Introduction to Graft-versus-Host Disease (GVHD)

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Introduction to Graft-versus-Host Disease (GVHD)

April 27, 2024

Presenter: Luke Mountjoy, MD, Assistant Member Physician, Colorado Blood Cancer Institute

Many thanks to Incyte, Sanofi, and Pharmacyclics an AbbVie Company whose support helped make this Survivorship Symposium possible. 

Summary: Graft versus Host Disease (GVHD) is a common complication after allogeneic stem cell transplant. Learn the difference between acute and chronic GVHD and how each develops. Both standard therapies and exciting new prevention and treatment interventions are discussed.

Key Points

• Acute GVHD is caused by T-cells. These immune cells attack the skin, digestive tract, and liver. Chronic GVHD not only involves T-cell activation but also B-cells. B-cells are immune cells that develop antibodies that deposit in tissues, causing symptoms such as dry eyes and mouth, tightening of the skin and tissues, decreased appetite, and diarrhea.

• In the past, the incidence of acute GVHD was 70%. However, with the introduction of new interventions such as post-treatment Cyclophosphamide (Cytoxan® ), graft manipulation, and ORCA-T, the incidence in clinical trials has decreased to 5-6%. This has also led to improved one-year relapse rates and overall survival rates in clinical trials.

• There are now new drugs approved for GVHD treatment, including Ibrutinib (Imbruvica®), Ruxolitinib (Jakafi®), and Belomosudil (Rezurock®). Although each drug can have side effects, they are helping improve patients' symptoms and overall quality of life.

Highlights:

(03:15): When you receive a stem cell transplant, lymphocytes are infused along with the stem cells. Lymphocytes fight and kill whatever blood cancer you're dealing with, but they also can fight you. They can cause graft-versus-host disease

(07:00): Acute GVHD can occur a few weeks after transplant and usually peaks a few months after transplant and resolves by 1 year. Chronic GVHD can start a few months after transplant, and usually peaks between 1-2 years after transplant. However it can also persist for years.

(10:08): Risk factors for GVHD include the HLA mismatch between patient and donor, a donor who has had multiple pregnancies and older donor age.

(12:15) Clinical features of acute GVHD include skin rash, elevated bilirubin, nausea, vomiting or anorexia and diarrhea. Acute GVHD is graded from 1-4 with 4 being severe symptoms.

(14:44) Chronic GVHD is the most serious and long-term complication of transplant. It occurs in 30-55% of patients. 50% of patients will have 3 or more organs involved. On average, therapy is required for 2-3 years.

(19:31) Transplant success is measured using a GRFS score. This stands for GVHD, relapse-free survival. The goal is to have a successful transplant with no GVHD.

((22:02) Post-transplant Cytoxan®  is a new strategy to minimize GVHD. It is a dose of Cytoxan®  (Cyclophosphamide) infused on day 3 post-transplant. It works by targeting the T-cells that cause GVHD. In a small study, patients who received post-transplant Cytoxan®  were 20% more likely to be alive without relapse and without GVHD at 1 year post-transplant.

(26.21) Clinical trials utilizing ORCA-T are very encouraging. ORCA-T amplifies or increases a patient’s regulatory T-cells which help decrease GVHD. These are then infused back into the patient. Acute GVHD decreased to 5% and chronic GVHD to 6% compared to historical controls. Patients also had improved relapse-free survival and overall survival. Studies are ongoing.

(30:16) The backbone of GVHD therapy is steroids and immunosuppressants. However, the FDA has approved 3 new drugs for the treatment of GVHD including Ibrutinib (Imbruvica®), Ruxolitinib (Jakafi® ) and Belumosudil (Rezurock® ®). These newer medications have been very helpful in managing both acute and chronic GVHD.

(36:55) The prevention and treatment of GVHD are improving at a remarkable rate. There are currently many clinical trials focused on learning more about how we can continue to minimize transplant complications of GVHD while improving outcomes.

Transcript of Presentation

(00:00):  [Michelle Kosik ]:  Introduction. Hello, my name is Michelle Kosik, and I will be your moderator for this workshop. Welcome to the workshop Introduction to Graft-versus-Host Disease. Before we begin, I'd like to thank Incyte, Sanofi, and Pharmacyclics, and AbbVie Company, and Johnson & Johnson, who support help make this workshop possible.

(00:21):  It is now my pleasure to introduce Dr. Luke Mountjoy. Dr. Mountjoy is an assistant member physician at the Colorado Blood Cancer Institute and is a co-lead of the Lymphoid Disease Group. His research focuses on stem cell transplantation and the prevention and management of GVHD.

(00:37):  Dr. Mountjoy's interest in medicine began as a teenager when his father was diagnosed with pancreatic cancer. Shortly thereafter, Dr. Mountjoy was diagnosed with acute myeloid leukemia. These life experiences led him to pursue a career in medicine, with plans to become a medical oncologist/ hematologist. Now, please join me in welcoming Dr. Luke Mountjoy.

 (01:06): [Dr. Luke Mountjoy]:  Overview of Lecture. Thanks, Michelle. Again, thank you guys, for allowing me to talk to you about this. This topic is near and dear to my heart. This is what I spend endless, probably 70 plus percent of my working hours dealing with. This is a big topic. Right now we're going to go through the introduction to it, and I think later on this week you'll get into the nitty-gritty details of organ-specific graft-versus-host disease and things of that nature. Let's dive right in here.

(01:40): I want to quickly go over the outline here, just basic talk about allotransplant. We'll go through mechanisms, GVHD, how it presents, and things of that nature, but then, for the money, we want to be sure we talk about, how do we prevent it and how do we treat it. Because this is a really exciting time. Maybe that sounds like a cliché, everyone says, "Oh, it's a really exciting time."  Well, I'm going to show you some of these new studies and new interventions coming up and you'll see why I say that. This is real, and we are getting really good at this and things are looking good, looking up for a bright future here.

(02:20): Understanding Allogeneic (allo) Stem Cell Transplant.  With that being said, I just want to go through briefly, you guys know all this, but so we're on the same page, we're doing a stem cell transplant. For those of you fighting acute myeloid leukemia, your cancer is forming here at the stem cell phase when it's trying to turn into the myeloid cell. For those fighting acute lymphoblastic leukemia, it's a cancer when the stem cells turn into the lymphoid stage. And those with (myelodysplasia) MDS, you have damaged stem cells. And all through the course here, people can develop cancers at any point along the way. Things like chronic myelomonocytic leukemia has differentiation right here. But what we're doing with a stem cell transplant is we are giving some form of chemo and or chemo/radiation to completely wipe out these stem cells and then transplant new bone marrow, new stem cells into you.

(03:15): The other thing that we transplant into you are these lymphocytes here. These lymphocytes are the things that we love because they can fight and kill whatever blood cancer you're dealing with, but they also can fight you. They can cause graft-versus-host disease, and that's what we're going to spend time talking about.

(03:35): So again, transplant from a donor, you're getting the blood-forming cells from the donor, and that's awesome because they make your healthy red blood cells, your healthy platelets, your healthy neutrophils, and then they make those immune cells, those immune cells, specifically those T cells, those T lymphocytes that recognize and attack the leukemia, attack the tumor.

(04:02): This is something that all of our immune systems are hardwired to do. You get a cancerous cell form, your immune system recognizes: this is mutated, this shouldn't be there. It attacks and kills it.

(04:13):  For reasons that we don't know, sometimes the immune system short circuits and doesn't recognize the developing malignancy or the developing tumor forming. It's a double hit. It's a combo punch here. We wipe out the bone marrow, wipe out the stem cells with what we call the conditioning regimen, whether it's chemo and radiation, and then we transplant the new stem cells into you, and then you get that new immune system that attacks and kills those cancer cells. But, we have to be careful because we don't want them to attack you and cause symptoms of graft-versus-host disease. This is the baseline principle here.

(04:54): Introduction to Graft-Versus-Host Disease. Graft-versus-host disease is the consequence of transplanting a new immune system into you. Just to speak it in generalities, what happens is, those immune cells develop from the bone marrow. In addition, you do get a bolus of T cells that go into you, pure T cells, pure immune cells from the donor.

(05:22): And what happens is, those immune cells recognize that, "Wait a second, this is not the body that I belong to. This is the body of someone else. This looks foreign to me." Those immune cells come into contact with surface proteins on your tissue, on your skin, on your digestive tract, on your liver, and they can recognize them; ‘Ooh, this looks very similar, but also it looks a little different. This looks foreign to me. This looks like an abnormality. This almost looks like an infection. I am going to attack it because I don't recognize this as friendly, and I'm going to attack it.” And that's what graft-versus-host disease is.

(06:06): But it's actually pretty complicated. It's that principle, but there are things that can drive it. If you've got tissue damage from chemo and radiation causing inflammation, inflammation then stimulates immune response. Cytokines, which those of you that are familiar with CAR T therapy may hear the word ‘cytokines’, maybe more frequently than in years past.  Cytokines fuel and stimulate immune activity. You can imagine, if you've got damaged organs and such from chemotherapy and or radiation, this causes inflammation, this stimulates immune activity. This can drive inappropriate upregulation of the immune system causing graft-versus-host disease.

(07:00): There's kind of two flavors that graft-versus-host disease come in, there's early graft-versus-host disease and there's late graft-versus-host disease, or there's acute and chronic graft-versus-host disease.

(07:14): Acute graft-versus-host disease. On the x-axis, we have a timescale here. Generally, acute graft-versus-host disease comes on early, and that's a really inflammatory condition because acute graft-versus-host disease is driven almost exclusively by T cells. T cells are these immune cells that will latch onto specific cells, skin cells, digestive tract cells, liver cells, and kill them by immune effect. And that causes a lot of inflammation that can cause a red-raised skin rash. You can get nausea, you can get vomiting, you can get diarrhea, you can have a poor appetite. The liver can get irritated.

(08:00): Chronic graft-versus-host disease. Whereas chronic graft-versus-host disease comes on later as you can see there. And we do have moments where the two things can overlap.

(08:08): What's unique about chronic graft-versus-host disease is that there's still a component where the T cells are playing a role. But what happens is that you start getting the B cells to play a role, meaning you get immune cells that start making antibodies and then they start releasing antibodies, and those antibodies deposit in the tissue. And that can cause things like dry eyes and dry mouth and tightening of the skin. They can cause decreased appetite. You can have diarrhea because you're getting antibody deposition along the line of your digestive tract. They're different, but there are elements where they overlap.

(08:54): Acute graft-versus-host disease is one of the major drivers of mortality from a transplant. Historically, 70% of patients can get some form of graft-versus-host disease. That's a really scary number. It's like, "Oh, my god, are you kidding me?" Those odds aren't in my favor. Well, that's changing, and I'm going to get into that. We've got some recent literature showing that we are compressing these numbers way down compared to historical averages. This is historical, but I'm telling you, I don't cite these numbers to my patients with some of the new technology that we have and some really exciting technology coming in the future.

(09:40): Acute graft-versus-host disease starts a couple of weeks after transplant. It can be longer as from that last slide I told you, there's this idea of late-onset acute graft-versus-host disease that can come several weeks later. And the big thing that we don't want to have happen is for acute graft-versus-host disease to kick in and not respond to our first line of treatment, i.e., not respond to steroids.

(10:08): Risk Factors for Acute GVHD. Some of the risk factors for this, some of you who are pre-transplant may have been told by their transplant physician, "Hey, you have a perfect match." And some of you may hear, "Oh, you have a close match, but it's not fully matched. It's a mismatch." Or what we're doing exponentially more numbers of, is this idea of half-matched or half-low identical transplant. Here you're getting stem cells from mom or dad or brother or sister or son or daughter when they're half-matched. And again, historically those have been associated with higher complications, but we are getting so much better at this that that's not the case anymore and that we're seeing really good outcomes regardless of donor source.

(10:54): But here's just for full information, these things that play a role. One of the things I want to highlight here is this HLA. The HLA is that idea of what your tissue match is. Are you full-matched? Are you partially-matched? Are you half-matched? So obviously, historically, the better the match, the lower the rates of GVHD.

(11:15): Women that have had multiple pregnancies that are donating their stem cells, there can be a higher risk of GVHD there. And that makes sense, right? Because when a mom is delivering her baby, there's a little bit of mixing of mom's blood and baby's blood, and that can stimulate some immune activity and that can increase the risk of graft-versus-host disease. That risk is modest. So if you have a family member, a friend or a donor that they say, "Ooh, they've had a couple of pregnancies," I don't want you to be alarmed. "Oh my gosh, my rates of graft-versus-host disease are much higher." That is not the case.

(11:54): We also know that donor age plays a role in graft-versus-host disease. The older the donor, the higher the rates of GVHD. The National Donor Registry program knows this. And as you get into your 40s, you are actually no longer eligible to donate because of these risks.

(12:15): Acute GVHD: Clinical Features and Grading. So acute graft-versus-host disease, we say this is an inflammatory process because it's T-cell mediated. This is a grading criteria by the Mount Sinai GVHD Consortium. This is a very standard, almost every transplant center across the country uses this grading system. The idea is that if you have just a little bit of skin GVHD, that's a low-stage and a low-grade graft-versus-host disease. And then as you can see here, as the rash covers more body surface area or BSA, it becomes a higher-grade graft-versus-host disease.

(12:55): We see the same thing with the liver. If we see your bilirubin rising higher and higher, that's a more extensive graft-versus-host disease.

(13:01): Then we have just upper GI symptoms, meaning "Ugh, I'm nauseous, I don't feel hungry." And that's a really difficult one for all of us, for us clinicians, and for you because it's like, "Luke, you gave me chemo and you gave me radiation, and now you have me on all these pills and I'm nauseous because you're giving me all these pills, and some of these pills you're telling me I have to take on an empty stomach?" (Tylenol makes me nauseous if I take it on an empty stomach.) So upper GVHD can be a hard one to diagnose because it's like, "I'm not really hungry," and it's one of those things. But the key here with upper GVHD is that it's progressive.

(13:46): And then lower GI GVHD is, we're talking about how much diarrhea are we having, which again can be a frustrating thing because we use medicines like mycophenolate, for those of you that are post-transplant and familiar with that drug, that can cause diarrhea. It's like, am I having diarrhea from the drug or having diarrhea from graft-versus-host disease? And this is one of these things when we don't know, we can make that diagnosis by doing an endoscopy or a colonoscopy where we take random biopsies of the lining of the digestive tract and you can actually see the graft-versus-host disease taking place. There are very characteristic things we see with these immune cells infiltrating into the lining of the digestive tract and causing damage to the lining of the digestive tract. So that's an important thing that we do sometimes when we're having difficulty teasing it out.

(14:44): Risk factors for chronic graft-versus-host disease, again, is a little different. Yes, there's a lot of overlap with it. I say to my patients, the biggest risk of chronic graft-versus-host disease is, how much acute graft-versus-host disease do you get? We get a lot of early graft-versus-host disease. You can have more chronic graft-versus-host disease, but really we're talking about how well-matched is your donor historically. But I don't usually go into the nitty-gritty with that saying, "Oh, well, you're a mismatch. Your donor is not fully matched, so your rates of graft-versus-host disease are going to be higher," because that's not really true anymore with the advances in technology. Again, this comes late.

(15:30): What's frustrating about chronic graft-versus-host disease is that while acute graft-versus-host disease, we can hopefully put you on some steroids for a few weeks to a month and taper them off, chronic graft-versus-host disease, we got to have you on therapy for a lot longer months, sometimes years. And again, it's because it's those B cells, there's a component of these B cells where they're producing antibodies. Those antibodies are depositing in your tissue and they're causing more fibrotic dry eyes, dry mouth, tightening, and things of that nature, not as inflammatory.

(16:07): Symptoms of chronic graft-versus-host disease. We grade ... Oh, excuse me, this is more just some of the, again, this is highlighting the difference here while I told you, let's use the skin for an example. I told you skin acute GVHD, you got a rash, it's red, it's itchy, it's raised, it feels like a sunburn. Or for those of you that have ever been in the Midwest, like my wife got in contact with poison ivy out there when we were in Iowa. Thankfully we don't have much of that in Colorado, but in Iowa, she got in it. Boy, this just red, inflamed, skin rash, itchy sometimes can break open. That's what we see with acute GVHD. But with chronic skin GVHD, it's more of this hardening of the skin where your skin can kind of dimple like an orange peel. You can get sclerotic sort of stuff, like these dry plaques. That can happen in your mouth, that can happen in vaginal tissue, which can be uncomfortable.

(17:07): And then a gut graft-versus-host disease, chronic gut graft-versus-host disease can have similar symptoms to acute graft-versus-host disease, as you can see, the diarrhea and all of these things. But it's a malabsorption issue because you're getting those antibodies that deposit. Now, again, you can still get this component of T-cell activity where you can have this overlap of symptoms. So chronic graft-versus-host disease can be more complicated, and really any organ in the body is at risk for these things. We just more commonly see it in the skin and in the digestive tract and the liver because those organs at baseline have a lot of baseline immune activity to them. So that stands to reason that those are the places that we see more of that because there's more immune activity in those areas.

(18:06): So chronic graft-versus-host disease, we don't grade it like we do with acute where we say, "Oh, is it grade 0, 1, 2, 3, 4?" We say, "Is it mild? Is it moderate? Is it severe?" Basically, it's mild if really just the skin or maybe just a little bit of the liver is involved, but it's severe if you're having dry eyes and dry mouth and tightening of the skin and diarrhea, we say that's severe.

(18:37):  How do we define a successful transplant? GRFS Score. To take a pause here for a second, how do we define success from a transplant? Well, we cure the cancer and we don't want graft-versus-host disease, right? I mean, that basically sums these things up. And in the transplant literature in recent years, we have come up with a more composite endpoint instead of looking at all these things individually. We used to just look at, "Hey, we cured the cancer," and we'd pound our chest and be so proud of ourselves that we cured it, but if the patient is miserable with graft-versus-host disease, yes, it's great that we've cured the cancer, but if your quality of life is awful, is that really a success?

(19:31): And because we've recognized these components of it as a community, there's a more uniform composite endpoint that we look at nowadays that some of you may have heard of called a GRFS score, and I'll get into that more. But GRFS score stands for graft-versus-host disease, relapse-free survival. I mean, you're alive with no graft-versus-host disease and no relapse of your cancer. I mean, that should cover it, right? These are the endpoints that we're looking at nowadays for studies.

(20:08): General Schema: Allogeneic Transplant. The schema from a transplant is this idea of this combo punch. We need to condition your body, wipe out the cancer, wipe out the immune system to prevent rejection, because we don't want your immune system to attack and kill the stem cells that we're going to infuse into. We condition the body, we wipe out the disease, we wipe out the immune system, we transplant the new donor immune system into you, and then those new immune cells go in and they start attacking and replicating and expanding, but we want to keep them in check so we don't cause graft-versus-host disease. And we do that with this combo of different immune suppressants as listed here.

(20:53): If you guys are on forums with your, colleagues isn't the right word, but those people that are going through transplant and other centers, you might be comparing notes and saying, "Well, wait, I'm doing this immunosuppressant combo and you're doing this one and I'm doing that." And at the end of the day, there's not a right answer. It's more contingent upon what's your donor source, how well-matched the donor and these sorts of things. These are all acceptable regimens to use for immune suppressants to prevent graft-versus-host disease.

(21:28): Strategies to Decrease GVHD. There are other ways we can reduce the rates of GVHD other than just, "Hey, let me slap you on a bunch of immunosuppressant medicines like Tacrolimus and Methotrexate and Sirolimus and CellCept® ." There are other things that we can do, and some of this is getting really, really exciting because we are understanding how the immune system works much better. This idea of something called a regulatory T cell and this other idea of something called a naive T cell, and I'll get into the details of that right now.

(22:02): Post Transplant Cytoxan® . Excuse me, let me just touch on one other thing before I get into those studies. This is something that has changed, and this is Luke Mountjoy's opinion. This idea of post-transplant cyclophosphamide (Cytoxan®), I think has completely changed the game in transplant. This is where you guys get your stem cells transplanted into you. And then three days after the transplant, we give you a dose of chemotherapy, Cytoxan® or cyclophosphamide, we call it PTCy. (Post-Transplant Cytoxan® ).

(22:35): And the idea with that is that you get your conditioning regimen, you get the stem cells transplanted into you, and when you get your stem cells transplanted into you, immediately you get these T cells. And we've known this, the studies have shown this, that immediately these bad T cells, these alloreactive T cells that cause graft-versus-host disease immediately start dividing.

(22:58): Going into cell cycle, their DNA unwinds, they're exposed, they're replicating, but they're vulnerable because they're dividing. Your healthy stem cells are not in cell cycle yet. They're not dividing, they're not as vulnerable to chemo. You give the new stem cells, and those T cells, those bad immune cells that can cause graft-versus-host disease immediately start dividing and then we kill them all because they're vulnerable. Their DNA is exposed. Cytoxan®  is a chemotherapy that alkylates or cross-links exposed DNA. You kill all of the alloreactive T cells and then you leave behind all the good T cells and the immune cells.

(23:47): We've been doing this in half-matched transplants with unbelievable success. I don't want to be graphic, but if anyone had a family member who had a half-matched transplant 15, or 20 years ago, the GVHD, the graft-versus-host disease from that, it was horrible. It was horrific. Now, with this idea of post-transplant cyclophosphamide, we see the rates of graft-versus-host disease in half-matched transplants are as good, if not better, than in patients with fully matched. I mean, it completely flipped things on its head.

(24:27): The BMT, the Bone Marrow Transplant Clinical Trials Network, the BMT CTN did a landmark study that was just published last year, BMT 1703, and that was led by the consortium, the research consortium, where they took fully-matched donors and they randomized them to the standard where we give tacrolimus and methotrexate, or we do this idea of giving that post-transplant chemotherapy.

(24:59): And what did we find? Well, people who got the post-transplant cyclophosphamide were 20% more likely to be alive without relapse and without GVHD one year post-transplant. I mean, are you kidding me? We just improved outcomes by 20%? And I can't impress this upon you guys enough. Dr. Shernan Holtan out of Minnesota has been one of the biggest blessings in all of transplant. So, if you guys ever see Dr. Holtan give a lecture on anything, you listen to that one. She is a godsend to this field and she led this study and we are so lucky that she did that.

(25:39): Look at these things, these rates. I told you earlier, 70% rates of GVHD, 6%, are you kidding me? I mean, this is huge stuff here. I can tell you, even in my anecdotal experience of doing this, my job has gotten so much easier in the past eight months since we started doing this post-transplant cyclophosphamide. And I'm not saying that every single one of you needs this. There are nuances to it and your transplant physician will talk to you about the risks and benefits of doing it and not doing it. But you can see the reduction in the complications overall.

(26:21):  Graft Manipulation. I want to talk about this idea here, this is some interesting technology. We have these naive T cells and we have memory T cells. Naive T cells are the ones that cause graft-versus-host disease. Memory T cells are the ones that help us fight infection.

(26:37): A great study was done by Dr. Bleakley where they depleted all of the naive T cells in the donor stem cell batch, and then they transplanted those cells into patients, and they found that they had substantial reductions in the rates of GVHD with exceptional three-year overall survival. Very impressive results there. This is not yet readily available. We're still working through the studies on these things, but it's the idea that you laser out these naive T cells with these radioactive beads that bind to and kill those naive T cells, and you leave the memory T cells alone. They did not see any major complications, including no major complications of infection.

(27:29): ORCA-T. This is going to be really interesting, and we're lucky enough here at CBCI to have this clinical trial open, this idea of ORCA-T. So ORCA-T is a company that is doing this trial where they're trying to figure out how we can reduce the rates of GVHD.

To take one step back, we know that there is a component of our immune system called a regulatory T cell. Every single one of you have regulatory T-cells in your body. If you didn't have regulatory T-cells, every single one of us would have autoimmune conditions. We would have lupus and rheumatoid arthritis and all these things because regulatory T-cells exist in our tissue at a tissue level and they calm the immune system down. When an immune cell comes to the tissue, the regulatory T-cell calm it down, "Hey, relax, I'm your friend. Don't attack anything around here. It's all good. Leave us alone." Calm the immune system down-

(28:34): So ORCA-T has this question, can we harvest the donor's stem cells, amplify the regulatory T cell, and infuse this back with additional doses of regulatory T-cells to reduce the rates of graft-versus-host disease? And they did this study. They did it in what we call a single-arm study where they just did this to everybody and they compared the results to just historical controls in the database.

(29:04): And again, 5% GVHD. Are you kidding me right now? I mean, this is unbelievable results. Right now, this study is in a randomized phase III, meaning that there are people who are getting randomized to standard transplant GVHD protocols or ORCA-T.

(29:26): We all have our eyes laser-focused on the results of this study to see if we can continue to improve outcomes. Because 91% survival, 5 to 6% rates of GVHD. I mean, let's go! This is so exciting. These are the things that we're watching, and this is why our outcomes are getting better and better and better and are going to continue to get better and better and better.

(29:58): And there's your GRFS score. 76% of patients are alive without GVHD, without relapse on this ORCA-T study compared to historical averages. And then hopefully we'll have results of the randomized study in the future, but something to keep an eye on.

(30:16): GVHD Treatment. With the last few minutes here, I'm going to talk about treatment and then we'll leave some room for questions here. So, treatment, if you really just want to break it down to the basics, it's steroids, steroids, steroids. Steroids are the mainstay of treatment for both acute and chronic GVHD. We generally use Prednisone, it is one of the go-tos. Some people use Dexamethasone. Both are very reasonable, but I would say that most of us use steroids for treatment of graft-versus-host disease.

(30:50): The problem is that if you've got a little bit of skin GVHD, do you really want to get hit with high doses of Prednisone and have inability sleeping? And for us guys, including myself, that take steroids, you get really irritable. You can thin your bones and cause osteoporosis. You can get glaucoma. It can cause diabetes. Do you really need big doses of steroids? Can I just use topical steroids like hydrocortisone?

(31:19): One of the problems is gut graft-versus-host disease. It's kind of hard to treat. We really like to use steroids at even higher doses there. We tend to use a little bit higher doses of steroids for gut graft-versus-host disease. But there's other studies that have looked at using different immune suppressants to spare you from steroid exposure. But generally, that's only when you're dealing with mild graft-versus-host disease. When you have more severe graft-versus-host disease, steroids are the mainstay.

(31:49): But again, you can see how we're getting better because we are getting all of these FDA approvals for these new drugs. Ibrutinib (Imbruvica®), Ruxolitinib (Jakafi®), Rezurock® , these are all new drugs. I just want to spend some time talking about them real quickly.

(32:06): So Ibrutinib is a great drug. We've used it and we've been using it for a long time, but more recently have been using it in graft-versus-host disease that is resistant to steroids. Ibrutinib is what we call a BTK inhibitor. It inhibits the activity of B cells. This makes sense why it works so well on sclerotic and chronic GVHD because of that mechanism that we talked about earlier, that chronic graft-versus-host disease is more fibrotic, sclerotic in nature because of the B cells that are playing a role there. This works really well in myofascial GVHD. Great drug. I use a lot of ibrutinib, it is well tolerated. It can cause some heart arrhythmias, and it can cause some low blood counts.

(32:58): The other thing that you always have to be careful of is, anytime you're using an immunosuppressant, it puts you at risk for infection. But thankfully, we have very good drugs these days to protect against infection.

(33:10): Ruxolitinib, or Jakafi®, is another great drug. There are two big trials looking at this, for both acute and chronic GVHD. It inhibits something called JAK, that's why it's called Jakafi®  or Jakafi® . If there's any pharmaceutical companies on here, they'd probably get mad at most of us call who it Jakafi®, but it's actually Jakafi® . We've been using it for years in other diseases, and it inhibits something called JAK. Well, JAK, specifically JAK3, are on T-cells. You can inhibit the replication and activity of T-cells with Jakafi® .

(33:46): There were two studies done. The first was the REACH trial where they looked at using Jakafi®  and steroid-refractory acute GVHD compared to sort of best available therapy. And they saw really good results. I mean, 62% of patients that were steroid-refractory respond compared to our historical other treatments of using other drugs like Sirolimus or CellCept®  or something called photopheresis, which you will hear more about probably in the next hour. I'm assuming that they'll talk about photopheresis for skin GVHD. Great, great treatment for that. They saw good responses here for acute GVHD.

(34:32): And then they also looked at it in chronic GVHD. And again, compared to historical treatment, much better response rates here. Again, it takes longer to see the responses there. And here's the money that I always love to see in any study, is patient quality of life, better quality of life. I mean, it's a pill you take twice a day, well-tolerated. You don't have to get levels checked in your bloodstream like you do for tacrolimus and sirolimus and things of that nature.

(35:08): Ruxolitinib (Jakafi® can cause some low blood counts because JAK, JAK2, is on our stem cell. You can inhibit some of the stem cell activity and know it will not kill the stem cells themselves. It can just suppress them. You don't have to worry about that. And then again, anytime you're talking about suppressing the immune system, there's that risk for infection.

(35:29): The newest kid on the block is Rezurock® , this is a great drug. It's a ROCK inhibitor. The key here that has been so sorely needed are for patients with chronic graft-versus-host disease that have the sclerotic or fibrotic tightening of the skin, tightening of the joints, that dimpling, that orange peel, dimpling that you can see, some of that banding. If you have those tight bands in your neck and stuff when you are trying to move your neck, it helps break that up. It helps break down that fibrotic stuff there. I have seen some just amazing results with this drug. It's a great drug, very well tolerated, high response rates. It also looks like we see activity of it in patients that have been prior exposed to some of the previous drugs that I mentioned there.

(36:26):  Rezurock®can cause some fatigue, edema, things like that. I use a lot of Rezurock®. I haven't seen it. In general, it's pretty well-tolerated. Like I said earlier, anytime you take a pill, you think about GI upset just because. Like I said, if I take Tylenol on an empty stomach, I can upset my stomach too. But there are a lot of ways to mitigate those things.

(36:55): Treatment and Prevention of GVHD is Improving. A Lot of information here guys, and I'm sorry if that felt fast, but you're going to get into the nitty-gritty detail of organ-specific GVHD. But, we are getting better. This isn't some sort of cliche where the physician hangs this carrot, “oh, we'll get better at it someday, hopefully in our lifetime." I'm like, "No, we are getting better." As of eight months ago, we have just compressed the rates of graft-versus-host disease by another 20%. And we have these really exciting technologies that are in active clinical trials that will hopefully show a massive benefit and get FDA approval. Everything is rapidly improving.

(37:37): With that, I just want to say thank you to the BMT InfoNet, but thank you guys for just letting me take time out to discuss this. This job is, from what Michelle Kosik said at the beginning, I have a very personal reason for doing this. I know what it's like to sit on the other side of that screen and listen to some oncologists talk about their leukemia or whatever, and how scary it was. And just thank you for letting me sit on this other side of the screen and talk to you guys. And with that, I'll leave it to the questions.

 (38:22): [Michelle Kosik ]:  Questions and Answer Session. Thank you, Dr. Mountjoy, for that incredibly informative presentation. We will now begin the question and answer session.

(38:45):  I'm going to go ahead and start with, "My daughter age 30 is having a GVHD flare, which is causing her pancreatitis, but it's also causing vaginal bleeding. She is postmenopausal from the chemo. She is on Rezurock®. Have you seen bleeding as a GVHD symptom?"

(39:04): [Dr. Luke Mountjoy]:  Yeah, you can see that. And I don't know if she's had anyone take a look, do a hysteroscopy to see if she has got a substantial amount of inflammation in her endometrial lining, or if this is more superficial that she's having what we call mucocutaneous GVHD like within the vaginal wall itself. I think that if they don't know the cause of the bleeding and it's not getting better with intervention like the Rezurock®  or whatever other treatments she might be on, it would be reasonable to have someone like an OB-GYN do a hysteroscopy and take a biopsy of the endometrial lining and assess what's going on there. Do we see that T cell infiltration into the lining of the endometrium, or does it look more superficial there?

(40:02): [Michelle Kosik ]:  The next question now, "I'm having issues with chimerisms eight months after transplant. I've had two DLIs which prompted the skin GVHD. Is this good or bad?"

(40:15): [Dr. Luke Mountjoy]:  So important tidbit on chimerism: two things. We try and sort the chimerisms in the sense that what is the percentage of donor DNA in the stem cell lineage to the myeloid cells, and what is the percentage of donor DNA in the T cells or the lymphoid cells? If you have an acute leukemia process or MDS that you were transplanted for and you have mixed chimerism studies showing that your myeloid lineage, your CD33 cells are mixed, it raises a concern that you could relapse. Not always the case. If you have mixed chimerism in the CD3 compartment or the T cell compartment, then you worry, is your own immune system recovering and could you start getting rejection of the graft by your own immune system? So the idea is that you get an infusion of donor immune cells to tilt the scales.

(41:22): Now, I would say if you're having active graft-versus-host disease, I would not do any more DLI. And it kind of is important, the chimerism is just giving you a data point. You want to trend those things. You keep checking them, see if the percentage is changing for the better. Is it changing for the worse? If it's changing for the worse and let's say your CD33 chimerisms are becoming more and more your DNA, concerning for relapse, that's where your physician might put you on a drug like Azacitidine to suppress the potential for relapse to allow more time for those immune cells to attack.

(42:03): It's a great question. It's just a complicated question that I could spend three hours talking to you about. But ultimately, we do see some patients have chronically mild mixed chimerism that is not clinically significant. You want to be sure you're not chasing a number and just be sure you have that thoughtful conversation with your transplant doctor.

(42:28): [Michelle Kosik]:  Can fibrotic changes in myofascial GVHD be fully reversed?

(42:35): [Dr. Luke Mountjoy]:  Yeah, that's absolutely a goal, and there are more therapies in trial looking at these anti-fibrotic agents we saw at the recent transplant meeting, some really exciting, what we say phase I studies, meaning they're just very small, but we're seeing some of this reversal. Rezurock®  is a great drug where I have seen some incredible reversal of those things. The goal is yes, and if you have a lot of fibrotic deposition, a consideration would be to discuss with your transplant doctor about Rezurock® . It takes a while to see the responses. You need at least a few months before you start seeing those responses.

(43:20): [Michelle Kosik]:  Is Rezurock® considered an immunosuppressant like prednisone? And what are the advantages of using Rezurock® versus prednisone?

(43:29): [Dr. Luke Mountjoy]:  Yeah, so good question. We don't see the rates of infectious complications near as much with Rezurock® . I do tend to treat it as an immunosuppressive when I keep people on acyclovir and things of that nature. But also remember that chronic graft-versus-host disease in and of itself is an immunosuppressive state that you're in. So that's always one of the challenges, to try and tease out how much something could be suppressing your immune system. It is definitely not as immunosuppressive as Prednisone or Jakafi®  or Ibrutinib.

(44:13): The advantage to Rezurock®  is if you have that fibrotic, sclerotic sort of GVHD, a higher chance of probably reversing that. Now Prednisone can do that too, but here's the problem with prednisone in chronic graft-versus-host disease. You've got to be on therapy for a long time, like weeks to months. And that long-term exposure of prednisone is how we get into trouble with osteoporosis, glaucoma, diabetes, and things of that nature. I mean, sometimes you just have to do it, right? But we try to do everything we can to minimize long-term steroid exposure.

(44:52): [Michelle Kosik]:  Can you talk about the time-frames around chronic GVHD risk? At what stage do the risks go down over time?

(45:02): [Dr. Luke Mountjoy]:  Yeah, good question. And really, it's a hard thing. I showed you those curves, those timetables where it's like, okay, acute graft-versus-host disease comes early and then maybe after a hundred days, then it's less likely to happen. And then you start worrying more about chronic graft-versus-host disease. Well, the immune system doesn't have to read our textbooks. And I don't say that to disparage anything, I'm just saying it because sometimes we get caught up with someone that gets a flare of graft-versus-host disease six months after transplant, and we say, "Okay, well it's chronic." Well, that could be late-onset acute graft-versus-host disease. We have to be thoughtful about what happens.

(45:43): But there's not a hard fast timeline where you could say, "Oh, I am out of the woods forever." I will say that if you're a couple of years post-transplant with no signs of GVHD, it is atypical to get flares of graft-versus-host disease. But it still happens. It's a very complicated question because it's like, "Okay, how much acute graft-versus-host disease did I get? What is the status of my leukemia or lymphoma or myeloma? What was my donor match? What was my prophylaxis that I did?" All of these things play a role in trying to predict those things, but if you're several months out, off immune suppression with no GVHD, you're more than likely going to be out of the woods.

(46:35): [Michelle Kosik]:  Dr. Mountjoy, do you see cramping as a complication? I have GVHD in my eyes, mouth, and fascia, muscle wasting as well. I've seen a correlation in my cramping with my muscle wasting. I'm about seven years out of transplant and I started Rezurock®  at the first of the year.

(46:54): [Dr. Luke Mountjoy]:  Yes, you can see that stuff. The idea here is that if you're getting these antibodies from those B cells depositing in that muscle tissue, causing those contractures and causing that fibrosis and causing that stuff, you can definitely have the cramps. I wish there was a silver bullet for cramps. It's all these cliché things people talk about. "Oh, tonic water and whatever." I haven't had a lot of luck with things like tonic water.

(47:28):  I will tell you, always sure that your physician is checking your magnesium levels, especially if you're on tacrolimus. On top of the Rezurock® , tacrolimus is really notorious for causing our bodies to waste the magnesium. So those are some easy things that you can do to improve that. But hopefully that Rezurock®  starts soaking in and can break up some of that scarring and hopefully help your cramps.

(47:52):  But another thing, physical therapy, can be really helpful there. They can give you stretching exercises to kind of break up some of those fibrotic bandings and stuff that you're getting.

(48:06): [Michelle Kosik]:  I'm taking both Rezurock® and Jakafi®. Can these be counterproductive?

(48:12): [Dr. Luke Mountjoy]:  Yeah, that's a really good question. We sit around and we hem and haw about this a lot as a group. I mean, I guess I'll just tell you we don't know. We don't know the answer to that. These are kind of new drugs, and looking at the combo of them isn't well studied. There are concerns that that's a possibility.

(48:37): However, when people have severe graft-versus-host disease, I have seen people use a combination of Jakafi®  and Rezurock® . I generally do tend to avoid that combination. It's an awesome, awesome question that we don't know the answer to right now, and hopefully with more experience and more data through things like the CIBMTR, we'll get a better feel for that.

(49:06): I definitely don't think you're putting yourself at a detriment, so I don't want to alarm you or anything. It's just kind of an unknown. But in general, I say, well, geez, if someone's not responding to Jakafi®, I'm going to go to something else, and especially in the chronic setting that has been refractory to Jakafi®, I'd go to Rezurock® .

(49:29): Now, if you're talking about myofascial GVHD, again, we don't know the answer to this either, but ibrutinib is a really interesting drug in that space. At our transplant center for isolated myofascial GVHD, we do like ibrutinib in that setting.

(49:50): [Michelle Kosik]:  What if you have failed Jakafi®, Rezurock®, and Imbruvica®, what else is coming up? This patient is currently doing photopheresis, but they're trying to taper off.

(50:00): [Dr. Luke Mountjoy]:  Sure. There are more drugs coming and I know, sorry, if you guys are like, "Yeah, we got it, Luke." But Rezurock®  is another great drug and there are more drugs on the dock here, monoclonal antibody-based drugs. These are antibodies that will go in and help clean up GVHD, there's a lot coming.

(50:23): Photopheresis is a really good option. I know they're tapering you off of that. Always remember it takes about 12 weeks to start seeing response with photopheresis. Otherwise, sometimes just going back to good old Tacrolimus, Sirolimus, Mycophenolate, those are good drugs too.

(50:45): Historically, we always go to these newer drugs, the Jakafi®, the Rezurock® , the Ibrutinib. If you haven't had Ibrutinib, that'd be another drug I'd think about. Oh, you said you had that. Excuse me.

(50:58): [Michelle Kosik]:  Is Rezurock®  effective for lung, mouth, and eye GVHD?

(51:03): [Dr. Luke Mountjoy]:  Good question. I would say that if it's more of a fibrotic, sclerotic thing, I would say it's definitely worth a trial. The lung GVHD is always a complicated thing because it's not as common. When you're doing these studies looking at treatment for chronic GVHD, they look at all comers and there's always going to be less people with overt lung involvement, making it hard to fully answer that question.

(51:33): One of the things that most of us would argue is, a mainstay of treatment for lung GVHD is what we call FAM therapy, which is inhaled Fluticasone, Azithromycin, and Montelukast, F-A-M. Montelukast is Singulair. That's a really important treatment for pulmonary or lung GVHD. And ultimately though, Rezurock®  is systemic.

(52:01): I wish I could tell you definitively yes, that's going to fix those things. I think I've seen good responses with oral GVHD. I personally have not seen a lot of responses with Rezurock®  from a lung standpoint. That's not to say it doesn't work. We need more time with this drug to know for sure, but I would argue that it's important to discuss if you're not already on FAM therapy to do FAM therapy, F-A-M therapy, and talk to your transplant doc about that.

(52:33): [Michelle Kosik]:  Tacrolimus is hard on the kidneys, what drug might be a better option?

 (52:37): [Dr. Luke Mountjoy]:  Yeah, no kidding, that is what's so frustrating about tacrolimus. Ugh, it just drives me. You having kidney issues with that is, probably everybody on Tacrolimus listening to this and nodding their head right now, it is very common to have that. So yes, we have other drugs. We have Sirolimus, which is an mTOR inhibitor. That can kind of cause more diabetic complications and things of that nature.

(53:07): CellCept®  is another drug, also known as Mycophenolate. That can cause diarrhea. But we like Tacro, (Tacrolimus) but also Jakafi® . Jakafi®  is a good drug. If I have someone that is having a lot of issues with their blood sugars and their kidneys are getting banged up from the Tacro, I tend to reach for Jakafi® . And I tend to find, interestingly, it's always the middle-aged guys that for whatever reason tend to have the most issues with nephrotoxicity from tacrolimus. It is a very common thing that we see there.

(53:49): [Michelle Kosik]:  Well, we're running out of time, so this will have to be our last question. Other than medications, are there any treatments available for post-transplant patients four years out?

(54:06): [Dr. Luke Mountjoy]:  Medications? I guess I misunderstood, Michelle. Like for GVHD, other medications?

(54:12): [Michelle Kosik]:  It looks like, yes.  Other than meds, are there any of these treatments available for post-transplant patients that are four years out?

(54:24): [Dr. Luke Mountjoy]:  Well, I'm trying to understand the question, but let's say you're having some smoldering GVHD and you want to do treatment for your GVHD that does not include taking some sort of oral drug that can suppress your immune system systemically. It's a tricky question. I would say yes, based on what's going on with you.

(54:48): For example, if you're having skin GVHD, topical steroids is maybe all you need. If you're having skin GVHD, there's something called PUVA, which is psoralen, which is a creamy rub on your skin, and then you do ultraviolet light like you're going to the tanning salon. And the next presenter I think will talk about these things where she's talking about skin GVHD, which I think is the next discussion. Talk about PUVA, that's not systemic.

(55:15): I'll also tell you that if you're having some gut GVHD, there's a drug called Budesonide. Budesonide is a steroid, but Budesonide, when you take it orally, coats the lining of the digestive tract and then it's completely metabolized by the liver. You generally do not get the systemic side effects of budesonide unless you're on other medicines that could slow its metabolism. But I just wanted to highlight, if you're not on anything and you're having a little gut GVHD, budesonide by itself is a great drug because it just coats that lining of the digestive tract and you tend to not get all of the classic side effects from steroids.

(56:03): [Michelle Kosik]:  I lied. We're going to ask one more question since we've got three minutes. "I'm on Jakafi® now and I have had some relief. Is there any advantage to changing to Rezurock® for more relief for my skin and ocular GVHD?"

(56:17): [Dr. Luke Mountjoy]:  Yeah, so great question. There's good data showing Jakafi®  is really helpful for ocular GVHD in particular. And this is one I would hold court right now with your Jakafi®  because it takes so long to start seeing that response. And when I say so long, when we put that in context, it can take several months to see that maximal response. I would keep on that Jakafi® . Keep going. And then if your response starts plateauing or you start losing it, that's when I would go to Rezurock® . But if you're starting to get relief from Jakafi®, it could just be a tincture of time that you need more time on it, and I would not jump ship to Rezurock®  just yet.

(57:09): [Michelle Kosik]:  Thank you Dr. Mountjoy. On behalf of BMT InfoNet and our partners, I'd like to thank Dr. Mountjoy for his very helpful presentation and his question and answer opportunities. I'd also like to thank the audience for your excellent questions. Dr. Mountjoy, there's been a lot of comments about your great presentation, and it is very clear that we have an international audience that has been benefiting from your knowledge and explanation. Thank you.

(57:39): [Dr. Luke Mountjoy]:  Thank you, guys. Yeah, this too will pass. I know what it's like to sit on that other side. Thank you for taking time out of your day to sit down and talk together.