Updates in the Management of Chronic GVHD: An Advanced Practice Perspective

Erin Kopp: 

Welcome to part two of our roundtable discussion on chronic graft-vs.-host disease. My name is Erin Kopp and I'm back with my colleagues Katie Sellers and Adrianne Maurer. Katie, can you tell us what we're going to discuss today and tell us a little bit about yourself and what patients you see? 

Katie Sellers: 

Sure. Thank you for the warm welcome. I'm Katie Sellers. I'm a physician assistant working with Texas Oncology in our Blood and Marrow Transplant Center in Dallas, Texas. I have been managing chronic graft-vs.-host disease patients for about the past 12 years, and in our previous video, we reviewed the clinical presentation of chronic graft-vs.-host disease. So, now we're going to dive into the management of these patients. So as with both acute and chronic graft-vs.-host disease, the frontline treatment is generally always steroids, corticosteroids. So, they are the mainstay of treatment in the acute setting, and we see that transition into the chronic setting as well. 

So, we often can incorporate topical and oral therapies, whether that's oral dexamethasone rinses for oral graft-vs.-host disease, topical triamcinolone for cutaneous manifestations. We can try adding topical corticosteroids, but also adding systemic steroids. So, generally the most common dosing is one milligram per kilogram per day, followed by a taper. Erin, is that what you all are starting with as far as dosing for corticosteroids? 

Erin Kopp: 

I'd say overall that would be the average. I know, like you, it's been a long time since I've been doing this. So, in the beginning I would see variations two mgs per kg per day. Some people would do one mg per kg per day every other day. So, I think we've kind of landed on this one milligram per kilogram per day for those patients who are showing with an acute or a new onset of chronic GVHD. I love how you talked about the topical, I always try to go topical first if we can. Even the budesonide that just sits there in the upper gut, for upper GI but doesn't have the systemic effect. I know you're going to talk a little bit about it. Systemic steroids have lots of pluses and then some of their challenges. 

 Katie Sellers: 

Absolutely. Well, we throw steroids at about everything. My patients don't necessarily love it, because my answer is usually steroids, and then when they come with me with a side effect, I say, "Oh, that's probably steroids." So, they have usually experienced steroids during their treatment courses for their initial disease. So, I think it's important as we look at the landscape of chronic graft-versus-host disease to look at the definitions of steroid response to graft-versus-host disease.  

So, we have steroid refractory chronic graft-versus-host disease. So, these are patients who do not adequately respond to corticosteroids or are intolerant to corticosteroids or have unacceptable toxicities. 

So, we can have progressive disease, chronic graft-versus-host disease. So that's despite a dose of prednisone or equivalent of one milligram per kilogram per day for one to two weeks. I can say often clinically, I'm practicing on the earlier end of that if they're not seeing much relief within a week or so, we're starting to look forward to the next agent. And I'm seeing some head nods from my colleagues. 

Stable disease is qualified when they have been on a dose of prednisone or equivalent of 0.5 milligrams per kilogram per day for four to eight weeks or four to six weeks, and their disease is the same, maybe not completely resolved. It's really unchanged, and so they haven't had much improvement ,or they haven't regressed. Steroid-dependent are these patients that you cannot paper below a 0.5 milligram per kilogram per day dosing. So, for an example, like a sclerotic feature or sclerotic manifestation of chronic graft-vs.-host disease, these patients need to be on super prolonged courses. These are the ones that you're tapering by 2.5 milligrams of prednisone and you cannot get them off steroids.  

Adrianne, do you see that sometimes you have the people that just love that one milligram? 

Adrianne Maurer: 

All the time. Yes, I can think of a handful of patients who are tapering by one milligram a month, if that, or one milligram every other month. Most often I see these prolonged tapers with sclerotic disease, with lung GVHD, or occasionally those with extensive oral features that impact how they're eating and drinking. And then sometimes with myofascial presentations. 

Katie Sellers: 

I completely agree. I definitely see it in more of the sclerotic cutaneous manifestations and then the myofascial. The steroids we are usually adding onto what they are taking as far as like a calcium urine inhibitor like our tacrolimus. So, we're maximizing those at the same time we have them on the steroid course. So, we're wanting to try to maximize their response rates because a lot of this ties back to their quality of life. And ultimately we don't want them on long-term steroids because we know of the side effect profile of steroids. 

So, we are often looking forward if they meet the criteria of steroid refractory or stable disease or steroid dependent or they're intolerant. We're looking at what's next. And I mean for the many years that all of us have been in the transplant world, there have been a slew of therapies available. That could be anything from photophoresis, PUVA therapy, mycophenolate mofetil, sirolimus, rituximab. 

I mean, you look at the treatment options that are out there and the list is expansive. So, I'm going to call out a couple of those because our time is limited, and we could spend all day on possible second therapies to add. But the first one I want to call out, I think it's probably one that we all jump to quickly, is an ECP or extracorporeal photopheresis. So, this is the reinfusion of UV irradiated autologous lymphocytes, which then decreases the number and function of circulating lymphocytes due to the inhibition of DNA. 

The treatments are generally twice a week, generally two days back-to-back, and they require central venous access with a more large bore, a tri-fusion catheter is what we use at our center. We see great overall response rates up to 65% in these patients that get ECP. And oftentimes they're able to taper off steroids a little more rapidly than other therapies. Sometimes there are limitations with the response to ECP because the more extensive their disease is, if they had a history of acute GVHD and then if they have cytopenia, thrombocytopenia in particular, these patients can be really hard to manage on ECP.  

Erin, do you jump to ECP at your center pretty quickly when you have a cGVHD that's been maximized on steroids? 

Erin Kopp: 

Definitely an option we love to do in combination with other things, but I have to give the caveat that we're at a major center and we have it on site. So, it's one thing I think with the three of us if you have access to it. So that's a discussion of whatever second-line therapy you want to do, does patient have access to that? And I'm thinking probably many of the individuals listening today may not have that. So, they don’t see it as often. 

Adrianne Maurer: 

Yes, it may not just be, does your center offer it? Is it feasible for the patient? Often with some of these larger centers, we have patients that come in from hours and hours away. Is it feasible for them to be here for several hours twice a week? Is that something that they want to do? Katie, you touched on their quality of life. Is this therapy going to impact their quality of life? 

Katie Sellers: 

Right. Great call-outs, ladies. I mean, I think proximity to the treatment center and then the patient's ability and their resources is huge. So, sirolimus is the next one I'd like to call out. I think all of us are pretty accustomed to utilizing it. So, this inhibits the target of rapamycin and suppresses the cytokine-mediated T-cell proliferation, which we know is a big mediator of chronic graft-vs.-host disease. We often are using this in combination with tacrolimus and steroids, and we can see response rates of up to 63%. Pretty well-tolerated. It's another one that you have to check trough levels on to make sure you're within a therapeutic dosing range. 

We can see side effects, notably renal insufficiency. You can see some cytopenias related to it if you're not careful. Definitely one that we incorporate. Notably when we see some hepatic GVHD, we are often incorporating some sirolimus. We can see some good response. Mycophenolate mofetil, a lot of patients may have experienced this drug in their prophylaxis phase. So MMF is an oral tablet that's taken two to three times a day depending on the dose, generally well-tolerated except it can cause some GI side effects. So, some patients already have an adverse feeling of CellCept because they were eager to get off at the beginning. Erin, I can tell that you have had the patients that want off CellCept. 

Erin Kopp: 

And it makes it confusing when I'm trying to differentiate what's going on. If they're on a medication like you mentioned, that causes side effects. How do you know if it's the GVHD or GVHD is progressing to another system if we're giving an agent? So yes, that is one that I keep an eye on knowing that it's going to have some GI issues. 

Katie Sellers: 

Sure. Well, we're fortunate that really since 2017, we've had so many advances in the development of therapies for chronic graft-vs.-host disease. That was a few years into my career, and we were throwing the kitchen sink at some of these patients, just adding on layers upon layers of therapy and trying to get control of their cGVHD. And so, I want to call out the newer agents that are available to us. And the nice thing about the three that I'm going to call out, they're all oral. So as ECP, we obviously discussed the limitation. These are all oral options that can be utilized in the management. 

The first one, and it's because it was the first one that was put on to the market as an FDA-indicated cGVHD in the steroid refractory setting is ibrutinib, which is a BTK inhibitor. We see it in the use of, or in the space of CLL and mantle cell. So, we're all pretty familiar with that with underlying disease, but it inhibits the B cells in the manifestation, but also had some T-cell inhibition. And we don't have a ton of experience at my center with it. We haven't used it a lot. We used it a lot initially, but as additional agents are being approved, we've kind of jumped on the bandwagon as more of those have been approved.  

Adrianne, have you ever seen fantastic responses from ibrutinib? Is that something that you still grab in the management of your patients? 

Adrianne Maurer: 

These days, we're using it more like third-, fourth-, fifth-line if they're progressing past some of these newer agents. And the reason I think most often we don't reach for it initially is because of that higher risk of AFib, especially in our older population. We have a lot of patients who are already in that risk category and having that transplant elevates their cardiovascular risk even further. So, we're a little hesitant to push the button on that. 

Katie Sellers: 

Totally understand, and we've seen it happen when we're using it in the other indications. So, something to definitely be on the lookout for. Great call-out.  

So next on the approval, so I think the next two were both approved in 2022 was belumosudil, which is a ROCK2 inhibitor, and it reduces the helper T cells and enhances the activity of the TReg cells. So belumosudil is dosed at 200 milligrams once a day. And it does require some dose modifications if they're using a strong CYP3A inducer or if they're on a PPI, they may need twice daily dosing. The response rates have been pretty remarkable at 76% with an overall response rate, which when we're talking about chronic graft-vs.-host disease and the slew of manifestations that could be really impactful for our patients. 

And then the next one is ruxolitinib, which was studied in the REACH3 trial. A lot of us may have been familiar with this on the first indication, which was for acute graft-vs.-host disease. So, I know our center was very familiar with its use in the acute setting, and it was easy to transition it and translate it into our chronic patients. So, this is a JAK1 and 2 inhibitor that interferes with the cytokine receptors and it helps to down-regulate inflammation and tissue damage that we see caused by chronic graft-vs.-host disease. 

Generally, it's a 10-milligram dose twice a day. You do need to often watch their cell counts closely as it can cause cytopenias, and so you can modify it for those if you do start seeing those happening. The overall response rate is 50% vs. best available therapy at like 25 to 26%. So just really impactful data that it's really hopeful for our patients.  

Adrianne and Erin, I know our time is limited, but I'm sure you all are reaching to our ruxolitinib and our belumosudil often as they have kind of become key stakeholders in the transplant. Erin, can you speak to what your experience has been? 

Erin Kopp: 

Definitely patients prefer an oral agent, which makes adherence a little bit easier. I think we had a lot of experience with both of these agents in the clinical trial setting and then also post-approval setting. So, it's really what our goal is. And I think it's one thing to look at is are we going to get a complete response? We're not getting a lot of that in our clinical trials, but it's goal setting in the beginning with the patients and really giving some key factors that we're looking at to see where we see improvement. And definitely utilizing these newer agents in a more focused, more like precision medicine like everything else. We're moving away from... I love how you said the kitchen sink. I like to compare it to, we threw everything at the dartboard, whatever we had and whatever landed is what we use. So, we are definitely using our newer agents more often. Adrianne? 

Adrianne Maurer: 

I have nothing to add. You said it perfectly. 

Erin Kopp: 

All right, well on that topic, and I wish we had hours to talk about this, but this does bring us to the end of this part of the discussion. So, Katie and Adrianne, thank you so much for taking your time to talk with me today. For more information and to view our other discussions on chronic GVHD, please visit JADPRO online at JADPRO.com.