Graft-versus-Host Disease: Gastrointestinal Tract

Transcript of Presentation:

(00:01) Michala O'Brien: Introduction. Welcome to the workshop, "Graft versus Host Disease: Gastrointestinal Tract." My name is Michala O'Brien and I will be your moderator for this workshop.

(00:10): It's my pleasure to introduce today's speaker, Dr. William Clark. Dr. Clark is an Associate Director of Medicine in the Division of Hematology and Oncology at Virginia Commonwealth University (VCU). He is also the director of CAR T-cell Therapy at Massey Comprehensive Cancer Center. Dr. Clark's research focuses on identifying biomarkers to predict GVHD after transplant. He participates in clinical trials, studying ways to prevent and treat allogeneic stem cell transplant complications, with a primary focus on acute and chronic GVHD. Please join me in welcoming Dr. Clark.

(00:51) Dr. William Clark:  Overview of Talk. Good afternoon. My name is Dr. Bill Clark from VCU in Richmond, Virginia. Thank you so much to BMT InfoNet. I'm honored to be here today and to share information with patients, loved ones of patients, and family members about acute GVHD of the gut. I do love this Celebrating a Second Chance at Life Survivorship Symposium, because what we do here is cure cancers that would not otherwise be curable. And so, it really is giving someone a second chance at life.

(01:23): Today I will start with a brief overview of allogeneic stem cell transplant (a donor transplant); the risk factors for acute GVHD, specifically related to the gut, stomach and colon; a little bit of basic colon biology and the gut microbiome, which is becoming even more important; diagnosis and assessment of acute GVHD; and the prevention and treatment of acute GVHD, mostly focused on GVHD of the intestinal tract.

(01:56): Stem cells make blood and other vital cells that carry oxygen and fight infection. So, back to the basics here, this is a diagram of your stem cells. These are hematopoietic stem cells. They're blood stem cells that live in your bone marrow. They're very unique cells. When we talk about stem cells, it means the cells have a special property where they can make more of themselves, so these cells can regenerate and make blood for your entire lifetime.

(02:22): These stem cells can do a lot of different things, including making your platelets for blood clotting, your red blood cells for carrying oxygen, and your white blood cells to help fight infection.

(02:31): There are a dozen or so types of white blood cells, but the two most important are the T-cells. The T-cells are the ones that are responsible for cell to cell killing. They're also really critical for distinguishing things that should be in your body versus things that should not be in your body, so your normal cells on your skin or your eyes versus COVID, flu, or a staph infection.

(02:59):  And then the other cells, the ones in orange, are B cells. These are also very special immune system cells. They make antibodies. You may remember back at the beginning of COVID when we took the antibodies of COVID survivors and gave them to people that were sick in the ICU to help get them through their COVID.

(03:17): Allogeneic transplants kill cancerous cells and introduce donor cells. Some of these cells may attack the patient’s body as foreign to them, resulting in graft-versus-host-disease (GVHD). So generally, with an allogeneic stem cell transplant we give patients high doses of chemotherapy to kill more of their cancer. (Going forward, for the purposes of this presentation, I'll use the word  leukemia in reference to all diagnoses, but I realize there's more than one diagnosis that requires transplant.) The side effect of the chemotherapy though, is that we kill the stem cells, so we can rebuild the blood by putting stem cells in the patient from another person. They can make all the blood and red blood cells, but it comes with new T-cells.

(03:53): And those new T-cells, they're going to go into the patient's body and look at how different it looks from the body it came from. And it may react to that body. And the amount that it reacts to that body is the amount of GVHD that the patient will have.

(04:09): However, the T-cells can learn in your body over time. And the plan, if things go well, is that people will not need immune suppression six to 12 months after transplant, as those new T-cells will have learned and adjusted to your body.

(04:26): So, this is the journey our patients undergo. We see them in the first initial consult. We do an evaluation to make sure that their leukemia (or other disease) is appropriate for transplant and that they're fit enough for transplant. We test the heart, lungs, liver, and kidneys.  

(04:47): The better the match between patients’ genes and their donor cells, the more successful the transplant is likely to be. At that first visit, we do HLA typing. HLA is a gene you get from your parents. You get six from your mom and six from your dad for a total of twelve and eight of those are important. So we look for an eight out of eight for a full match donor. We also look at sibling donors. People have about a 25% chance of matching with their siblings. A match with an unrelated donor, depending on race and ethnicity, can range from 40 to 80%. And then we also look at mismatched donors. Given all the donors that we can look at now, 99.7% of people find donors.

(05:25): When we choose a donor, we look at the HLA typing. We look at age and gender of the donor versus the patient, their blood types, and what source of stem cells we're going to use. We use bone marrow or peripheral blood,  which is T-cells collected through an apheresis machine like they do at the Red Cross. Both sources of stem cells can have different impacts on the risk of developing acute GVHD.

(05:54):  After the patient has been through all their testing, we're ready to discuss the plan. This is a very important time because all the choices we're making now can have an impact on the risk of the leukemia returning, ongoing long-term remissions, the risk of GVHD, and the risk of infection.

(06:16): A transplant plan first requires deciding about the intensity of chemotherapy to be used. First, let’s talk about the chemotherapy plan. We have three levels of chemotherapy that can be given with or without radiation. We have full intensity, reduced intensity, or very reduced intensity. Full intensity comes with a slight reduction in the risk of relapse of the leukemia, but comes with more side effects of the chemotherapy, such as more nausea and vomiting, more problems with the liver, severe low blood counts, increased risk of infection, and increased risk of GVHD. Reduced intensity and very reduced intensity come with less damage to the body, but there may be a slightly increased risk of the cancer coming back.

(06:59): Now let’s talk about GVHD. How do we try to prevent GVHD? We're developing new plans to prevent GVHD more effectively over time. The goals of this part of the process are to decrease the risk of relapse as much as possible, decrease the risk of GVHD, and manage the risk of infection so that at the end of the day we improve people's chance of surviving with a good quality of life after transplant.

(07:27): Next, the patient comes into the hospital. Sometimes this can be done in the outpatient setting. They receive four to seven days of chemotherapy, with or without total body radiation. Then they have their stem cell transplant on day plus zero. It's a stem cell infusion. It's like a blood transfusion, perhaps right in the hospital bed. There's no other surgery involved and it's a very exciting day for everybody. It's their new birthday, their second chance at life.

(07:55):  The most standard way we prevent GVHD starts after transplant. On day three and four, we give doses of IV chemotherapy called Cytoxan. Cytoxan is really good at killing T-cells that are growing too quickly. The T-cells that are going to react to the patient's body are going to grow the fastest and the Cytoxan kills them off with two days of chemotherapy. The T-cells that are not going to react as much to the person live on and, over the next several months, rebuild the immune system.

(08:31): We also start other immune suppression at day plus five. The main ones we give are called Tacrolimus or Sirolimus, and they usually go for two to six months depending on the situation. Patients are in the hospital for two to four weeks or in clinic during the intense part of their transplant. At the end, they all want to ring the bell when they leave the hospital and go down the elevator.

(08:56): Transplant survival rates have improved with recent innovations. This shows how we've been making improvements in transplant survival year to year. You can see in 2001, we had about a five-year survival of 40%. That's now up to and higher than, I would say 60% on average for transplant. So, all these little things that we're talking about – donor selection, using different chemotherapy, changing the GVHD prevention, antibiotics to prevent infection – are making improvements in outcomes in transplant.

(09:29): I did want to talk a little bit about HLA. HLA is how we find donors and it's how the immune system tells whether something is from you or from somewhere else. For example, in people with kidney transplants, the HLA doesn't match, so the person's immune system would reject the kidney that's a foreign object in their body. They must be on immune suppression the rest of their lives. With stem cell transplant, the new T-cells can learn the HLA and not overreact to it so that you don't have to be on immune suppression the rest of your life.

(10:04): When we're looking at HLA and donors, we're looking for mostly a full match. That would be an eight out of eight match, but you can see here since we've been using post-transplant Cytoxan, whether you have an eight out of eight match or a seven, eight out of eight match, the survival is the same.

(10:23): And then, the GVHD survival is the same. That's the graph on the left. The graph on the right shows that if you have a seven out of eight mismatch or a four out of eight mismatch, survival is the same. So really HLA is not the most important factor anymore in choosing donors for transplant.

(10:42): The vast majority of patients have good matches, making transplant a viable option for many more people. Age is probably the most important factor and this makes transplant more available to all people. There used to be a lot of people we would have to turn away because they didn't have a good match. Now, 99.7% of people have a good match.

(10:59): So on to acute GVHD of the gastrointestinal tract, the gut. This is caused by the new donor cells attacking the patient's cells that line the colon. This usually happens in the first 100 days. The average onset for acute GVHD is two to seven weeks after transplant, but it can happen at any time, even 180 days afterwards in the right setting.

(11:28): Acute GVHD is not defined by the timing, but by the symptoms. It's a red rash, liver damage, diarrhea, persistent nausea, vomiting, loss of appetite, or weight loss.

(11:42): The incidence of acute GVHD in the gut is 30 to 50% and most of those cases are mild. Moderate to severe cases are less than 10%. Over time, with improvements in immune suppression, we have seen improvements in the amount of severe acute GVHD. When you think about mild, moderate, or severe, mild and moderate have little impact on outcome for the patients. I'm more concerned about the patients with severe acute GVHD.

(12:11):  You can see over the last 20 years, we've made huge improvements in the incidence of severe acute GVHD. Twenty years ago, 20% of people had acute GVHD; 10 years ago, 15%; and with the most recent studies, about 6% have severe acute GVHD. This is particularly important because only 5-20% of people survive severe acute GVHD. So these improvements in preventing severe acute GVHD are critical.

(12:45): There's also chronic GVHD. This usually occurs 4 to 12 months after transplant, around the time that we're removing immune suppression from people. The symptoms of this are dry eyes, dry mouth, and dry skin, but it can affect any organ including the lungs. It's like an autoimmune disorder like lupus or Sjogren's, which is dry eyes. And we treat that with more immune suppression.

(13:09): We've also seen improvements in chronic GVHD outcomes over the past several years. In 2015, about 35% of people had chronic GVHD compared to currently about 21%. And this will be more in the moderate to severe range.

(13:26): Chronic GVHD does come with a benefit though. People with chronic GVHD have less relapse, which means they have more graft versus leukemia effect. That's the new immune system fighting and killing the cancer and providing surveillance so that the cancer will never come back. You don't have to have chronic GVHD to remain in remission though.

(13:50): GVHD is diagnosed based on a patient’s symptoms. How do we diagnose acute GVHD of the gut? GVHD is a clinical diagnosis. It's not based on biopsies; it's based on symptoms. The symptoms we see include a raised red rash, called a maculopapular rash, diarrhea, and damage to the liver based on increased bilirubin. Increased bilirubin turns people's eyes yellow, it's called jaundice. Other symptoms include persistent nausea and vomiting, more than 10% weight loss, and decreased appetite.

(14:18): Biopsies are not required, but if possible, we do biopsies. Skin biopsies are easy to do, if needed. We try to do colon biopsies on a regular basis, especially for people with severe acute GVHD. We want to make sure that it's GVHD, but even more importantly, we want to make sure that it's not a misdiagnosed infection. Liver biopsies are usually not practical during this time but can be done in the right setting.

(14:46): There are factors that increase your risk of acute GVHD of the gut. First is the intensity of the chemotherapy and radiation before transplant. Full intensity transplants cause more damage to the cells that line the gut. Those cells, when they're being damaged, release chemicals that stimulate the immune system to say, "Hey, something is going wrong here," and those new immune cells come in to repair the damage.

(15:09): But the new T-cells that come in to repair the damage are not yet ready for it. They don't know how to behave. They're like a bunch of minions running around with their heads chopped off. And even if they can help repair the damage, they don't know when to stop overreacting to the gut T-cells, and so they damage the gut T-cells as they're trying to heal them.

(15:36): There are other risk factors for GVHD besides HLA matching, which plays less of a role now.

(15:42): Infection is a risk factor for GVHD. One infection that can increase your risk of GVHD is Clostridioides difficile or C. diff, which is a common infection in transplant survivors. C. diff can increase the GVHD risk because of inflammation in the colon. Other infections, such as norovirus, can also increase the risk of GVHD.

(16:05): Damage to the gut microbiome is also a risk factor for GVHD. Your gut microbiome is an amazing complex living organism that has positive interactions with your own gut, as a feedback loop. Your gut helps support the gut microbiome and the gut microbiome helps support your gut, and without one or the other, things don't go well. It is very important to have a healthy gut microbiome.

(16:35): We're going to talk a little bit more about how we assess and grade GVHD of the gut. There are two other grading systems for liver and for skin, but we're going to focus just on gut here mostly with all the lower GI tract.

(16:51): Most people's stool output should be about 200 to 300 milliliters a day. A stage zero would be less than 500 milliliters, equal to half a quart or 16 ounces. Stage one would be persistent nausea or a half a quart to a quart of diarrhea, equal to a liter of diarrhea. And then when we're getting to the moderate to severe forms, grade two, three and four, you would have a liter to over a liter and a half to two liters of diarrhea. I've even seen up to four liters or four quarts of diarrhea.

(17:28): GVHD of the gut can be graded. Grade four is the most severe form, with severe abdominal symptoms, abdominal cramping, and pain. When people have that, let's say they have a liter and a half of diarrhea, we would order a colonoscopy. Usually it's not the full colonoscopy, but a shorter version of one.

(17:50): You can see here on the left is a normal colon. The layers that line the cells are tan; they don't look inflamed. You can see easily through them and you can see the blood vessels coursing through them.

(18:06): On the right, you can see what acute GVHD of the colon looks like. All that texture, and how the light reflects off of it, is gone. It looks like everything has been obliterated. It's like a moon landscape almost. You can even see ulcers here where the T-cells are attacking the colon. All the redness is related to GVHD. It looks like there's a sunburn there, but it's inside the colon.

(18:35): So then, we take a biopsy. The picture on the left is a normal colon, and you can see these little fingers that go into the wall of the colon. Those are called the crypts of the gut, and that's where all the action happens. The stem cells that make the gut, and that make the cells that line the gut, are there. These special cells, called goblet T-cells, make the mucus in the gut and keep the gut healthy. But if you look on the right, that pattern and landscape of a normal gut has been completely obliterated. It's like a bomb has gone off in the gut and all the normal architecture there is gone.

(19:16): This is a better look at what those gut crypts look like. You can see these little indentations that go in a U-shaped pattern. At the bottom of the U, there are very important T-cells called gut stem cells. These are the cells that give rise to all the cells that make the gut. These blue cells are called goblet T-cells, and they make the mucus that lines your gut and protects it from the outside world.

(19:44): Then there’s the healthy gut microbiome. You can see the bacterium. There are a dozen different colors there. They’re all doing different jobs. They’re making butyrate to support the health of the goblet T-cells. Butyrate is a critical fatty acid that helps the gut heal from damage and support gut health.

(20:06):  In GVHD of the gut, the new immune system kills off critical cells in the microbiome. But in GVHD, the new immune system has killed some of these critical cells. You can see the goblet T-cells are dying, so there's no mucus. The gut microbiome is very limited. Only 10% of the micro bacteria that should be there is present and they're not producing the good part that helps support the gut health. The gut stem cells are damaged so the gut can't repair and heal itself. There's a lot of issues going on during this time with damage to the gut from the colon, that the colon is having a hard time dealing with.

(20:40): How do we manage acute GVHD? Acute GVHD doesn't come with the benefit of the graft-versus-leukemia effect. The key strategy is prevention that includes all of the pre-transplant considerations: a healthy gut microbiome, what kind of GVHD prophylaxis we're going to do, what kind of chemotherapy we're going to give, and how much damage is going to be done to the colon. Then we consider the treatments, which are our first-line therapy and second-line therapy. Mostly I'm going to be talking about severe acute GVHD. A lot of supportive care comes into play to get people through this, not just active treatment with medications.

(21:27): I want to talk a little bit more about the gut microbiome. It's a topic that has been rising in interest over the last decade or so. The gut microbiome is a diverse community of trillions of bacteria, viruses, and fungi that are essential for life. You can equate the gut microbiome to the Amazon rainforest or the rainforest in Costa Rica where there's the most diversity on earth of different living organisms, and it works with your gut and supports life.

(21:54): Without the gut microbiome, human life would not be what it is. Transplant patients have a less diverse gut microbiome because they've had a lot of chemotherapy. We give people a lot of antibiotics to prevent and treat infections and by the time people with leukemia or MDS get to transplant, they've been through a lot of chemotherapy and they’ve had nausea. Nutritional status has varied during this time for them and sometimes they have a limited diet which limits the gut microbiome.

(22:25): This picture is a little bit complicated. Honestly, it's very difficult for me to interpret it as well but try to look at it with simple eyes. Each color on the graph represents a different microbe in the gut microbiome. When you have more colors on the graph, that means there's more diversity in the gut microbiome. On the left side, you can see the gut of people who are not transplant patients. There are a lot of different colors for the normal gut microbiome. But on the transplant side, the gut biome is very limited.

(23:03): One is beautiful and has all these great colors. It’s very diverse. It's like the Amazon rainforest. But for transplant patients, it's like Death Valley. There are some things that can survive what they've been through, but not many. And this puts people at risk.

(23:21):  A healthy gut microbiome can be supported by probiotics and prebiotics. So, how can we support the gut microbiome? We can use probiotics. Probiotics are living bacteria that restore the healthy gut microbiome. This can be complicated as we don't know which living bacteria we should give to fully restore the gut microbiome.

(23:39):  Most of the probiotic pills you take over the counter only have one or four or a dozen different bacteria, not the hundreds or thousands of different bacteria that you would need. So prebiotics are. what people are looking at. These are nutrients that are necessary for a healthy gut microbiome.

(23:56): For example, one species of bacteria called Blautia helps protect the gut microbiome, and people who have Blautia have less risk of acute GVHD. Blautia is very critical for making butyrate for gut health and for mucus production for the goblet T-cells.

(24:17): How can we support the Blautia? One way is to increase fiber, particularly fermentable fiber. You get that through whole grains, beans, vegetables, prebiotic foods such as garlic and onions. At the University of Michigan, they've done a study and found that these cells need butyrate to help support gut health. They looked for the best place they could find the highest amount of butyrate, and they found resistant potato starch. This is found in a product like Bob's Red Mill Potato Starch, available at Whole Foods. They gave it to patients after transplant with a decreased risk of acute GVHD of the gut.

(25:05): This study is potentially moving forward with the bone marrow transplant clinical trials network and a national clinical trial to help reduce GVHD. They have patients drink a small cup of the potato starch and water. I'm sure that it wasn't very tasty, but these are some of the things we can do to help support the gut health.

(25:31): Another way to support gut health is antibiotic stewardship. This means that we should be thinking about the antibiotics we're giving people every single day. Certainly transplant can't be done without a lot of infection prevention, but when people have fevers, we should minimize the amount of antibiotics they are on, keep the patient on them for the shortest period of time, and make them as specific to the infection as we can to help preserve the gut microbiome.

(26:01): You need a diverse diet. Generally for diets, I recommend a healthy, well-balanced diet, and per USDA guidelines, that would include a lot of fruits and vegetables, a lot of fiber, less meats, oils, fats, and sugars in smaller amounts.

(26:24): Improved sleep and exercise routines can improve the gut microbiome. There's a lot of data that says that sleep patterns, anxiety, and depression are linked to healthy gut microbiomes.

(26:35): Fecal transplant is the best way to replace the microbiome in the gut, because it has all the bacteria, fungus and viruses that are necessary. But this comes with risks. While we can give all these good bacteria back, there's a chance we could give back a bacteria that's bad, or a virus like norovirus, that wasn't found before we gave it to the patient. So while this is something we're interested in trying as a way to regrow the gut microbiome, we need to be very cautious about this plan.

(27:18): GVHD prevention is important. The main take-home point here is post-transplant Cytoxan, which we've already talked about. Tacrolimus and Cellcept are other medications we use to help prevent GVHD.

(27:29): We can also change the cells we give back to the patients. So when we collect T-cells from the donor, they'll include stem cells, B-cells and T-cells. And we can remove all the T-cells from the donor's blood after we take it out and give it to the patient.

(27:49): When we remove all the T-cells, people don't have any GVHD at all, but if we remove all the T-cells, they also have an increased risk of relapse because there's no T-cell there to kill the cancer or the leukemia.

(28:04): What we're looking at now is removing the T-cells, separating them into the good T-cells and the bad T-cells, and then giving T-cells back over time to rebuild the immune system.

(28:19): Several medications can help with GVHD including Abatacept, Ruxolitinib (Jakafi), and Vedolizumab (Entyvio). There's another medication that's been FDA approved called Abatacept. It works on slowing down T-cell responses. In the first 60 days of giving Abatacept, there is very low, 1% to 5%, risk of acute GVHD, but right now, it has a kind of a limited scope.

(28:42): Other ways for prevention include ruxolitinib (Jakafi), which was the first medication ever approved by the FDA for treating acute GVHD. Now, it's in early studies for preventing acute and chronic GVHD, and in some studies, less than 5% of people develop chronic GVHD.

(29:06): Vedolizumab (Entyvio) is another IV medication. It has completed its clinical trial. This medication is approved for ulcerative colitis, so you can see where it may have a role in preventing or treating GVHD. The data looks promising, but we're waiting FDA approval. I did have a patient recently with ulcerative colitis that we continued his Vedolizumab through the entire transplant and he did very well with no acute or chronic GVHD. You can't make too many judgments on one patient. That's what the clinical trial is for.

(29:43): How do we treat acute GVHD? The first line of therapy is with high-dose steroids. All of these come with numerous side effects, which we'll discuss in a minute. High-dose steroids are up to two milligrams of steroids a day. That would be for most people, 120 to 200 milligrams of steroids, which come with some side effects, but also come with the best and fastest responses.

(30:09): If people aren't responding to steroids in three to seven days, we have the first approved FDA medication for the treatment of acute GVHD, which is Ruxolitinib (Jakafi). This is a pill taken twice a day and we've seen big improvements in 28 day responses and six-month responses for acute GVHD as well as improved survival. This is a key component in treating people with acute GVHD.

(30:37): The next therapy is extracorporeal photopheresis (ECP). This is when we take blood from a patient with GVHD, run it through a machine equipped with a special light that kills the T-cells responsible for GVHD, and then return the rest of the blood to the patient. This is one of the ways that we use to help bring the steroid dose down faster to eliminate some of the side effects from the steroids.

(31:06): Budesonide is an oral steroid. It's a topical steroid that coats the stomach. It doesn't really get absorbed into the bloodstream.

(31:14): Mesenchymal stem cells are approved for the treatment of acute GVHD of the gut for children. Mesenchymal stem cells are in the bone marrow. These are essential cells to help the stem cells do all the things they need to do to – make the red blood cells, white blood cells and platelets – but they also have a relationship with the T-cells and can slow down the active T-cell response. This has minimal side effects. Since there are limited options, it's always reasonable to consider clinical trials.

(31:53): What are the side effects of these treatments? High-dose steroids come with the most side effects: infections, increased blood sugars, diabetes, and people needing to be on insulin. High-dose steroids cause weakness in the legs, especially the thighs, the hips and the shoulders, cataracts over time and bone damage. Some people have damage to their hips and months or years later and may need hip replacement surgery.

(32:18): Ruxolitinib (Jakafi) can cause low blood counts and increase the risk of infection.

(32:26): The main risk of photopheresis, and it's very minimal, is that you need a port or a line, like a dialysis catheter, for this procedure. Anytime you access a line, there is a risk of infection, but it's a minimal risk considering we're accessing these lines anyway.

(32:44): Mesenchymal stem cells really have no side effects. There's a potential for a mild infusion reaction that's probably from the medicine we use to help freeze the cells.

(32:58): Supportive care is critical. When it comes to nutrition for GVHD of the gut, we always prefer to do oral nutrition, but if people are having two liters of diarrhea a day the gut just needs to rest. If you keep putting food into the gut – sandwiches, baked fish, and things like that – the gut won't be able to heal because the lining of the colon doesn't ever get to heal. So a lot of these people are on IV nutrition, which is adequate but not as good as oral nutrition.

(33:33): Almost all the treatments we use increase people's risk for infection, so patients need to be on antiviral, antibacterial and antifungal medications to prevent infection. We monitor for infections on a regular basis.

(33:50): Other supportive care includes physical therapy. We talked about the muscle weakness from prednisone, so a physical therapist comes see the patient. People may be in the hospital for a long period of time. People with grade four GVHD could be in the hospital somewhere between four and 12 weeks. If they do well and recover quickly from their acute GVHD, this may mean they need inpatient rehab or other resources after they get out the hospital.

(34:18): People who have had acute GVHD have an increased risk of chronic GVHD, so we need to pay attention to how we back off on the immune suppression to treat GVHD.

(34:34): On this slide, I've highlighted the things I want you to remember. In summary, allogeneic stem cell transplant remains the only curative option for many blood cancers, but it comes with risks. One of those risks is acute GVHD.

(34:47): Acute GVHD is measured by a red rash, diarrhea, and liver damage. There are many risk factors for developing acute GVHD: the donor's age and HLA; maybe the age of the patient receiving the transplant; the choice of chemotherapy; the choice of GVHD prevention, such as post-transplant Cytoxan; and the choice of treatment for GVHD.

(35:18): Jakafi is the first approved medication for GVHD. It has been critical since 2019 to improve outcomes, even for the most severe forms of grades three and four.

(35:28): Mesenchymal stem cells are also approved, and ongoing clinical trials offer new hope for preventing and treating GVHD.

(35:36): I'd like to thank BMT InfoNet for inviting me to this program. It's been a critical resource for our patients and our families. And I'd also like to thank all the patients and my families who I interact with. We learn from each other every day. There's always something new to learn, and I'll be glad to take any of your questions.

Question and Answer Session

(36:00): Michala O'Brien: Thank you, Dr. Clark. We'll now begin the Q and A session.

(36:03): Once you get GVHD under control, what are the odds of it coming back?

(36:22): Dr. William Clark: Once it's under control, the critical part is tapering the immune suppression over time. The chance of it coming back - it's hard to say a number because it varies for each person, but it's significant. I would probably say 30 to 50%.

(36:41): And it may come back not as acute GVHD, but it could come back as chronic GVHD. So it would be a different form. It's not unusual for someone to have acute GVHD of the gut in the first 100 days that all goes away. We taper the immune suppression and then, when we're tapering the immune suppression, they have dry eyes and a dry mouth, and then we treat that and that goes away. And then they have GVHD of the lungs and then that goes away, and then, they have GVHD of the skin.

(37:17): Michala O'Brien: In slide 23, you mentioned a potato starch or a butyrate. Do you recommend a butyrate supplement for the prevention of acute or chronic GVHD in the GI?

(37:30): Dr. William Clark: ‘Only on a clinical trial’ would be my answer to that, or if you talk to your doctor about doing that. We are not giving patients butyrate off of clinical trial. We'll have a clinical trial open at VCU for that. We are not giving people butyrate.

(37:49): Michala O'Brien: This patient is three years in remission but still experiencing chronic GVHD and C. diff for more than about four times. Is this normal after transplant?

(38:01): Dr. William Clark: It's hard to define what normal after transplant is. I think a lot of different things can be normal, and I certainly have seen patients in this situation. Keeping in close touch with your transplant infectious disease doctors for the C. diff, your local transplant doctors, and maybe GI doctors would be key to helping minimize those symptoms.

(38:25): Michala O'Brien: Is acid reflux associated with the use of prednisone?

(38:30): Dr. William Clark: Yes, we put people on acid prevention while they're on steroids. Heartburn, gastric reflux, gastric ulcers are all things that can be related to use of high-dose steroids. Talk to your local doctor about your specific risk, please.

(38:53): Michala O'Brien What are your thoughts on a probiotic strategy to prevent the recurrence of C diff? What do you think about Florastor?

(39:02): Dr. William Clark: I'm not familiar with Florastor. If there is a probiotic, and we're talking about living bacteria, it's very important to know what immune suppression you're on. Bring the bottle of probiotics to your local doctor and discuss it with them and the pharmacist to see if it would be safe for you to do.

(39:29): Michala O'Brien: Would individuals with GI GVHD follow a plant-based diet?

(39:36): Dr. William Clark: I usually recommend a healthy, well-balanced diet, which would mostly be plants, vegetables and fruit, grains and so on, with some meats and less fats and sugars. A good diet to follow would be something similar to a Mediterranean diet.

(40:01): Michala O'Brien: This person is starting to have some GI issues three years after transplant. Should they see a regular GI specialist or should they see a GVHD GI specialist first?

(40:16): Dr. William Clark: I would usually recommend they start with their transplant physician and they can maybe help navigate the best path for getting to the right resources in the medical system more efficiently.

(40:33): Michala O'Brien: This person has a daughter who had a stem cell transplant six years ago, and she has pain across her stomach in the middle, under her chest. She had her gallbladder removed, and that helped, but she said that she's heard the vagus nerve has been impacted by the stem cell transplant. Does that vein impact the GI functions?

(41:06): Dr. William Clark:  Okay. That sounds like a very complicated situation. I'm sorry that your daughter is suffering. I think that one is hard to answer over the phone and please continue to follow up with your local doctors and ask them those questions. I think that's a unique and specific situation. I'm not sure I can comment on that without knowing more.

(41:34):  Michala O'Brien: Does eating sugar cause inflammation in people with GI GVHD?

(41:41): Dr. William Clark: I think eating excessive amounts of sugar does cause inflammation, especially if your blood sugars are elevated like they would be for diabetics eating too much sugar. I think these foods are limited when people have severe acute GVHD, but part of the IV nutrition does include dextrose, which is sugar. So I think it depends on the situation that you're in. It's hard for me to recommend that cancer survivors and transplant survivors shouldn't be able to have a chocolate chip cookie every once in a while, but the sugar should be in moderation.

(42:33): Michala O'Brien: Does GVHD eventually burn itself out? What are some signs I can look for?

(42:42): Dr. William Clark: When we're talking about GVHD burning itself out, we're mostly talking about chronic GVHD. In that scenario, it depends on the severity and the length of time that you've had it. Sometimes it does get less overtime. I would say people that have severe chronic GVHD, about 30 to 40% of them will not need any more immune suppression two to three years after they start their treatment for chronic GVHD.

(43:18): Acute GVHD can be put into remission. I think we don't usually talk about it as burning itself out because the story is not finished at the end of acute GVHD as there may be a risk of chronic GVHD in the future. Then if people have severe chronic GVHD, we do wait for it to go in remission. That would be the burning itself out. That would be in 30 to 40% of people.

(43:56): Michala O'Brien: Do you have any recommendations for the management of acid reflux with chronic GVHD? Is there any way to prevent it from returning?

(44:09): Dr. William Clark: For chronic GVHD of the gut, we usually have our people on proton pump inhibitors, medications like Prilosec, Nexium, or Protonix. Sometimes, we have a few people on Protonix and on Pepcid at the same time.

(44:19): If you have chronic acid reflux, it may be worth having an EGD where someone takes a camera and investigates the stomach and esophagus to look for damage there. Some people can have Barrett's esophagus and cancer survivors are at increased risk of other cancers. So, in the appropriate setting, cancer screening would be warranted. Talk to your transplant doctor about your specific risk of gastric reflux, how to best treat it, and if there are better options. Then ask if there is a reason for a referral to a gastrointestinal specialist.

(45:06):  Michala O'Brien: What are some of the differences to tell if you've had chronic versus acute GI GVHD?

(45:15): Dr. William Clark: Acute GVHD is kind of easier to diagnose because it would be just a red rash, an elevation in bilirubin, and diarrhea or persistent nausea with a weight loss of more than 10%. Chronic GVHD is more difficult and sometimes you can have both chronic and acute GVHD at the same time. Chronic GVHD would be more like a dry skin rash, dry mouth, and dry eyes. People can have tight skin, so they may not be able to move all their joints to the full extent.

(45:57): Michala O'Brien: This person has random flare-ups in their gut that last about a week, causing pain and digestion, nausea, and fatigue. Is that pattern normal?

(46:13): Dr. William Clark: Lots of things can be normal after transplant. I think it depends on the time since they've been on transplant and what medications they're on, as to what the cause of that would be. I certainly see a lot of those symptoms in the first 100 days, as people are recovering from their chemotherapy and they're having a difficult time advancing their diet. But it really depends on a lot of circumstances for those symptoms. I would have them discuss their symptoms with their doctor to see if there's a pattern to it or if there are other things that need to be investigated.

(46:53): Michala O'Brien: What are some suggestions for a spouse, caring for somebody who feels nauseous quite a bit due to GI GVHD?

(47:05) Dr. William Clark: I know that has a lot of stress for all our people that provide support for my patients and on multiple levels, but nutrition is one of them. So things you can do to support them is just to be patient.

(47:22): We want to make sure they have enough calories, so keep track of what they're eating. It's very difficult for humans to count their calories without getting a calculator or an app to count their calories to make sure they're getting enough nutrition. Focus on the foods that work well for them. If there's a food that's not working for them, whatever it may be, then come up with a different plan.

(47:51): You can always use supplements to help with nutrition as well, but if they don't like Ensure, then try a different brand or a different product. Some centers have nutritionists that can give you advice about nutrition when you come into the clinic.

(48:11): Michala O'Brien: Are there certain foods that you should avoid with GI GVHD?

(48:22): Dr. William Clark: It depends on the amount of GI GVHD, if you have. If you have a grade one upper GI GVHD with persistent nausea and you don't feel like eating, then you can eat mostly what you want if the food is washed and cooked appropriately.

(48:46): But if the food doesn't agree with you, then avoid that food for a few weeks or a month or two and then try it again. I try not to limit food too much, but it's really up to how the person's experience with that food is and everyone's journey is different. It's a little bit of trial and error about what works best for you.

(49:09): Michala O'Brien: This will be our last question for the afternoon. This patient's tacrolimus has tapered off without signs of GVHD. What's the probability of chronic GVHD will decrease as time goes on?

(49:25): Dr. William Clark: Chronic GVHD should decrease as time goes on. The average onset is usually between 120 and 300 days after transplant. Theoretically, the risk could be lifelong, but don't take that as an overstatement. The risk does go down with time.

(49:47): If you had a rash eight years after your transplant, I would be skeptical that that was GVHD unless someone really proved it to me with a biopsy. So, yes, it should decrease over time. Your immune system will get stronger every day that you live, and your new immune system will get to know your body every day that you live, and the risk of GVHD should continue to decrease.

(50:18): Michala O'Brien: Closing. On behalf of BMT InfoNet and our partners, I'd like to thank Dr. Clark for a very helpful presentation. And thank you, the audience, for your excellent questions. Please contact BMT Info/net if we can help you in any way and enjoy the rest of the symposium today.