Graft-versus-Host Disease: Advances and New Therapies on the Horizon

[00:01] Moderator: Thank you so much for joining our session. 

My name is Penina Seidman, and I will be your moderator today. 

This workshop is Graft-versus-Host Disease, Advances and New Therapies on the Horizon. 

Before we begin, I'd like to thank Insight, the William G. Pomeroy Foundation, and Mesoblast, whose support helped make this workshop possible. 

It is now my great pleasure to introduce Dr. Corey Cutler. 

Dr. Cutler is the Director of Stem Cell Transplantation Program at Dana-Farber Cancer Institute and a Professor of Medicine at Harvard Medical School. His research focuses on the prevention and treatment of acute and chronic graft-versus-host disease. 

He also studies the role and timing of transplantation for myelodysplastic syndromes and is the immediate past president of the American Society for Transplantation and Cellular Therapy. 

Please join me in welcoming Dr. Cutler. 

[00:51] Dr. Cutler: Thanks very much for that nice introduction. And hi to everyone. 

I know many of you have been on these webinars for the past two days, and you have seen a number of presentations on graft-versus-host disease. 

That being said, I'm going to review some of the newer updates in GVHD prevention and therapy. I think perhaps you might have heard some of these issues or some of these topics discussed by my colleague, Dr. Holtan, a couple of days ago, but hopefully there won't be too much overlap here. 

[01:29] So, here are the objectives. We're going to try to understand the current landscape of GVHD prevention and then therapy in both acute and chronic graft-versus-host disease. 

For those of you who are new to this space, graft-versus-host disease is the clinical syndrome that we see after an allogeneic transplant when a donor's immune system attacks the tissues that it finds foreign within the recipient or the patient who is receiving the transplant. 

While all organs and tissues are theoretically at risk of being the targets of graft-versus-host disease, we really see the manifestations of GVHD occurring in a number of very important target organs. And there are specific lectures in this series about the management of GVHD in those target organs, for example, the eyes or the skin. 

[02:38] What everyone needs to understand is that GVHD is really one of the most important causes of impaired quality of life after transplantation. So, we as transplanters do everything we can to try to minimize the incidence and then minimize the severity of GVHD if it occurs. 

[03:01] Prevention is critical here, an ounce of prevention versus a pound of cure, that old saying, and what has entirely revolutionized our space in the last 10 years or so is the use of a regimen called PTCy, or post-transplant cyclophosphamide, to prevent graft-versus-host disease. 

Now, when we do a transplant, we throw in a number of immune cells from the donor. We can't really control what those immune cells do, but some of them are destined to become GVHD-causing cells, and some of them are not. 

When we do a transplant now using this PTCy regimen, what we do is we allow those immune cells to grow unimpeded for the first 72 hours after the transplant, knowing that the ones that are destined to cause GVHD are going to expand, whereas the ones that are not involved in GVHD are going to be quiescent. 

After three days, we give chemotherapy, a drug called cyclophosphamide, which preferentially kills those activated and expanding T cells. 

[04:27] But what it also does is it spares the cells that are resting. Presumably, these are cells that are going to be important for infection fighting, in particular infections that are not currently ongoing in you, the recipient. So, this is a nice way for us to prevent graft-versus-host disease, and it is really the method that we use in about 80% of all transplants at this time. 

The reason why we use it so widely is seen in this slide. This is a pivotal trial that we did as a community that demonstrated that the use of this PTCy regimen, the line shown in black, is substantially better than our older regimen, we're calling tacrolimus and methotrexate. 

You can see that by using the PTCy-based regimen, we can get more than 50% of our patients alive and well and without their disease relapsing and without them getting any amount of graft-versus-host disease. So, it's a substantial advantage to the old standard. 

[05:44] Now, there is certainly room for improvement. PTCy is associated with a couple of important downsides. It takes a little bit longer for our stem cells to make graft, so a longer time at risk of bleeding and infectious complications, and we see that here, so there's more bacterial and viral infections. 

[06:07] Because it is chemotherapy, it does have the potential to cause organ toxicity, in particular, to the heart and to the urinary bladder. It also is associated with slightly impaired graft function over time. So, there's lots of room for us to improve on this. And we have a couple of different strategies that we're actually examining. So, we can either modify and try to improve our old platforms, or we can sort of fine-tune the PTCy platform and even investigate entirely novel platforms. And I'll talk briefly about these three approaches. 

[06:48] Some people have felt that the dose of Cy, the cyclophosphamide that we give, is just a little too high. It causes too many side effects, too much delay in graft. So, the group at the NIH have been testing lower doses of the chemotherapeutic agents. What they are showing in this graph is this happy middle ground, the happy face really in the middle, whereby if you give a half strength of the post-transplant cyclophosphamide, the vast majority of patients get no graft-versus-host disease, and the small subset get only very minor graft-versus-host disease, what we call grade I. 

[07:33] If one gives the highest dose on the left, the black circles, most of the patients get no graft-versus-host disease. If we go too low, we start to see more patients getting higher grades of graft-versus-host disease, as demonstrated by the triangles on the right side. 

We have this middle ground that we have come to think might be the right dose, although there is no such thing as a free lunch. So, we are concerned that if we lower this slightly, we are going to end up seeing a little more graft-versus-host disease in the long term. These are very small numbers here. 

[08:15] If we're going to see more late graft-versus-host disease, what else can we do? Well, we can add additional agents, and so, this is the schema of a trial from my colleagues at the University of Wisconsin, where they are adding a drug called ruxolitinib, shown on the right-hand side of that timeline, to patients who are undergoing transplant using lower-dose cyclophosphamide. 

We know that ruxolitinib is an active drug to treat graft-versus-host disease, so it makes sense to move it into the preventative phase of transplantation. 

What we see in the table on the bottom right-hand side is, in a trial of roughly 50 subjects, the rate of graft-versus-host disease was extraordinarily low. Only one subject out of the 46 involved in this report ended up with chronic graft-versus-host disease. 

[09:23] Now, I'm going to admit, if our rates of graft-versus-host disease fall to 2%, I'm going to be out of a job pretty quick because I do work on GVHD prevention therapy. So, this would be a very welcome early retirement for me. I won't lie. 

There are other platforms that we are using to test novel additions to post-transplant cyclophosphamide. 

There are two here. One of them is ruxolitinib, shown on the right-hand side. And the second is a drug called abatacept, which is also FDA approved in prevention of chronic GVHD. 

[10:11] This is the large ruxolitinib trial that we as a national community are about to embark on. This is going to be a very large study, probably about 300 patients or so that are going to be randomized into one of two groups. 

The first one being a standard platform with ruxolitinib, and the second one, a standard post-transplant cyclophosphamide. And participation in clinical trials like this is critical. We can't advance the field unless you, the patients, agree to participate in our studies, and we, of course, make sure that all of these trials are done with the highest regard to patient safety and the ethics of doing experiments on willing human participants. 

[11:07] Something that's coming down the pike is a brand new platform that's being developed in California. This is a company that is effectively a spin out from our colleagues at Stanford University. And they have developed a way of taking the stem cell graft and dividing it into its component parts and administering what they feel are optimized doses of those component parts on different days of the transplant. 

On one day, we administer the actual stem cells along with a regulatory T-cell group, and regulatory T-cells are the brakes of the immune system. 

And then two days later, we administer the standard T-cells. These are the infection-fighting cells that are important for us to prevent life-threatening infections after transplant. 

[12:05] This has been tested in very large clinical trials, and you could see one here. This is about a 200-person study where this novel platform, which we call Orca-T, was tested against a standard platform. and the results were very convincing, shown here, with a very marked improvement in the outcomes in the subjects who received the Orca-T transplant in comparison to the standard. 

Now, I've just told you that the standard is now post-transplant cyclophosphamide, or PTCy, They didn't use that as the standard, so it's not clear to us yet where this therapy will be used when it gets put out into the community after it is FDA approved. 

[13:07] There are other platforms that are out there. There are a couple of others that we're now testing that are also manipulating the stem cell graft. And the specifics don't really matter, but we have fancy names for them. Everybody has their preferred set of cells that they think are the culprits in terms of causing graft-versus-host disease. And so, there are a couple of homegrown approaches to try to prevent graft-versus-host disease. 

Alpha-beta T-cell depletion is very commonly used among our pediatric colleagues, and naive T-cell depletion is being tested formally by our colleagues at the Fred Hutch in Seattle. 

[13:58] So that's what's on the horizon for graft-versus-host disease prevention. Very exciting because it's really reducing rates of graft-versus-host disease down into about the 20% range or so, and it is making the management of graft-versus-host disease that much easier. So now we'll move into the management of acute graft-versus-host disease. 

[14:30] We have only one drug that is FDA approved for the management of acute graft-versus-host disease. And that's a drug called ruxolitinib. It is, in fact, better than the standard that we have, which is just steroids and other immunosuppressants. However, it's not perfect. 

[14:55] Because it isn't perfect, it tells us that we really need to be finding agents that are better than ruxolitinib or to give to the patients who are not expected to respond to ruxolitinib. So, we now focus a little bit on the GI tract. 

Why the GI tract? Well, in acute graft-versus-host disease, there are only three organs that are involved. the skin, the liver, and the GI tract. It's the GI tract that is associated with the most severe complications. It's in fact, the organ that is most closely linked with morbidity and in fact, mortality from transplantation associated with GVHD. 

We have a number of different ways of thinking about how we can help the GI tract out, and some of them are shown here, and I'm going to go over a few of them in greater detail. 

[15:57] The first are a class of drugs that you think you might be familiar with. So, we're going to talk about the GLP-2 drugs. If you've been anywhere on this planet, you probably know about the GLP-1 drugs, which account for about 50% of These are the weight loss drug, and those weight loss drugs block a protein called GLP-1. 

But we have another protein called GLP-2 that is associated with growth and health of the intestinal tract. And we give GLP-2 drugs, in particular, to kids who have short gut syndrome and who can't absorb their nutrients. It causes the intestinal tracts to grow and flourish, and they are actually quite helpful. 

[16:55] We've started testing a group of compounds here that help the intestinal tract recover. It stimulates the intestinal stem cells to grow. 

I'm going to show you the results of one of these clinical trials here. So, this is a study of a drug called apraglutide that was tested in patients with resistant graft-versus-host disease. We now give our trials all fancy games. This was what we call Stargaze trial. I don't know where they got that name from, but that's what we're calling it. 

[17:32] The Stargaze trial was designed to see if we could give this GLP-2 analog in combination with the standard drug, called ruxolitinib for patients with advanced GVHD of the GI tract, so we looked at ruxolitinib in three different doses of this apraglutide compound. 

What we can see here is that there was a really nice response rate, which we measure as how often patients get better. You can see that roughly half the patients actually improved in response to receiving these two compounds. 

[18:19] Some of the patients improved completely, what we call a complete response, CR in the dark blue. And the other proportion of patients had improvement but not complete improvement, so partial responses. 

What's important here is that the responders appeared to maintain their response over time. Very important that the responses were not lost early after initiating this compound. 

[18:50] This led to a very nice improvement in overall survival. About 60% of patients being alive and well at about a year. I know 60% doesn't sound like a lot, but steroid-resistant GVHD used to really be a very bad outcome, so 60% is really quite an advance. 

[19:15] Now, I'm quite sure that Dr. Holtan talked to you about this compound, human chorionic gonadotropin, or HCG. Now, you've probably heard of HCG. It's a pregnancy drug. It's a drug that's used to help women go into cycle for artificial insemination. And it is, in fact, the chemical that we measure in pregnancy tests. When you get one of those sticks from the pharmacy, you're actually measuring the level of HCG in the urine. 

Now, the commercial preparation of HCG actually contains a whole bunch of other growth factors. And an important one is epidermal growth factor, or EGF. 

[20:08] Now, EGF, epidermal, stands for the layer of tissue that is found in the lining of the gut and on our skin. And Dr. Holtan and colleagues did a number of studies looking at the addition of this compound to GVHD therapy in both the first line and second line. As you can see by the bars in orange, really were able to show that a good number of patients actually responded to this compound over time, so it's a very promising approach to the treatment of acute graft-versus-host disease. And for those of you interested, the reference is shown here on the right-hand side. 

[21:00] Another approach that we're taking to the management of acute GVHD is something called mesenchymal stem cells. You might have heard about MSCs through some of the sort of rejuvenation talks that people talk about, that these are cells that are sort of the fountain of youth, if you will. These are cells that help regulate our immune system, and when you give them intravenously, they sort of float around the blood and find their way to sites of injury, tissue injury, and aid in tissue repair, so people are looking at these cells to help with spinal cord injury or degenerative arthritis, etc. 

But we're using them to treat patients with graft-versus-host disease, and they are, in fact, currently approved for the management of GVHD, but only for pediatric recipients. So, we are trying to do clinical trials to see if we can make these cells available to adults. 

[22:13] This is the schema for a very complicated trial that we're doing through our National Bone Marrow Transplant Clinical Trials Group, something called the Blood and Marrow Clinical Trials Network, or BMT CTN. 

This is a trial that has had a long gestation. The trial was initiated in 2023 in terms of its design, and it isn't open quite yet, so hopefully in a couple of years, we'll have a little more data as to whether these cells are in fact useful. 

[22:49] The next big thing that everyone is talking about, the new buzzword, is the microbiome. The microbiome is the set of organisms that live full-time in our intestinal tract, so we all have this symbiotic relationship with the bacteria that live within us. 

We actually need those bacteria. They are very important regulators of our immune system. What's important to know about our microbiome is that the more diverse it is, the better. When individual bacteria strains or subtypes outgrow or outcompete their neighbors, that's actually associated with less GI health. 

[23:44] In graft-versus-host disease, we actually can demonstrate that patients have low microbial diversity. 

How do you replace or improve that diversity? Well, you give them a transplant directly into their gut of a healthy microbiome. And yes, the transplant has to come in the form of bacteria that are isolated from stool. 

[24:13] So we call this process a fecal microbiome transplant, or FMT, which we'll use. FMT has actually been tested formally. 

For those of you that are curious, how do you do this? Well, there's two ways, two entry points, if you will. the microbiome can either be given through an enema, or actually you could sort of prepare this into capsules or freeze-dried and can be swallowed. And it's not as bad as it sounds. 

In these trials, we were actually able to show that almost two-thirds of subjects who had severe intestinal GVHD actually responded with about half of them having complete responses. This is really quite promising. It really is sort of a natural way of treating graft-versus-host disease by restoring the normal homeostasis within our GI tract. 

That's the last I'll speak of in terms of novel ways that we are trying to treat acute graft-versus-host disease. 

[25:32] Now I'm going to flip to the later time points, chronic graft-versus-host disease, and this is, in fact, where I've done most of my work. 

At the moment, we have four FDA-approved compounds to treat advanced graft-versus-host disease, and you might have heard some of these names. 

Ibrutinib or Imbruvica was the first drug approved in 2017. This is a drug that predominantly works on the B-cell pathway, and B-cells are in fact important for graft-versus-host disease. 

[26:12] The next drug that was approved is a drug called belumosudil, which uses the trade name Rezurock. This is a unique compound that selectively inhibits an enzyme called ROCK2. ROCK2 is very important both for fibrosis and for inflammation in the immune system. This was the second drug that was FDA approved. 

[26:40] Very shortly thereafter, a drug called ruxolitinib was approved in chronic graft-versus-host disease. Now, we've talked about it in acute GVHD already, and it is FDA approved there as well. And it was, in fact, approved in acute GVHD long before it was approved in chronic graft-versus-host disease. 

[27:03] The most recent entry into this space is a drug called axatilimab, which works entirely differently than the other compounds. And it, in fact, interacts with a cell type called our monocytes and our macrophages. We believe it has a distinct role, be it fibrosis in graft-versus-host disease. 

[27:28] What's on the horizon in chronic disease? Well, now that we have these four drugs that work on four very different pathways, we are generating second and third generation compounds that hit those pathways that are a little more effective and potentially have fewer side effects. 

We are moving some of these compounds that are only intravenous to orally available compounds. For patients who are far out from their transplant, the concept of going back and forth to the clinic to receive intravenous therapy is really a little less palatable. So now we have the option of using pills rather than this. 

[28:17] We're exploring ways that these drugs can be given together in combination. Because they all work on different pathways, it's not clear whether these drugs are going to be additive or synergistic in a 1 plus 1 equals 3 format. And we'll learn about that. 

[28:39] Then the last thing we're really doing is trying to understand what is the right drug for the patient sitting in front of you. What are the biologic pathways going on in that patient that make drug A, B, or C the preferred choice? 

[29:03] Now that we have all these compounds that are approved in later stage patients, how do we get those drugs to the front line, using them earlier in the patient's disease course so that they can be more effective? I'm going to show you now a few of the examples of those trials where we're moving them to the front line now the front line is traditionally the role of the steroid. Our strategies, both taking these active compounds, moving them up front, will allow us to get rid of corticosteroids as the mainstay of therapy in chronic graft-versus host disease. 

[29:47] So this is the largest national trial that's currently ongoing. 

It is what we call a phase three trial, which means it is practice-changing. We are randomly assigning patients to receive the standard of care, which is steroids, with or without a new compound called axatilimab, that fourth drug that is currently approved in steroid-refractory chronic GVHD. 

Here, patients are actually required to come to the clinic every two weeks and get an intravenous placebo or an intravenous drug. We have to blind this, and we're going to determine whether the addition of the novel compound axatilimab is additive in the frontline setting. 

[30:46] We're also testing in the frontline setting combinations of drugs. 

Here's a trial where we are testing two compounds, axatilimab and ruxolitinib, in combination with each other against ruxolitinib alone or against the standard steroids in what we call a randomized phase 2 trial.  

This is not practice-changing. The results of a trial like this with a sample size of about 40 patients per arm, this will be strongly suggested. This will lead to whether we should be doing further studies with any of these combinations. 

[31:33] Then finally, we're testing a strategy where we avoid steroids entirely. This is a trial that I'm calling pre-frontline therapy. 

So very often patients will arrive in clinic and they will have early manifestations of chronic GVHD, perhaps a little bit of oral involvement, a little bit of eye involvement. They do not need pill form therapy for their GVHD, so things like steroids. 

The goal of a trial like this is to test a very safe compound called belumosudil and see if it can prevent patients from requiring steroids at all at some point in their future. We're sort of calling this pre-frontline therapy or preemptive systemic therapy for their chronic graft-versus-host disease. 

[32:33] So I'm going to wrap up. 

What I think I've tried to impress upon is that we've really had quite tremendous advances in the prevention of GVHD, both acute and chronic. 

We have new options for the management of advanced acute and chronic graft-versus-host disease. And I think we're learning now how to do upfront or first-line therapy for acute and chronic GVHD better. both to improve response rates and to avoid some of the chronic long-term complications of having had advanced chronic graft-versus-host disease. 

Then finally, steroids-sparing strategies are critical. No one likes steroids, neither the patients nor the doctors that have to deal with it.  

So, with that, I think I'm going to stop. and I would be happy to take questions. I see there's a number of them that have come into the chat. And so, I think we will push this back to Penina to help us out with the prioritization. 

[33:53] Moderator: Thank you so much, Dr. Cutler. This was an excellent presentation. We do have a lot of questions and if you have a question that you'd like to ask, please put it in the chat in the ask question box on the lower left side of your screen. We have some really overarching questions. 

One of them is, what are the key factors that help guide changes to medical management of chronic GVHD? How do you go into that vision point? 

[34:27] Dr. Cutler: Yeah, that's a great question. So, the key drivers for us have to do with response and how you as a patient are feeling. Depending on the drug, we have to give that drug between 2 and 12 weeks to work. 

The scenario for acute graft-versus-host disease is often on the shorter side. For chronic GVHD, we allow a longer time period to determine if the drug is going to work. 

So, it depends a little bit on the mechanism of action. It depends on the clinical urgency, and it depends very much on how you, the patient, are feeling and doing with respect to your graft-versus-host disease. So those are the type of factors that go into our decision. 

Obviously, if the disease is progressing in front of our eyes, we have to switch sooner rather than if things have stabilized and we're still waiting for a response to the disease. 

That's a really good question. 

[35:40] Moderator: Thank you. 

This is a question that comes up all the time when folks are reaching out to BMT InfoNet. 

in chronic GVHD with multiple organs affected, how long does medication need to be taken? Is this a question about medication will be needed to manage the immune system for life? What are the thoughts on that? 

[36:02] Dr. Cutler: Yeah, so it's another very good question, and it's one that actually does not have a formal answer. 

Our approach is really all about minimizing immune suppression wherever possible. Because any amount of immune suppression increases the risk of infection. So, we want to give the minimum amount of GVHD treatment required. 

Typically, what we will do is we will treat the GVHD until it appears to be resolved, and then over the course of months to sometimes even years, we will slowly, slowly back off the GVHD drug sequentially. 

We all have different ways of doing this. I typically try to get patients off of the drugs that are most toxic. So steroids, I often use drugs that work the best. Most patients can eventually get off all drugs, but some patients might require a real small amount of chronic therapy.  

And quite frankly, you know, at a certain point, you kind of say, well, I'm really good where I am. Why do I want to try to stop these medicines and risk having the GVHD flare? So it is a little bit of a personal thing, and it's definitely an individualized approach, patient to patient. 

[37:40] Moderator: Thank you. 

To expand on that a little bit, you mentioned about the possibility of coming off steroids with some of these other medications. We do have questions in the chat about other sorts of treatments. 

So, for example, topical treatments, drops for ocular GVHD. What is the thinking about whether or not some of the medications that you mentioned in your talk could replace some of the additional topical medications that someone is using? 

[38:08] Dr. Cutler: So we look at topical therapy or local therapy as an adjunct to systemic therapy, which means pills or a trip to us. And for most people, some combination of the two is the right answer in the long term. 

Some of the topical therapies, they come in two classes, those that are directly immune suppressive and those that are supportive for that organ. 

As an example, we'll talk about the eye, for example. And you can give steroid eye drops, which are anti-inflammatory to the eye. Or you can just give hydrating eye drops or Refresh-type tears. And they both have different roles, but they're both important for the organ-specific management here.  

So, the topical therapies are adjunct. Sometimes it's all that's required for an individual patient, but really one doesn't necessarily replace the other. They are adjunctive to each other. 

[39:22] Moderator: Great. Thank you. 

We have a few questions about clinical trials. And folks were kind enough to write in a little bit about their personal health background. 

But one person wrote in about having now seven years post-allogeneic transplant and they have had chronic and acute GVHD.They recall at the initial time of their treatment, they were being offered a clinical trial, but were a little bit nervous about some of the chemo drugs that might be included there. 

How do patients know when to accept clinical trials when offered? 

Then a second question, very similar, is if someone has a certain number of symptoms, how do they know which trial might be right for them? 

[40:08] Dr. Cutler: Yeah, and again, these are all extraordinarily individualized problems to have. So, your best resource is your physician, because they're going to be most acutely aware of what trials might be available, what trials you might be eligible for, and which trials are really not suitable for. 

You know, when we design trials, we have to write in what we call inclusion and exclusion criteria. And we do that so that we have a homogenous patient population where we can make a conclusion at the end of the day. 

If we left it open to all patients, then we would quickly find ourselves in a scenario where we'd be doing trials where every single person would have a unique thing, and we wouldn't be able to make generalizable statements. 

While that doesn't seem like it's fair for the patient who gets excluded, from a grander, holistic and societal point of view, it does allow us to move the needle forward. 

So, there are resources available for patients. I often refer people to the National Marrow Donor Program website where they discuss clinical trials there fairly extensively. Each of the individual disease organizations like LLS and the Myeloma Foundation, they all have a website that has sections on choosing clinical trials. 

But really having a discussion with your clinician to find out what is best for you and what might be an inappropriate trial for you to participate in is probably the most important thing to do. 

[41:57] Moderator: Thank you. 

We have a few questions in the chat about folks who have plateaued on their current GVHD regimen. And how do they know what to choose next? 

Which drugs might be a good option for them if they're plateauing on the current treatment? 

[42:16] Dr. Cutler: Also a really tough question. 

One has to understand that, you know, with longer duration chronic GVHD, there is scarring in the target organs. And as the farther up you get from transplants, you have to ask yourself, do I actually have active chronic GVHD or do I just have the chronic sequelae of having had GVHD? 

I'm going to use the eyes again as an example. 

So GVHD of the eyes often affects the tear glands, the lacrimal glands, and if you have GVHD long enough, those tear glands get scarred or fibrose. And the glandular tissue gets destroyed. And so, someone in that scenario is going to have chronic dry eyes, no matter what magic drug you give them, because you're not going to grow back tear glands. 

Patients and doctors need to decide, is there active inflammation in the target organ, or is this just the results of having had inflammation in the past? 

So in the latter area, one has to really maximize the supportive care measures, but pulling back on immunosuppression or GVHD drugs is often the right thing to do in those situations. 

[44:01] Moderator: Thank you. This is also a great question. 

Someone is somewhat comforted by the fact that they understood chronic GVHD or GVHD in general to be an indication of good graft versus disease. And with the better treatment of GVHD, does that mean that the original graft is less effective? 

[44:30] Dr. Cutler: There's a bit of a, I'm not sure it's a myth or just something we like to tell ourselves to make ourselves feel better; that a little bit of GVHD is a good thing because it often prevents relapse. 

It's not entirely clear that that holds true in the modern day. Perhaps in the early years of transplantation that was a truism, less obvious today. 

Our goal is always to treat GVHD to resolution. We don't think that treating it to resolution impairs the ability of the immune system to prevent leukemia or lymphoma from relapsing. So, the goal should always be to treat GVHD to resolution. 

[45:23] Moderator: Thank you. 

In some of the trials and the new data that you've been discussing in this talk, how could those be applied to people who are currently dealing with and experiencing chronic GVHD? 

[45:38] Dr. Cutler: Yes. All of these drugs were given to patients, tested on patients with active and resistant GVHD. If you still have GVHD, you can talk to your doctor about cycling through to the next drug and to the next drug, and the next drug. 

These are drugs that are designed to treat patients with active GVHD. The novelty is using them in patients with newly diagnosed. That's what we don't know about. So, by all means, you should be continuing to test new drugs until you find the right one that works for you. 

[46:18] Moderator: A new question came in just as you were speaking about a little bit of misunderstanding of that myth you just mentioned that GVHD can or cannot increase risk of relapse. Can you repeat that for those who might not have understood the first time? 

[46:34] Dr. Cutler: Yeah, so very early on in transplantation, it became obvious that patients who did not get GVHD had a higher likelihood of relapse. That might have been a statistical sort of misunderstanding, if you will. 

People felt that having GVHD was indicative of an immune system that was actively fighting leukemia. We don't know that that is necessarily true today. While we used to say a little bit of GVHD is a good thing, You have to be careful what you wish for because we don't have a dial to turn GVHD up or down a little bit. 

We tell patients no amount of GVHD is good. And should they get GVHD, we really try to treat it to resolution. 

[47:29] Moderator: Great. Thank you. 

Are there differences in symptoms between upper GI GVHD and lower GI GVHD? 

[47:39] Dr. Cutler: Yes. GI-GVHD is largely an acute GVHD phenomenon. The upper GI tract is typically manifest by things like nausea, dyspepsia, acid reflux, a general sense of abdominal malaise, whereas lower GI-GVHD is predominantly manifest by watery diarrhea. 

They're pretty easy to tell apart. Often they travel together, but they are separate clinical systems. 

[48:16] Moderator: Great. Thank you. 

We've had a couple of questions about photopheresis, the effectiveness response rates and what the current thought is. 

[48:28] Dr. Cutler: Yeah. This is a black box, if you will, as is the ECP machine. 

So, for those of you who don't know what that is, ECP or extracorporeal photopheresis is a procedure where we filter out white blood cells from the active bloodstream using a dialysis machine. 

Those white cells are treated with phototherapy or light. 

That light therapy inactivates those cells, and then they are put back into circulation with a goal of re-educating the immune system. 

We don't understand terribly how this works, or if it works at all. It has been tested less stringently than other therapeutics in GVHD. but it does, we believe, work to some degree in both acute and chronic graft-versus-host disease. 

It does require a long time for it to work. It really is a therapy that one has to have patience. It often requires a three-month trial of twice-weekly sessions to see if it's going to be effective or not. It's not for patients who are really desperate to get a response. 

[49:51] Moderator: Thank you. 

Can you speak to any recent studies about both ocular eye GVHD or mouth GVHD? 

[50:03] Dr. Cutler: We have not done a ton of organ-specific studies. There are a few things for the eye, but they're largely supportive care measures. 

Similarly, for the mouth, we've tried to compound some of our drugs into rinses and stuff, but there have not been any important trials that are dedicated directly at GVHD or directly at oral GVHD treatment for the reasons you might imagine that these are hard patient populations to isolate. Because if someone comes into the clinic with a combination of liver and skin and mouth GVHD, we're not going to put them on a trial that is only going to treat their mouth. That doesn't make sense. 

Patients with single organ involvement that we can put on clinical trials are fairly uncommon. 

[51:03] Moderator: Thank you. If someone is experiencing GVHD and is stable in their GVHD, but they are concerned about it becoming worse in any way, would you recommend one of the drugs that you discussed in your talk? 

How would they go about speaking with their doctors about whether to stay on their current regimen if they're stable or to seek something that might show improvement? 

[51:33] Dr. Cutler: Well, I mean, you've answered the question in the question itself. That is, this is a discussion between you and your physician. 

Are you in a good spot? Could you be doing better? Should you be doing better? Again, a very personal discussion between you and your physician. 

[51:57] Moderator: On that note, we do have a number of questions remaining that are very, very specific to individual cases, individual dosages of medication. And certainly, while Dr. Cutler is an expert, he cannot be an expert on your particular case. And so, if there are other questions that anyone would like to ask about GVHD, the treatment of GVHD a little bit more in general, we'd be happy to take them. 

One question that came in is about GVHD that's coming in and presenting as chronic fatigue. Are there ways to address that? 

[52:46] Dr. Cutler: Well, chronic fatigue is so multifactorial. There are literally dozens of things that could contribute actively to fatigue in a given patient. 

Fatigue itself would not be considered sufficient to make a diagnosis of chronic GVHD. I don't think we would treat fatigue alone as a manifestation of GVHD. Fatigue with other signs or symptoms, of course, is different. 

The one thing to think about when fatigue is presenting alone is that perhaps you're misinterpreting fatigue as shortness of breath. And checking lung function would be the one thing to do in all patients who have unexplained fatigue but don't have other manifestations of GVHD. 

[53:44]  Moderator: Thank you. 

Do you have any information on potential butyrate supplementation for acute GVHD? 

[53:53] Dr. Cutler: Now we're getting really into the weeds. Butyrate supplementation is a way of addressing the microbiome. So, there are certain bacteria, and we think favorable bacteria, that require butyrate, which is a common chemical found in our food, to thrive. And so we are, in fact, testing butyrate supplementation in a fairly simple clinical trial format. 

We are going to be giving patients what we call resistant potato starch as part of their transplant. And they're going to eat potato starch, which is a good source of butyrate, to see if it can actually prevent graft-versus-host disease. I would not recommend people go out and binge eat potato starch for their GVHD. 

[54:49] Moderator: We know that different centers have different practices regarding immunization following transplant. There are questions in the chat specifically about immunizations with certain GVHD drugs and whether or not there might be contraindications. 

Someone brought up specifically that their understanding is that with Jakafi, the MMR measles vaccine is not recommended. 

Is there information about any sort of interaction between immunizations and the GVHD medications? 

[55:22] Dr. Cutler: Yeah, so there are a couple of blanket statements we can make and everything else is very individualized. 

The MMR vaccine is a live virus vaccine. And we don't recommend administering the MMR to anyone who has any amount of immunosuppression or active GVHD ongoing. So, a very theoretical concern of the MMR vaccine. 

All the other vaccines are what we call attenuated. They're not live. Some are just protein based. They can all be given in the context of immune suppression for GVHD. 

The question of their effectiveness remains to be seen. And that's why it's an individual discussion with you and your physician as to whether you should be delaying your vaccines for a short time or they should be because there's no obvious end to your immunosuppression in sight. 

[56:20] Moderator: Great. Thank you. We are nearly at time. 

And so for the questions that remain in the chat about the specifics about ocular GVHD and learning a little bit more about that or lung GVHD, we do have sessions on both of those. 

If you are not able to make those sessions, all of the recordings are available on the symposium website and will be available to you whenever you are able to join. 

And then on behalf of BMT InfoNet and our partners, I'd like to thank Dr. Cutler for his very helpful talk and remarks. And thank you to the audience for being here and for your excellent questions. 

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Thank you.