Graft-versus-Host Disease of the Gastrointestinal Tract and Liver

Graft-versus-Host Disease (GVHD) can affect the mouth, gastrointestinal (GI) tract and liver are affected. Learn the symptoms and treatment options.

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Graft-versus-Host Disease of the Gastrointestinal Tract and Liver

Sunday May 1, 2022

Presenter: Paul Shaughnessy MD, Sarah Cannon Transplant and Cellular Therapy Program at Methodist Hospital, San Antonio, Texas.

Presentation is 32 minutes long with 23 minutes of Q & A.

Summary: Half of patients who have a stem cell transplant using donor cells (an allogeneic transplant) develop chronic graft-versus-host-disease (GVHD). In up to a third of those patients, GVHD affects the mouth, esophagus, stomach and/or GI tract. GVHD can also affect the liver and/or pancreas. This presentation describes the symptoms and treatment options for GI and liver GVHD.

Highlights:

  • Risk factors for developing GVHD include older age, males transplanted with cells from a female donor, use of cells from a mismatched donor, use of peripheral blood stem cells rather than bone marrow and an intense conditioning regimen.
  • GVHD in the GI tract and liver can mimic other diseases. Biopsies and other tests are often needed to make an accurate diagnosis.
  • Treatment with post-transplant cyclophosphamide can reduce the risk of developing GVHD.

Key Points:

(08:36): Use of very broad-spectrum antibiotics after transplant can destroy the good bacteria in our bowels and lead to more GVHD.

(11:46): GVHD can damage saliva glands in the mouth, causing dry mouth, mouth sores and an increased risk of cavities or periodontal disease

(13:32): Several therapies are available to add back moisture to the mouth.  

(16:34): GVHD can cause stomach upset, diarrhea, malabsorption, malnutrition and weight loss.

(18:11): GVHD in the esophagus can cause esophageal webs and difficulty swallowing.

(22:21) Jaundice and an increase in bilirubin may be a sign of GVHD in the liver.

(25:29): Mild or moderate GVHD may be treated with localized or topical agents. Severe GVHD is typically treated with systemic corticosteroids or calcineurin inhibitors.

(26:24): Jakafi and Rezurock have recently been approved by the FDA to treat GVHD that does not respond to steroids.

(28:14): Extracorporeal photopheresis, which is FDA-approved for patients with cutaneous T-cell lymphoma, can also help patients with GI or liver GVHD

(30:30): Several specialists including dentists, gastroenterologist, nutritionists and physical therapist may be needed to effectively treat GVHD.

 

Transcript of Presentation:

(00:00): [Mary-Clare Bietila] Introduction. Hello, my name is Mary-Clare Bietila, and I'm welcoming you to the workshop Chronic Graft-versus-Host Disease of the Gastrointestinal Tract. It is my pleasure to introduce today's speaker, Dr. Paul Shaughnessy. Dr. Shaughnessy is the program Medical Director for the Sarah Cannon Transplant and Cellular Therapy Program at Methodist Hospital, San Antonio, where he closely follows transplant patients and helps them manage challenging medical situations. His research focuses on stem cell mobilization, and improving the treatment of graft-versus-host disease. Please join me in welcoming Dr. Shaughnessy.

(00:44): [Dr. Paul Shaughnessy] Overview of Talk. Great, well thank you very much. It's really my pleasure to be here and talk to patients about graft-versus-host. We'll focus on graft-versus-host disease of the stomach and bowels and the liver. I'm the Medical Director at the Sarah Cannon Transplant Cellular Therapy Program at Methodist Hospital in San Antonio, Texas. Been here for over 20 years now, treating transplant patients.

(01:12): Today's agenda is we're going to talk a little bit about the pathophysiology and incidence of GVHD, and specifically GVHD of the GI tract and liver, and as well as prevention ideas and therapies for both of these entities.

(01:30): Using stem cells from the peripheral blood (bloodstream) for transplant, as well as the intensity of the conditioning regimen, impact the risk of developing GVHD. So, a little bit about the overview of chronic graft-versus-host disease. And I know Dr. Alousi gave a wonderful presentation and overview yesterday, but just to further explain that when we do an allogeneic stem cell transplant, the bone marrow stem cells can come from the peripheral blood or the bone marrow. And, of course, that can impact the incidence of graft-versus-host disease because there are many more lymphocytes or immune cells in peripheral blood. Our conditioning regimen, and how intense it is, can cause tissue damage and affect graft-versus-host disease.

(02:06): And then why do some people get graft-versus-host disease, and some don't, even with the same type of donor or transplant. And honestly, there are things we don't understand about immune reconstitution, but it can be very complicated as the immune cells are re-educated through the thymus, and we develop reactivity to viruses and expand the repertory of our immune system. And we can have normal immune reconstitution, and no graft-versus-host. Ideally, we get no graft-versus-host, but maintain that immune effect of graft versus leukemia to prevent relapses from transplant. And of course, sometimes we can have the alloreactive immune cells develop where the immune cells see the normal tissues as different, and we'd have immune dysregulation and acute and chronic graft-versus-host disease.

(02:58): There are two types of GVHD: acute and chronic. They can occur at any time after transplant. This slide just shows that there is an overlap of acute and chronic graft-versus-host disease, things don't just change at day 100. We generally do see acute GVHD before day 100, but it can certainly happen after that. And chronic graft-versus-host disease can develop earlier before day 100 and it can run a much longer course. It can develop after six months, and even after a year's time, I've seen chronic GVHD develop. A lot of that has to depend on when we taper the immune suppression. And when that graft fully comes in and can become alloreactive.

(03:42) I won't go over everything on this slide. I think Dr. Alousi did an excellent overview of all the different manifestations of chronic GVHD. But this is just to show that it is a very variable disease that can affect many different organ systems, some not even listed on this slide, with many different presentations.

(04:01): Older age, female donor to male patient, and donors who are transplants, and using a mismatched donor increases the risk of developing GVHD. And today, as mentioned, we'll focus on the GI tract and the liver. Now first a little bit about the risk factors, because the best way to prevent chronic GVHD is to prevent getting any graft-versus-host disease. But we know we can see when we have older age of a patient, and that's as we live our lives and we get more exposed to antigens immune stimulation in our life, our immune systems can react to that new bone marrow graft.

(04:34): When we have a female donor to a male patient, there can be some alloreactivity and graft-versus-host disease, especially when female donors have had prior children and have those extra antibody exposures from the pregnancies they carried, that can actually lead to increased graft-versus-host disease In patients.

(04:54): Having [a] mismatched [donor] - obviously the better matched a transplant is the less graft-versus-host disease we see. But even a fully matched transplant - If you're not an identical twin - there are still many minor differences of the immune system that can lead to acute and chronic graft-versus-host disease.

(05:12): Using peripheral blood cells for transplant, instead of bone marrow, increases the risk of developing GVHD. I already mentioned the peripheral blood stem cells do definitely have a higher incidence of acute and chronic graft-versus-host disease compared to bone marrow stem cells. And the reason is when we get stem cells out of the peripheral blood, they're very good stem cells. They work just as well and engraftment can be very swift and complete. But there's more immune cells when we put that graft in, and that can lead to more acute and chronic graft-versus-host disease.

(05:42): CMV reactivation, and the stem cell dose can be important. And I believe the stem cell dose can be a surrogate for just more immune cells.

(05:52) Younger donors and cord blood donors are associated with lower rates of GVHD. Things [that] decrease graft-versus-host include younger donors When we look for unrelated donors or family members, we like those young adults who haven't been exposed to a lot of prior antigens or had pregnancies.

(06:08): Cord blood has been described of having less chronic GVHD. That may be because those very immature stem cells can cross those immune differences better.

(06:19): Post-transplant cyclophosphamide can reduce the incidence of GVHD. Using things in the preparative regimen like ATG and Campath and what's not mentioned here is cyclophosphamide. And I think cyclophosphamide has really revolutionized crossing immune barriers and decreasing the incidence of acute and chronic graft-versus-host disease.

(06:37): GVHD affects many organs, most often the skin, mouth and eyes. This slide just shows in different types of transplant - mismatched, haploidentical, umbilical cord – and the general incidence [of GVHD) in the different organ systems. So that's why I show this, just to show that we see more GVHD in skin, mouth and eyes, the GI tract is still over 50% and the liver a little bit less, and it can affect many different organ systems.

(07:04): Optimizing the donor match is the best way to prevent acute and chronic GVHD. What about therapies to try to prevent? As I mentioned, probably the most important thing to prevent both acute and chronic graft-versus-host disease is optimizing that match. And of course, when we match people, that means we're matching the major genes of the immune system. And that's why we look at these 10 or 12 areas that make it acceptable to do the transplant. But there are always many minor mismatches of the immune system, since you're not identical twins, that can lead to graft-versus-host disease.

(07:41): The use cyclophosphamide after transplant can reduce the risk of developing GVHD. Good graft-versus-host disease prevention as you go through your allogeneic transplant - using Prograf or cyclosporine and methotrexate - has been very common. The use of post-transplant cyclophosphamide - and I think for people going through their transplants now, they may see this more and more. This kind of revolutionized doing haploidentical transplants, but [we’re now] moving this into matched unrelated or even matched related sibling transplants. The unique thing about cyclophosphamide [is that] it's very good at immune suppression after the transplant, but it doesn't hurt the bone marrow stem cells and doesn't stop them from engrafting. And this has really helped allow us to have better engraftment and less graft-versus-host disease, especially less chronic graft-versus-host disease.

(08:36): Avoiding the use of broad spectrum antibiotics that destroy gut or bowel microbiota is important. Now using the broad spectrum antibiotics, of course, is often very necessary as people can get sick and get infections going through their transplant. But [we try] to avoid those very broad spectrum antibiotics that can affect the gut microbiota. Many of you are probably aware, we're learning more and more how the gut microbiota - all the healthy bacteria that live in our bowel - are very important to our immune health.

(09:05): And before transplant or going through transplant, avoiding use of antibiotics [that] can hurt the good bacteria in our bowel can be helpful. And many studies are confirming that now.

(09:18) Probiotics and fiber are important for good gut health. I mentioned your use of probiotics and fiber. Now always talk to your own transplant physician or specialist about any type of supplement or something that you use, but probiotics to support good bowel health and fiber can be very important. Of course, we don't want to do these, maybe, when you're neutropenic or early after a transplant, but maybe later on when your counts have recovered, and these can be helpful to just support good bowel health.

(09:50): An increase of bad bacteria in our gut can lead to more GVHD. Now, just a little bit more about the gut microbiota. This slide shows on the left, a healthy GI tract. You see what we call a crypt. And that U-shaped crypt in our bowel, we have thousands of these throughout our bowel. And there's a mucus membrane on top of that, and important cells, like goblet cells, that protect our bowel and keep the bad bacteria out, and give us good bowel health and allow good bacteria to support our immune system.

Radiation, chemotherapy, going through a transplant or graft-versus-host disease can damage our GI tract and allow bad bacteria, like enterococcus, to overtake and grow and good bacteria to become less. And so it's not a perfect balance, but the overall balance of our GI tract is very important. And when we have more bad bacteria and less good bacteria, that can lead to more graft-versus-host disease and worse outcomes with transplant. So trying to maintain that balance through transplant is something we're actively researching at many centers.

(11:09): More than half the patients with GVHD have symptoms in their mouth. Chronic GVHD of the mouth occurs in over half of all transplant patients and can take several forms. I did want to talk briefly about graft-versus-host disease of the mouth. I think this is part of the GI tract. Chronic GVHD of the mouth can be seen in over half of patients who go through transplant. They often have classic changes on the inside of their cheeks, called the buccal mucosa and [on] their tongue. We can see these lacy white changes called lichenoid changes. We can even see changes on the lips.

(11:46): GVHD can damage saliva glands and increase the risk of cavities or periodontal disease. Very often, people have dry mouth or xerostomia. And whether that's from the chemotherapy or radiation, we don't make saliva quite normally after a transplant. And, of course, the graft-versus-host disease can damage those salivary glands and prevent normal saliva production as well. And having dry mouth is very important to the health of the gums and the teeth. Having saliva to always be washing our teeth and preventing carries [cavities] and periodontal disease is very important.

(12:17): GVHD can cause redness, inflammation, ulcers, thinning of the mucosal and mucous blisters in the mouth. So other manifestations, we can see redness and inflammation of the mucus, the inflammation of the gums or gingivitis, and ulcers of that can hurt when we eat, the thinning of the mucosal and what we call mucoceles [which are] little mucus blisters that pop and come and go. We can also see pseudo membranes and these whitest streaks called lichen-planus. And all of these, we can follow, very characteristic of graft-versus-host disease of the mouth.

(12:54): Any changes to these over time should be evaluated by a dentist. And I really do think getting in with a good dentist or oral surgeon to help follow these changes, if they persist, can be very important.

(13:10): Now this slide is in black and white, but I think it shows well the inside of the cheek, [where] you see those lacy white line, tat's the lichenoid changes of the graft-versus-host. And just seeing this is diagnostic of graft-versus-host disease. And we can also see many other manifestations as well.

(13:32): Several therapies are available to add moisture back to the mouth.  So, things we can do. Some people have a little dry mouth and you can just hydrate well or use things like Biotene to help support the oral health and moisture of the mouth. Artificial saliva can be prescribed. And that's very important to use if your physician prescribes that.

(13:55): If people have pain or cannot eat, Decadron and tacrolimus rinses can be used relieve the pain. Now, when it starts to hurt, or people are losing weight, or they're having pain and can't eat what they want to eat, then we can intervene with medicines such as Decadron rinses. We try to avoid the systemic effects of steroids by just having the Decadron rinse in the mouth, around the gums, around the inside of the cheeks, and that can help decrease some of that inflammation. It's like, instead of putting topical steroids on your skin, you're putting topical steroids on the inside of your mucosa.

(14:28): Now that can also be done with tacrolimus. Where probably many of you are used to having tacrolimus as a pill you take early after your transplant, you can dissolve tacrolimus in the saline solution and then rinse and spit it. And you can actually combine the Decadron rinse with the tacrolimus rinse. And this has been well described in study to help control graft-versus-host disease of the mouth.

(14:55): Now, anytime we're doing this, we need to be careful about getting viral infections in the mouth or overgrowth of yeast, which is thrush. And so, many times, if you're on this, you need to be on something to suppress yeast in the mouth, antifungals, as well as we follow closely for any viral outbreaks in the mouth.

(15:17): Having a good dental provider review, twice a year, the impact of using steroids in the mouth on overall oral health is recommended. Hygiene is also very important. We should all have good relationships with a dental provider, a good dentist, or even an oral surgeon to really look over, not just once a year, maybe a couple times a year, using oral steroids or immune suppression. Having decreased saliva production can affect the health of the teeth, but also of the periodontal area and periodontal disease can be very important. Anything [like] a new ulcer or lesion, or a white plaque that persists for awhile should be evaluated by a dentist or an oral surgeon to see if biopsy is necessary.

(15:58): Up to a third of patients with chronic GVHD have symptoms in the esophagus, stomach and/or lower GI tract. Now moving to the rest of the gastrointestinal tract, from the esophagus down to the stomach and the lower GI tract. We can see up to one third of patients be affected with chronic GVHD here. It can range from difficulty swallowing and a very classic finding is an esophageal web, which is a little a protrusion that could prevent normal swallowing of especially dry food. And we can also see just stiffness of the esophagus as well.

 (16:34): GVHD can cause stomach upset, diarrhea, malabsorption and weight loss. People can have upset stomach or diarrhea and malabsorption or weight loss. And if we start to see people losing weight or, in young children, failure to thrive, then that's a sign that we need to look and see, do we need to intervene and help with why they're having these symptoms. Now very important when we see these things, having a good gastroenterologist and a gastroenterologist who knows graft-versus-host disease is very helpful. We need to do biopsies of the esophagus or stomach or the bowels to figure out, is it graft-versus-host, or is it an infection? Is it a virus? Is it something else that could be going on? '

(17:15): GVHD can affect the pancreas, the organ that makes enzymes to help us digest food. So the other thing we can see is the pancreas - which is an organ that makes enzymes [that] help dissolve our foods in our GI tract - can be affected. And when you're not making normal enzymes to dissolve food, you can get fat in your stool and undigested food in your stool. And if people are seeing that frequently, then that may be something also. We can measure pancreatic enzyme levels, and we actually can [inaudible] pancreatic enzymes and pills to help with replacing those pancreatic enzymes. A  gastroenterologist can do an endoscopy, and that means doing scopes down the esophagus into the stomach or through the rectum and into the bowels, to look and see why you're having these issues and look for classic findings.

(18:11): Upset stomach, diarrhea, and difficulty swallowing, and esophageal web can all be manifestations of GVHD. I mentioned the symptoms we can see, the upset stomach, the dysphagia, which means difficulty swallowing, and diarrhea. I mentioned the esophageal web, which is a classic finding we would see on endoscopy when we're down there doing this. And really just seeing that is diagnostic of chronic graft-versus-host disease. But, of course, we do biopsies and we prove it by looking under the microscope as well.

 (18:39): Malnutrition may be helped by a dietitian. So having malnutrition is also a big part of this and seeing a dietitian, and sometimes changes to the diet, at least temporarily, can help with better absorption of food. Or being on supplements can help us get over these, maybe, acute exacerbations until we get better and can absorb food better.

(18:59): It’s also important to distinguish C. diff, CMV, or colitis from GVHD to treat each issue effectively. We do want to rule out other things like C. Diff. Many of you may know about C. diff. It can be an overgrowth of a bad bacteria and it makes a toxin that can lead to diarrhea. And cytomegalovirus, is a common virus many of us have been exposed to. But when cytomegalovirus or CMV invades tissue, it can cause colitis and other infections that can lead to diarrhea and stomach upset. So very important to see the gastroenterologist, get these endoscopies done and get these biopsies to help rule out these other etiologies and find out if it really is chronic graft-versus-host disease.

(19:43): We can manage the diarrhea with antidiarrheal agents. We try to avoid those systemic steroids when we can. We can also use steroids like beclomethasone or budesonide, which you can swallow, and they coat the upper tract or the lower tract to give some steroid effect to the inside of the bowel, without giving a whole-body effect of steroids.

 (20:11): A gastroneurologist can help with swallowing problems. And then I'll mention a little bit about the gastroneurologist [who] can go into the esophagus and dilate the esophagus when there are strictures or the esophageal webs that need to be addressed, to open the esophagus and make swallowing much easier.

And nutritional supplements - seeing a nutritionist -and the pancreatic enzymes when necessary. Well, that's probably more of a rare incident that we need to do that.

(20:39): Esophageal dilation can help with swallowing. Now this slide just shows what's involved in esophageal dilation. Some of you may have gone through this already. And whether you get a localized stricture, or there's more like diffuse thickening and stiffness of the esophagus, then these slight enlarging tubes can be passed down. Now, this is done under sedation in the gastroenterologist office as an outpatient procedure. And you just dial up that stricture until it's more easy to pass the food. And this can be very individualized to the size of the person as well and how tight the stricture is.

(21:21): And another example would be to use more of a balloon approach where they can go in and actually blow up a balloon through a little catheter to address like one stricture and just carefully adjust how that dilation is done. Now, sometimes these do need to be repeated. And esophageal dilation for people with chronic GVHD of the esophagus can sometimes need to be repeated every few months or so, but it can lead to much easier swallowing and improved nutrition.

(21:55): The liver can be affected by GVHD. Now, what about the liver with graft-versus-host disease? Another very important component. We know the liver can be affected by acute graft-versus-host disease, but it is really a little different for a chronic graft-versus-host disease. I put this slide up again, just to show that although, maybe less involved overall than the skin and the mouth, that the liver certainly is a very important target of chronic graft-versus-host disease.

(22:21) An increase in bilirubin and jaundice may be a sign of GVHD in the liver. Things we can do for the liver that we watch out for: the increase in the bilirubin is one area where there can be the subtle increase in the bilirubin, and which is a marker of how our bodies [are] getting bile down into the GI tract to dissolve food and nutrients. And if this starts to back up in the liver, and if the bile's not getting out of the liver, then we need to think, is it a gallbladder problem? Is there some problem with the liver or can it be direct damage like graft-versus-host disease?

So, jaundice is what we see when the bile backs up and isn't really getting out of the liver like it should. And that's why we can see the yellowness of the eyes or of this skin. People can feel just not like eating and have anorexia or the upset stomach as well.

(23:14): Liver GVHD can mimic hepatitis or inflammation of the liver. Biopsies may be needed to distinguish GVHD from other issues. And another form of GVHD of the liver can be more of a like a hepatitis. And that means just inflammation of the liver. So, you'll see liver enzymes, like the alanine aminotransferase, start to go up and that can be associated with other enzymes. And that can go up quickly and sometimes we need to do liver biopsies and figure out, ‘is this a viral hepatitis? Is it damage from graft-versus-host disease? or some other drug effect [that]can do this as well?’ So knowing what's going on with the liver and needing to do a liver biopsy to really rapidly figure this out [may be needed] , because, as you can imagine, the treatment of graft-versus-host with immune suppression is not good if this is a liver virus like hepatitis. So very important to make a prompt diagnosis when we rapidly see those liver enzymes go up.

(24:14): The treatment for liver GVHD is systemic corticosteroids. Now, when we need to treat. If liver enzymes are rapidly increasing, then as the mainstay for all chronic graft-versus-host disease, when we need systemic therapy, it's usually with corticosteroids. And whether prednisone or Medrol, there can be different ways of dosing, IV or orally. And if you're not still on Prograf, we can add back a calcineurin inhibitor, which is Prograf or other agents, if needed, to try to settle down that chronic GVHD.

(24:51): If steroids don’t control liver GVHD, other agents like Imbruvica, Jakafi, Rezurock or extracorporeal photopheresis (ECP) may help. Now, if steroids are not working, or every time we try to taper the steroid, we see these symptoms increase, then we can add secondary agents. And we do have Imbruvica now. I don't have that listed here. That came out a few years ago. I have the recent ones that just came out in the last year. Ruxolitinib, which is a JAK kinase inhibitor. And now belumosudil, which is a ROCK inhibitor. And I want to mention extracorporeal photopheresis, which has been around for a long time. Many of you may have seen or heard about.

(25:29): Mild or moderate GVHD of the GI tract may be treated with localized or topical agents. This flow diagram just shows, for all GVHD. But when we see GI tract graft-versus-host disease causing organ damage, and people are being hurt by it, and we want to intervene systemically, we can follow this. Is it mild, moderate, or severe graft-versus-host disease? And if it's mild or moderate, maybe we can use localized or topical steroids such as the Decadron swishes or Prograf swishes of the mouth or doing things like dilating of the esophagus.

(26:05): For severe GVHD, systemic corticosteroids or calcineurin inhibitors may be needed. When GVHD is severe and people are losing weight, they can't eat or drink, or liver enzymes are rapidly increasing, then we may need to add systemic corticosteroids. And if those don't work, adding back the calcineurin  inhibitors and the other secondary agents.

(26:24): Jakafi and Rezurock have recently been approved by the FDA to treat GVHD that does not respond to steroids. I wanted to review some of the newer drugs we have out now, that have now become FDA-approved for treating steroid refractory chronic graft-versus-host disease. So, beyond steroids, beyond Imbruvica, we now see Jakafi. And by JAK1 inhibition, [Jakafi} has been shown to really help people with many different forms of chronic graft-versus-host disease. But just focusing on the liver and the GI tract, you see over here on the right side of this graph from the REACH3 study that was done looking at Jakafi and people with chronic GVHD who had failed steroids, you see overall response rates are much improved, almost doubling with the Jakafi compared to not using the Jakafi to treat chronic graft-versus-host disease.

(27:16): And the same for belumosudil (Rezurock), which now has just been approved. And this is the ROCK inhibitor which also may have some activity against fibrotic pathways. So, we're very interested in this agent. And using it long term, can it help with some of those deep fibrotic changes that we see with chronic graft-versus-host disease?

And also in this bar graph, you see specifically for the liver and GI tract, a very high complete response rates and overall response rates in these organs. So [it's] very exciting to be able to have now these FDA-approved agents, working through these different pathways, that we can use in the future to one treat people with a graft-versus-host. Many studies are ongoing to use these agents together, or in ways to maybe prevent graft-versus-host disease.

 (28:14): Extracorporeal photopheresis, which is FDA-approved for patients with cutaneous T-cell lymphoma, can also help patients with GI or liver GVHD. One other treatment I want to mention, because some of you may see this, and have questions about it, is extracorporeal photopheresis. For severe graft-versus-host of the liver or the lungs, I think photopheresis can be effective. And what this involves is taking blood out of the patient, separating out the red cells and giving them back to the patient. But the white cells are then mixed with a drug called Uvadex. The Uvadex causes DNA breaks in the white blood cells, and ultraviolet light is shown on [the cells] that to cause these breaks. And then those dying white blood cells are put back into the patient and those dying white blood cells tell the immune system to settle down. And this procedure's FDA approved to use in cutaneous T-cell lymphomas. And it's been used for many years, decades, in graft-versus-host disease with good response, especially in stubborn things like gastrointestinal GVHD or liver graft-versus-host disease.

(29:30): New agents are being studied to prevent or treat GVHD. Now I'll also mention there are many new agents out there that we're studying for treatment of graft-versus-host disease. And also agents we're studying to try to prevent graft-versus-host disease. And I still think the best way to counteract chronic graft-versus-host disease is to prevent any acute graft-versus-host disease in the first place.

(29:53): So, we know, in conclusion, that about half of all transplant patients are affected by chronic graft-versus-host. Sometimes I have patients in my clinic that are there for many years on low levels of immune suppression to manage their symptoms, prevention and treatment are getting better.

(30:11): New treatments like post-transplant cyclophosphamide have reduced the incidence of chronic GVHD. And I do think, especially with things like post-transplant cyclophosphamide, we are actually seeing less chronic GVHD over the last few years. I'm doing much less photopheresis and much less treatment of chronic GVHD because of the interventions we've made in just the last five years or so.

(30:30): Many different specialists may be needed to properly diagnose and treat GVHD. Oral or gastrointestinal and liver graft-versus-host disease could be mild and may [be] just managed symptomatically or can be severe and hurt people and cause symptoms. And people can lose weight or be more acutely affected. And we have to bring in for oral GVHD, or dentists and oral surgeons for the GI tract, especially with the esophagus and doing those endoscopies. We need our gastroenterologist to be able to see our patients and do those endoscopies and biopsies to confirm diagnoses and even help us address some of these treatments. So with that, we can be very effective in treating these specific forms of graft-versus-host disease. And I know many of my patients, with the help of my consultants, the dentists, the gastroenterologists and others, have really helped people live better lives with their chronic graft-versus-host disease. So with that, I will stop and I'll be happy to take questions from the audience and I'll turn it back over to let me know what the questions are?

Question and Answer Session

(31:40): [Mary-Clare Bietila] Thank you so much for this excellent presentation. We are going to take questions now. Our first question can high ferritin levels contribute to GVHD of the liver?

(32:01): [Dr. Paul Shaughnessy] The answer is yes. But with a caveat. So ferritin is something, it's a measure of a protein that stores iron in our body. And of course, we get lots of iron from lots of blood transfusions as you go through your treatments and that can cause inflammation and damage to the liver. And that inflammation, I believe, can lead to, just separately, graft-versus-host disease.

So iron overload, itself, can be damaging to the liver and that can lead to inflammation and forms of chronic GVHD as well. So, the real treatment for that would be to try to either chelate iron out of the body, or do phlebotomy if you've got good blood counts, and get that iron out of the body so it doesn't lead to this long-term damage to the liver, whether it's directly from the iron overload or from inflammation from that.

(32:56): Now I also mentioned isolated high ferritins can happen just from inflammation. So, when people get sick in any way or infected, or have anything inflammatory going on in their body, the ferritin levels can go up. So, an isolated ferritin needs to be evaluated to see 'why is that happening? Is there some other reason or inflammation going on?, Is really related to iron overload?' Then we can do studies to prove that, or even liver biopsies to look for iron overload in the liver and answer, 'is it graft-versus-host or is it just iron overload?' So a very important marker. We do follow the ferritin, but it can be a false marker sometimes if there are other forms of inflammation.

(33:46): [Mary-Clare Bietila] Alright. Interesting. Thank you for that. Our next question is, Is it typical to see a GI GVHD flare up, if you're going through a transition in your GVHD management medications, such as a transition from Jakafi to Rezurock?

(34:07): [Dr. Paul Shaughnessy] Anytime there's a change in medicines, you can see a flare of any type of your graft-versus-host. So yes, that is possible because there could be a dip in the real control of the immune suppression from the medicines that are being used. And sometimes we'll use pulses of steroids to control the GVHD as we taper off one medicine to go onto a different medicine.

(34:33): Now, the other thing I'll mention is all of these medicines, the ibrutinib, the Jakafi, the Rezurock, they can have side effects themselves. And some of those side effects are causing stomach upset and diarrhea. So, if you're switching from one medicine to another, and now all of a sudden you've got diarrhea that you didn't have before, it's possible it's just related to the medicine itself. And sometimes you need a lower dose of it, or just some time to adjust to being on the medicine. It doesn't mean that GVHD is worse. It just may be a side effect of the medicine. And I always say any medicine can have any side effect. So as good as these drugs are at treating the GVHD, we do need to be aware they could cause stomach upset, diarrhea, things like that to be aware of. And those could be managed symptomatically. [So] give yourself some time to see if your other symptoms of GVHD improve.

(35:34): [Mary-Clare Bietila] That is important to know. If treatment quickly gets liver chronic GVHD under control, how soon will steroids begin to be tapered? And they also are curious, how long does it take to determine if a response is durable and finally, what is the timeline for tapering immunosuppressants?

(36:01): [Dr. Paul Shaughnessy] I think it's a great question for all types of drugs that we use. But when it comes to steroids for acute and chronic GVHD, there's kind of some general rules we go for, and these are things you should talk to your transplant provider about. Sometimes there are different reasons when we taper, or don't taper. Generally, we would like to keep the steroids on for a solid week to see what the response is, and to try to maximize that response. So, if we put steroids on and somebody's just starting to improve, well, we might keep them on at that same dose for one or two weeks to really try to improve their symptoms. And then once we see improvement and some stability, usually after one to two weeks, initially, then we'll start tapering. And, generally, we try to do about 10% of the dose per week, and every week make these little adjustments.

(36:59): Now, if a week goes by and your symptoms are a little worse that week, then maybe we don't lower, or we look for other reasons why that may be going on. So, generally, when we start steroids, they do work the quickest of any treatment we have. Steroids work the quickest. Usually within one to two weeks of initially starting them, we are starting to taper. We generally try to do about 10% of the dose every week to bring down. And I always tell my patients to be prepared when we get to very low doses of the steroids, start to get down to 10 milligrams or less of prednisone, sometimes we have to go even slower on the taper. Just little changes can cause flares of the graft-versus-host disease. And also people are safer at those very small doses of steroids. So, we can go slower and try to prevent those flares. So ,did I answer all those questions?

(37:57): [Mary-Clare Bietila] I think you did. Our next question is what are the typical symptoms one might feel if their liver counts are too high due to chronic GVHD?

(38:08): [Dr. Paul Shaughnessy] That's a good question, because you may not feel any symptoms at all. You don't really feel the liver, and that's why we check the liver enzymes usually at every visit. When you're out past day 100, or you're at the six-month mark, we might be doing it only once a month or so. And that's why usually we'll check the chemistries, the kidney tests and all of the liver enzymes in the bilirubin, to screen for that and look for those changes. Now, if you are feeling changes, the liver can swell sometimes when it gets inflamed and there is a capsule around the liver and that can hurt. So, if the right side of your belly starts hurting, or if you start to notice, somebody tells you, gosh, you're looking yellow or jaundice, then you may want to call your doctor up and say, 'Hey, I think my eyes are looking yellow, my stomach's hurting on the right side'. And then you might want to go in and be checked out sooner than later.

(39:11): And I'll tell you, one other thing I see commonly in patients, gallbladder disease can develop after a bone marrow transplant. You can have gallstones. A gallstone can get stuck and you can get cholecystitis or inflammation of the gallbladder. And that's something else that needs to be looked for. And chronic gallbladder disease can lead to anorexia and pain with eating and diarrhea. And sometimes we need to just take out the gallbladder [so] those symptoms can get better. But real GVHD of the liver is actually rarely painful. When it is, it would be more advanced and you'd want to tell your doctor about it . And it's an easy thing to do then to check the liver enzymes.

(39:57): [Mary-Clare Bietila] Always important to report any and all symptoms to your doctor. The next question is this individual started Jakafi and it is greatly improved their chronic GI GVHD. And they were curious about the long-term negative effects on the body and how long it is safe to be on such a medication?

(40:22): [Dr. Paul Shaughnessy] Yeah, good question. And so even though Jakafi has been recently [been] FDA-approved for chronic GVHD, it's actually been FDA-approved for a long time for a disease called myelofibrosis, for years and years. And there are some people out there who have been on Jakafi for years of time and are doing just fine on it. Now it does need to be monitored. We want to check the blood count. Jakafi can cause decreased blood counts. It is an anti-inflammatory and there is obviously an immune suppressive effect. So anytime you're on long-term immune suppression, screening for secondary skin cancers or secondary cancers of any type, monitoring blood counts, those kind of things would be very important, but I've seen people stay on Jakafi for months or years of time and do just fine.

(41:14): And then it's always a question what's more important - to get off the steroid you were on and be off the steroids, but live a little longer on the Jakafi? So sometimes we try to get off the steroids, even if it means staying on the Jakafi longer, eventually. Yes. It's nice to get off all the immune suppressants just to allow the immune system to be more normal at that point.

(41:41): [Mary-Clare Bietila] Our next question is about bilirubin. This person's direct bilirubin is normal, but their indirect, it is elevated. Is an elevated indirect level concerning?

(41:55): [Dr. Paul Shaughnessy] I was just going to say about the direct bilirubin. It's really the direct bilirubin. What we worry about is the bilirubin getting stuck in the liver and damaging the liver. The indirect bilirubin is more out in the blood vessels from red cells being broken down. So indirect bilirubin can be a sign of hemolysis, but usually not of liver damage or graft-versus-host disease.

And there is something called Gilbert's disease, which many people out in the population have, and you can see your total bilirubin is little elevated, but it's all indirect. That actually is something we just watch and observe and don't necessarily do anything about. If it's a new thing for you, that can be a sign of [whether] there is some hemolysis going on. And if your donor was a different blood type than you when you did the transplant, we can see that sometimes. So, this should be something, I'm sure that's being monitored by your transplant provider. And they can address why this is going on with you, but indirect bilirubin is actually less concerning for chronic GVHD of the liver.

(43:06): [Mary-Clare Bietila] So the second part of the question is if a liver panel is elevated, but stable, does that indicate medication-induced or, or GVHD, is there a way to parse that?

(43:22): [Dr. Paul Shaughnessy] It really could be either. So, if the transaminases are elevated and their bilirubin is elevated and you start treatment, and things just stay the same, then is the treatment not working? Is it keeping it from getting worse? But if they're still abnormal, then we need to find out why that is because the treatment isn't working enough. Do we need to add treatment to try to get things down to normal? And I would say we want to try to correct things to the normal range, not just leave them abnormally high, even though they're just stable. Now, once again, there are a lot of caveats to that and adding immune suppression can be dangerous as well.

(44:07): So sometimes some transplant providers might observe or watch at a stable, but slightly high, level and see what trends are. And also, yes, some medicines can cause elevated liver enzymes as well. Many of the medicines we use, some of the antifungal drugs we have like Vfend or posaconazole, even Diflucan can cause elevation of liver enzymes. And sometimes the doctors may think, 'oh, it's just from the medicine effect. We can watch this. I don't think it's graft-versus-host'. So, there are some caveats to that, but ideally we treat back to normal and follow those.

(44:53): [Mary-Clare Bietila] Our next question is, can GVHD affect nerves and muscles of the perineum related to bowel and bladder emptying?

(45:03): [Dr. Paul Shaughnessy] Good question. So, there is the autonomic nervous system, which is like the 10th cranial nerve, the vagus nerve. When people get really anxious they get an upset stomach or diarrhea from that. So the bowel system is innervated by the autonomic nervous system and that nervous system can be affected from diabetes, from anything that can damage nerves.

Now does graft-versus-host disease directly do that? That is something I'm not aware of, or if that is, maybe a less common or really unstudied part of things. I think chronic GVHD can actually do many things, but I do think the autonomic nervous system, and its effects on the bowels are important. And that can be because of diabetes or prior chemotherapy or all the things that cause things like neuropathy, they can affect the nervous system there.

(46:07): Now, what do we do about it? That would be a conversation with the gastroenterologist and the symptoms you're having as to how that's best addressed. So, I don't think the nervous system of the GI tract is directly affected by graft-versus-host, but it certainly can be because of all the other things that happen to us as we go through chemotherapy or transplant and can be manifestations of your stomach problems, whether that's intermittent diarrhea and constipation. I would look for help from the gastroenterologist as well.

(46:46): [Mary-Clare Bietila] Thank you. Our next question is, have you seen any improvement with an anti-inflammatory diet or avoiding gluten?

(46:56): [Dr. Paul Shaughnessy] You know, I can't say directly I have. And what I tell my patients is, the diet that works for you is the best diet. I do think things like, especially in adults and especially after a bone marrow transplant or within the first few months or so, dairy products can be difficult to digest. And it's like, we all become lactose intolerant after a bone marrow transplant. Avoiding dairy or using Lactaid, which you can get over the counter, can help you digest some dairy products, [and] can really help.

(47:33): Now things like gluten and such, I'd probably have you see the gastroenterologist. We could retest, but if you weren't gluten-sensitive before becoming gluten-sensitive after, isn't necessarily something that will always happen after a bone marrow transplant. And the bottom line is, when it comes down to it, once you go through these things, maybe you see the gastroenterologist, you have your studies done. If there's not a clear answer, it's finding that diet, by process of elimination and trial and error, that works for you. And hopefully working with a nutritionist to find how we get a good nutritional diet that doesn't set off your symptoms. And sometimes that can be very individualized.

(48:20): [Mary-Clare Bietila] Absolutely. Our next question is, have you seen decreased gum tissue with mouth GVHD?

(48:29): [Dr. Paul Shaughnessy] Yes. And I think it depends on the graft-versus-host disease itself. And the dryness of the mouth can lead to a periodontal disease and that can cause some retraction of the gum. You can see red inflamed gums, and eventually you can see retraction of the gums. So treating that can help prevent some of that , whether that's oral steroid swish and spit, or Prograf swish and spit, and also really good follow up with a dentist and doing good dental cleanings and good hygiene of the teeth and gums can really pay off down the road because eventually you can get bone loss and loss of teeth over months or years of time.

(49:17): So being very proactive about these things. And of course, always talk to your transplant provider to ask when it's safe for you to go back to the dentist and good dental cleanings, because there can be some risks of infection and such when that goes on. So, communication between the dentist and your transplant provider and making sure it's safe for you will be very important. But regular dental cleanings and good dental hygiene can help prevent some of those long-term things in your mouth.

(49:50): [Mary-Clare Bietila] Absolutely. Our next question is, if your GVHD of the GI tract is active, might you see it reflected in blood chemistries? For example, might you start to show a depletion in potassium or magnesium due to lack of absorption? They're curious because, if you're having a great deal of diarrhea, would that possibly mean that your body is not absorbing the nutrient from your diet?

(50:21): [Dr. Paul Shaughnessy] Yes. And actually any diarrhea, anytime, any one of us has diarrhea, we can waste potassium and magnesium in our diarrhea. And often you'll need electrolyte supplements, whether it's Pedialyte or Gatorade. And that's why even when one of us just gets the flu and we get diarrhea, we might need those electrolyte replacements. And, so, with graft-versus-host disease of the GI tract, it's not like it's making your potassium [and] magnesium be wasted, it's an effect of the diarrhea. And it can be a measure of how bad the diarrhea is.

(50:59): One other thing I'll mention, too, that we see is the protein levels or the albumin - we check on the chemistry panel - we can sometimes see the albumin levels start to go low, and that can be one reflection of malnutrition. And so, if somebody comes in with chronic stomach problems and they're losing weight, and I see a low albumin, then that's concerning [that your body] really is not absorbing and getting the nutrients that they need.

(51:30): Now, one other caveat is that some people may come in looking swollen and they have a very low albumin and no stomach problems. And actually, there is a form of graft-versus-host disease of the kidney that can cause you to just waste albumin in what we call nephrotic syndrome. And you just pee out all your albumin and that can lead to swelling and also just be a very clear sign of graft-versus-host disease of the kidney. And then that needs to be addressed with a nephrologist and probably immune suppression as well. So, we do pick up clues on the electrolytes, just when anybody is sick or having diarrhea, the albumin level for nutritional levels, or they're wasting albumin. And that can be very revealing, as well, for low liver, looking at the liver enzymes and the bilirubin.

(52:26): [Mary-Clare Bietila] Thank you. Our next question is, are there any interventions for the decreased mouth opening stenosis?

(52:35): [Dr. Paul Shaughnessy] There are some exercises, it's almost like occupational therapy or physical therapy to do mouth stretches. And I won't try to tell you how to do those right now, but the gastroenterologist or occupational therapist can be very helpful. And I think there are some sessions coming up later this week where we can ask about that, but basically stretching of the oral cavity can be beneficial. And I think for all of the joints, lower and upper extremities, physical therapy, occupational therapy can be very important and actually stretching of the oral cavity. I do think for lip tightness, topical Prograf, there is a Prograf ointment that can go on the lips and over time can maybe help decrease some of the scarring there or the inflammation there and help relieve some openings. So not just dissolve Prograf, but a medicine called Protopic, which is a Prograf ointment that you can put on something like the lips that may be helpful.

(53:45): [Mary-Clare Bietila] Our last question, if someone has an esophageal webs, are there any modifications that can be done when they're getting an endoscopy or is it just problematic?

(54:00): [Dr. Paul Shaughnessy] Now, I would defer to a gastroenterologist, but it's mainly just doing the dilation. Is there a surgical intervention or taking out the web? You can imagine the complications that can occur there as well. Probably the simplest and safest thing to do is to do the dilation. I think if the web or the stenosis comes back very frequently and they're just having to do dilations over and over then, is there something more definitive to do. Obviously any surgery on the esophagus and such needs to be done very carefully and probably in consultation with a gastroenterologist and a thoracic surgeon who would do something like that. But for esophageal web, the main approach is to just do the dilation.

(54:51): [Mary-Clare Bietila] Closing. That was helpful. And on behalf of BMT InfoNet and our partners, I'd like to thank you, Dr. Shaughnessy for your very helpful remarks. And I'd like to thank the audience for these excellent questions. Please contact BMT InfoNet if we can help you in any way.

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