Ohio, the Director of the OSU GVHD program, and I'm happy to be here.
Dr. Cutler:
Great. So today we're going to be discussing recent updates in the treatment of chronic graft-vs-host disease using a case-based learning scenario to determine how we integrate these new developments into clinical care.
Our third and final segment now, we're going to discuss our patient with steroid-refractory chronic graft-vs-host disease, who's now had 10 weeks of second-line therapy, and who is now developing worrisome signs of sclerosis with fibrotic bands on the upper inner arms, with muscle cramps, which are worse at night, which I believe are a version of neurologic GVHD, small-fiber neuropathy. And he's developing shiny, hairless lower legs with an ulcer on the anterior shins. So really developing signs of sclerosis at this time.
So assuming we have not yet used a fibrosis-directed drug, what would you choose now, Betty, for the management of this fibrotic type chronic graft-vs-host disease?
Dr. Hamilton:
These are always really challenging cases where a patient may have already been treated with steroids, are already on a second-line agent, and I will just briefly say that I agree with Hannah in the previous segments is that, if there's a clinical trial available, that's always something that we would try to enroll this patient on first. Because there's continuing to try to find newer drugs that can help patients like this.
With what now sounds like deeper sclerotic and fibrotic manifestations, I think we have actually a couple options now. I think the two to three main ones that we talk about of course are ruxolitinib, belumosudil, and now axatilimab, which was recently FDA approved this past August.
I think that from a logistical standpoint, and if we're taking the case from previous, if this patient has already been on ruxolitinib before, I would likely recommend belumosudil as the next agent. Part of this is because although axatilimab is FDA approved, we don't quite have access to it quite yet, unless there are centers with expanded access trials. But we hope to have access to this in the next couple of months. But there are some other agents with similar pathways that are under investigation in clinical trials that again may be options for this patient.
Dr. Cutler:
So mechanistically, Hannah, do you think we can differentiate the way axatilimab, which targets the monocyte macrophage pathway through CSF1R, or belumosudil, which targets fibrosis and sclerosis through inhibition of ROCK2 and the myofibroblast, do you think we can tell which is preferable in a given clinical scenario? And just to add to what Betty said, would you also choose belumosudil based on ease of access and administration now?
Dr. Choe:
We have more detailed information towards the endpoints for sclerotic manifestation, specifically for axatilimab, than we do for belumosudil at this time. So it does make me more comfortable if I have axatilimab in hand to be able to prescribe it to patients for this particular case, especially.
Now as Betty mentioned, the reality of actually getting it to the patient is a little bit more difficult. And we do have to keep in mind that axatilimab is an IV formulation every 2 weeks, vs belumosudil, which is an oral formulation, a pill either daily or twice daily, which can be very attractive to a patient who then doesn't have to drive or commute back and forth, and doesn't interfere with their quality of life as much in terms of coming in to and from appointments.
Now that in mind, I would go to belumosudil because of ease of access, insurance approvals, et cetera, in combination with ruxolitinib in this patient, making sure that I'm limiting steroids as possible, and using either progression of disease or inability to wean steroids further to consider then moving to axatilimab relatively quickly. But what would you do, Corey?
Dr. Cutler:
Well, I agree. I typically, with both drugs in hand, I would almost always use belumosudil first, just from a patient point of view, ease of access and quality of life. These are people who are now a year from transplant perhaps trying to get back to life, to work, to their normal routine. And so I think in this scenario, belumosudil is almost always going to be an easier choice, unless the patient has issues with compliance. In which case, bringing them to the clinic every other week might be a better choice for that patient. So for us, belumosudil would be the obvious choice.
But I want to throw a curveball into the case, and tell you that the patient just continues to get a little bit worse. They develop real steroid myopathy, because they are still on steroids, and they're getting short of breath. And that shortness of breath is not related to an impairment in chest excursion because of deep sclerosis involving the torso, and it's always important to look for that.
And they develop pulmonary function tests that are really suggestive of bronchiolitis obliterans, with a marked drop in the FEV-1, a reduction below 70% in the FEV-1 to FVC ratio, and a reduction in the small airway flow now down to 48% predicted. And so now I think we're really into the realm of bronchiolitis obliterans and trying to understand which drug we should be using there, understanding that there is evidence for both belumosudil and perhaps axatilimab, although we haven't seen it all yet about responses in lung disease.
So Betty, what else do you do? This is someone who is going to be in trouble soon, so I'd love to hear how you approach the patient with bronchiolitis obliterans.
Dr. Hamilton:
Yeah, these are always very challenging cases, particularly when chronic graft-vs-host disease affects the lungs because there's limited data on very effective treatments for this.
I think it is important to note treatment/adjunctive therapy. We use a lot of FAM, which is fluticasone, a steroid inhaler, azithromycin, and montelukast, and that based on prior phase II studies has been shown to prevent progression of a bronchiolitis obliterans. So that is always something that we add once a patient is suspected to have chronic graft-vs-host disease of the lungs.
In regards to the best agent for lung graft-vs-host disease, I think as you suggested, I think that we still need more data. I think that the mechanisms of belumosudil and axatilimab are quite promising for lung graft-vs-host disease, and there's ongoing studies looking at these agents in specifically focused on bronchiolitis obliterans, particularly for belumosudil.
But I think that we're still waiting for the data to see which agent might have the most effect in preventing and potentially even improving lung function. For me, it's a little bit of a dealer's choice with the same logistical quality of life considerations, in terms of what I choose in terms of bel and axa. I think it all goes back to following these patients closely, doing very frequent pulmonary function testing to follow the FEV-1, and being able to pivot to another agent, particularly if the bronchiolitis obliterans is progressing.
And I work very closely also with our pulmonary colleagues to also collaborate with any supportive type of care that might be needed as well in these patients. These patients also are at high risk for concurrent infections and things like that, which can mimic GVHD flares as well.
Dr. Cutler:
You brought up a very good point about routinely following pulmonary function tests. Hannah, how often do you do PFTs in the first year following transplant?
Dr. Choe:
In the first year without any concern for BOS at that time, it's every 6 months. And sometimes, up to 1 year depending on if things happen and things get pushed back. But we try to do it every 6 months.
But once a patient has BOS, or concern for BOS, we shorten it to every 3 months. And also on top of the PFTs, I add CT imaging as well, because we might sometimes find those bronchiolitic obliterans syndrome imaging changes before we see that the PFTs will drop, and we can also use that to help differentiate vs other pulmonary diseases or infectious complications that might be clouding picture, as Betty mentioned.
But I think this also in terms of treatment for bronchiolitis obliterans, as soon as that enters the picture, talking about how we have to be nimble before bronchiolitis obliterans with the data we have published from Zach DeFilipp shows that we really need to be acting quickly. Because if we're going to start belumosudil, and we are expecting to see any improvement, then it has to be early on. We can't wait for more of a significant drop in the FEV-1 before starting therapy because any hope of trying to get a response at that point is severely limited. And even the improvement that you do get with starting it earlier is still somewhat less than ideal. So now that we have a line of therapy even beyond belumosudil, I think we'll even learn to be moving more quickly to next line vs next line vs next line.
Dr. Cutler:
Perfect. So I agree with that. So again, just to reiterate some of the key takeaways here, in the third-line setting, we definitely require antifibrotic drugs. We know that chronic GVHD progresses to sclerosis in most cases, and therefore choosing a compound with a mechanism of action that directly addresses fibrosis is critical. Although, ruxolitinib has been tested in sclerotic GVHD with some success, for pulmonary involvement, I think belumosudil might be the preferred agent based on the demonstrated reversal in FEV-1. But we will learn more when we see the FEV-1 data responses with axatilimab, as well. But again, being nimble in the third line and assessing your patient very closely is absolutely required.
So this brings us to the end of this case. I ask the listening audience to see the other segments for further discussion about the treatment of chronic graft-vs-host disease, or to please visit ascopost.com.
