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, 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'm Betty Hamilton. I'm one of the transplant physicians within our Blood & Marrow Transplant Program at the Cleveland Clinic. I'm Associate Professor of Medicine of the Lerner College of Medicine of Case Western.
Dr. Hannah Choe:
Hi, I'm Hannah Choe. I'm an Associate Professor at the Ohio State University Comprehensive Cancer Center in Columbus, Ohio. I'm the Director of the Ohio State University GVHD Program here.
Dr. Cutler:
Great.
So today we'll be discussing recent updates in the treatment of chronic GVHD and how we integrate these new developments through case-based learning. Our second installment will follow our patient previously treated with corticosteroids and ruxolitinib for steroid-refractory acute graft-vs-host disease.
So 7 months after the transplant, after being tapered off corticosteroids but while still on a small dose of ruxolitinib, 5 mg/d, the patient presents with new symptoms. Now this patient has generalized achiness but has full range of motion. They've developed a prominent dry mouth with oral sensitivity to spicy and acidic foods, and they've noticed that they have dry eyes and have started using rewetting drops two to three times per day. As experienced clinicians, we would recognize all of these symptoms as chronic graft-vs-host disease, although the severity of each of these is low. And so on our NIH chronic GVHD scoring system, this person would have an NIH score of 1 for the mouth, for the eyes, and for the myofascial system. Because there are three organs involved, overall, this patient would be diagnosed with NIH moderate chronic GVHD and therapy with prednisone at a dose of 0.5 mg/kg/d is started.
Eight weeks later, the eyes and the mouth appear to be improving, less sensitivity, a little more wetness in the mouth and in the eyes. They're not resolved, however. The muscle aches are unchanged at this time, but now the patient notes that he has some real tightening in his forearms and in his wrists without real functional limitation yet, but recognizing that this patient might be developing some sclerosis in a very typical location in the forearms. So this patient is now on steroids for 2 months and remains on a small dose of ruxolitinib.
So Hannah, how would you approach the management of this patient now, and what are your options?
Dr. Choe:
So now we have several different FDA-approved agents for chronic graft-vs-host disease. For next-line after steroid refractoriness is established, you have the option of using ibrutinib or ruxolitinib. We also have, though, for further-line options, belumosudil and axatilimab. And as we pointed out in the first case scenario, my go-to regardless of these would still be clinical trial.
So certainly we're actually in a great position right now for having more upfront clinical trials for chronic graft-vs-host disease or early options. This patient would be now at 8 weeks, proving that they are steroid-refractory chronic. But interestingly, as you pointed out, this patient is still on ruxolitinib. So it's a field that's still changing underneath our feet in terms of what to do about the ruxolitinib, do we add, do we stop, do we go to next-line therapy, do we consider this a ruxolitinib failure or not, and to that end, I'm interested to see what you and Betty think and what you would do individually because I think we would all do something slightly different, depending on the patient and, of course, considering what toxicities, or what their counts are, or what side effects we might think that they might be at higher risk for.
Personally in this case, I agree with doing a lower dose of steroids instead of the 1 mg/kg, starting at the 0.5 mg/kg, and I would certainly go up on the ruxolitinib dose first. Now, I would give it a relatively short leash though in terms of how long I would wait for to see response because we have a patient who is progressing relatively quickly in just a matter of months with concerning symptoms of further sclerotic symptoms, with the forearm, wrist tightening, et cetera, and we can expect, unfortunately, that they will develop those functional limitations. And so it does make me think that while I should certainly go up on the ruxolitinib because ruxolitinib had worked for them before in their acute graft-vs-host disease setting, there might be the possibility that it might not and we might need a more fibrotic or sclerotic-targeting agents or something that would target the sclerotic pathways a little bit more effectively. But again, every one of us would do something different. So what would you do in this case, Corey?
Dr. Cutler:
So I think the question at hand is whether you would've increased the ruxolitinib right away when starting the corticosteroids or actually even stopped it. I probably would have considered this to be a ruxolitinib-type failure, and I think at 8 weeks, I probably would move on, although as you mentioned, bumping the dose from 5 mg per day to 10 mg twice a day, either right at the onset of chronic GVHD or 6 to 8 weeks after starting steroids, both of those would've been viable options. I think the interesting point here is that this is someone with a B-cell malignancy, where ibrutinib is actually an FDA-approved therapeutic, and so it makes me think that here I might actually use ibrutinib as next-line therapy thinking perhaps that I'd get a little bit of GVHD control as well as a little bit of prevention of relapse, although that is certainly not proven.
Dr. Choe:
Would you do that in combination with the ruxolitinib or would you stop the ruxolitinib amount?
Dr. Cutler:
That's a great question. Betty, do you have any experience using ruxolitinib and ibrutinib in combination?
Dr. Hamilton:
I would say that in general, although I have used combination therapies, I have pretty limited experience with ibrutinib and ruxolitinib. I think both of you have made really excellent points. I think whether we consider this a rux failure is an important question. I also think that, thinking about sort of the biologic mechanisms and the fact that this patient has presented with fibrotic manifestations, it is important to consider more antifibrotic pathway or a drug that's targeting an antifibrotic pathway.
I actually do use, although I don't use a lot of combination of ibrutinib, I do use a fair amount of ibrutinib, and I do think that it's a very reasonable sort of next step. I do tend to overlap agents, even if the goal is not to necessarily use them in combination. The patient did have, at least once upon a time, have a response to ruxolitinib, so I sometimes don't want to necessarily trigger a flare while I'm starting a new agent by stopping the other agent. So fortunately, many of the agents that we're using now don't necessarily have overlapping toxicities or overlapping targets, and so we do, at least biologically or theoretically, do have some wiggle room, I think, to use combination therapies.
Dr. Cutler:
I completely agree. Go ahead, Hannah.
Dr. Choe:
How would you balance the history of the atrial fibrillation in this case? I mean, I guess you could have two different scenarios. So there's the history of atrial fibrillation, someone who underwent an ablation and was on amiodarone, vs someone who is actively having atrial fibrillation during their, say, maybe most recent hospitalization.
Dr. Hamilton:
I do think that, obviously, it's an important consideration and something to monitor closely, but I think if the patient has atrial fibrillation that is controlled, it wouldn't necessarily prevent me from using that drug. I actually think that the toxicity profile of ibrutinib and some of these drugs can actually be a little bit different in different disease indications. There's infectious risk, cardiac risk, it's obviously present, but I'm not sure that we see quite as much of it in our GVHD population compared to as a line of therapy in lymphoma.
Dr. Cutler:
I agree, and I think the one thing that we don't really understand, particularly for ibrutinib, is what the correct dose is in graft-vs-host disease and in the context of getting side effects or toxicities, whether dose reduction is really appropriate and enough to treat GVHD. So for diarrhea, I often stop the drug temporarily and then restart it at either 200 mg, a slightly lower dose, 140 mg or 280 mg rather than 420 mg, and titrate back up, sometimes not even getting to the FDA-approved dose. It's worth remembering that the trial that approved ibrutinib was designed as a dose de-escalation study, and we never did the dose de-escalation because in the first six patients, we didn't encounter DLTs. So that's not to say that 420 mg is the correct dose. We just don't think it's a too high of a dose.
Dr. Choe:
Now the study for ibrutinib though was done well before we had belumosudil and axatilimab though now, and we have a case here with a patient who has more sclerotic-fibrotic pathways. So would you weigh using ibrutinib here now, now that we have belumosudil and axatilimab, in a patient who has the sclerotic pathway, or does the B-cell malignancy history push you towards ibrutinib?
Dr. Cutler:
I think this is the one time where I really actually do reach for ibrutinib because of the B-cell malignancy history. You can make the argument that the patient has had steroids and some amount of ruxolitinib and, therefore, would be eligible for a third-line therapy. But again, I think this really comes down to dealer's choice and how each one of us individually would play this out, and there probably is not an absolute correct answer, as you point out, but keeping this patient within arm's length and not letting any particular round of therapy go too long before reassessment and being nimble in wanting to make a change, I think that's probably ultimately the right answer here, even though we can't actually all agree on exactly the correct therapeutic.
Final words about this case?
Dr. Choe:
I think I personally would probably move to using belumosudil, and speaking to combination therapies and nonoverlapping toxicities, we do have a growing sort of experiential database of using combination ruxolitinib and belumosudil at different doses as well. So at this point, I would feel personally very comfortable in weaning those patient steroids, moving to belumosudil, and monitoring for a response. But certainly I agree, very short lease, very short monitoring, follow-up to change as you need.
Dr. Corey Cutler:
Betty?
Dr. Hamilton:
I agree with Hannah. At this point, I would probably move to belumosudil just given more of the fibrotic manifestations. I also anecdotally have done belumosudil and ruxolitinib combination therapies together with minimal toxicities, and so I would certainly at the very least overlap them and then sort of assess, as you both have said, in a short time period so that we can determine how they are responding.
Dr. Cutler:
So I guess the key takeaways here are that we do need to remember to consider ibrutinib. It's a reasonable alternative in patients who are ruxolitinib-ineligible or have failed a trial of ruxolitinib, but we do have to exercise a little bit of caution when using these drugs in patients with a history of cardiac arrhythmias. We think about combination therapy and then we think about moving towards pathway-driven therapeutics, such as those that directly target the sclerotic pathways in patients like this.
So this brings us to the end of this case. I'd ask the listening audience to please see the other segments for further discussion about the treatment of chronic GVHD or visit ascopost.com.
