Graft-versus-Host Disease: Gastrointestinal Tract (GI) and Liver

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Graft-versus-Host Disease (GVHD): Gastrointestinal Tract and Liver

April 28, 2024

Presenter: Hannah Choe, MD, GVHD Program Director, Assistant Professor, The Ohio State University Comprehensive Cancer Center

Presentation is 38 minutes long, followed by 12 minutes of Q&A

Many thanks to Incyte and Ironwood Pharmaceuticals whose support helped make this workshop possible.

Summary: Graft-versus-host disease (GVHD) frequently affects the gastrointestinal tract and liver after a stem cell transplant using donor cells (allogenic transplant). There are two types of GVHD: acute and chronic. This presentation discusses the incidence, symptoms, risk factors for each and treatment options.

Highlights:

• Roughly 70% of patients with acute GVHD and 33% of patients with chronic GVHD have GI involvement.
• Six to 15% of patients with acute GVHD and roughly a third of patients with chronic GVHD will have liver involvement.
• GVHD in the GI tract or liver increases the risk of mortality in patients with acute GVHD, but not in patients with chronic GVHD.

Key Points:

(03:12): Risk factors for developing GVHD in the GI tract depend on the type of chemotherapy receive prior to transplant (the conditioning regimen) and how well-matched the stem cell donor and patient were.

(05:59): Symptoms of acute GI GVHD include loss of appetite, heartburn, nausea and vomiting, diarrhea and  weight loss.

(07:37): Patients with chronic GVHD will complain of oral dryness, mouth ulcers, blistering or sensitivities to food.

(08:33): The severity of chronic GI GVHD is assessed by how difficult it is to eat, whether there is narrowing of the esophagus, whether there is weight loss, and its impact on daily activities

(09:34): To properly diagnose acute and chronic GI GVHD,  multiple tests may be ordered including stool studies, endoscopy, colonoscopy and blood tests,.

(11:07): Biopsies can be an important to diagnose GI GVHD and rule out other problems such as infection or drug-induced liver damage that can mimic GVHD.

(12:31): GVHD in the liver can lead to cirrhosis and interfere with liver function.

(13:28):  Patients with liver GVHD may initially have no symptoms. Signs and symptoms of more severe liver GVHD include jaundice, swelling in the legs and abdomen, increased bleeding from the nose or rectum, confusion and/or dark urine.

(22:10): Without a liver biopsy, patients may be misdiagnosed and treated for liver GVHD when they actually don’t have it.

(28:13): Steroids are the first line of treatment for GI and liver GVHD. If steroids fail to control the disease, ruxolitinib (Jakafi®) or belumosudil (Rezurock®) may be used.

Transcript of the Presentation

(00:01): [Anna Stensvaag]:  Welcome to the workshop, Graft-versus-Host Disease: Gastrointestinal Tract and Liver. My name is Anna and I will be your moderator for this workshop.

(00:11): I'd like to thank Incyte and Ironwood Pharmaceuticals whose support helped make this workshop possible.

(00:19): Introduction of Speaker. It's my pleasure to introduce today's speaker, Dr. Hannah Choe  is an Assistant Professor and hematologist at The Ohio State University Comprehensive Cancer Center where she specializes in blood and marrow stem cell transplantation and treating patients with myeloid diseases such as acute myeloid leukemia (AML) and myeloproliferative diseases. She is also the director of the Ohio State University Graft-versus-Host Disease (GVHD) program. Her research focuses on new approaches to prevent and better treat GVHD. Please join me in welcoming Dr. Choe.

(01:09): [Dr. Hannah Choe]:  Thank you, Anna, and good afternoon. My name is Hannah Choe. I am a transplant hematologist oncologist at OSU, as Anna mentioned. For the next 40 minutes or so I will review graft-versus-host disease of the gastrointestinal (GI) tract and liver.

(01:28): Overview of Presentation. There's so much we could discuss, but we will keep it to the following learning objectives. We will discuss the incidence, or rate of occurrence, of acute and chronic GVHD of the GI tract and liver. We'll cover the risk factors and treatment options as well.

(01:51): We'll first review acute and chronic GVHD of the GI tract, the signs and symptoms and how GVHD might be diagnosed. Then we'll do the same for acute and chronic liver GVHD. And lastly, we'll review treatment options which are the same regardless of which organs are involved, but we will cover the responsiveness of each of the drugs that I'm going to discuss.

(02:13): There are few things that are more important than food and water and the GI tract helps us manage both. From our mouth to esophagus to stomach to small intestine to colon, and through the anus or rectum, the GI tract is responsible for digesting food and helping us derive our nutrients from our food and water. It is also our waste management system.

(02:39): The lining of our GI tract is sensitive to chemotherapy and radiation. Because the cells on the inner lining of our GI tract are constantly growing and sloughing off with very high cell turnover, our GI tract is more sensitive to chemotherapy and radiation, similar to how our patients will lose hair or have skin changes as side effects of the chemotherapy. But in particular, we know that many of the chemotherapies that we use for stem cell transplantation conditioning prior to stem cell infusion will cause GI side effects.

(03:12): Risk factors for developing GVHD of the GI tract depend on type of chemotherapy received prior to transplant (the conditioning regimen) and how well matched the donor and patient were. The risk of developing GVHD of the GI tract starts with the chemotherapy that our patients receive before they receive their stem cell infusion. Further risk of GI GVHD depends on how many donor cells a patient receives and how well matched they are to the patient. The better the match, the less likely a patient is to have graft-versus-host disease. But this risk can be offset by the GVHD prophylaxis medications or prevention medications that are used with that chemotherapy and then continued on for maintenance after stem cell transplant to prevent graft-versus-host disease.

(03:55): The GI tract is also an important site of immune system activation. At a continuous level, our immune system is at the ready in our GI tract in case the bacteria that are in our gut try to cross over. So, with chemotherapy that disrupts the GI tract causing damage and injury, the immune system is further activated and is not only there to just fend off bacterial infections but also there to repair the GI tract.

(04:28): This immune cell activation in our GI tract stimulates the donor cells, that we've just infused into the patient, and leads to more inflammation and sets off GVHD. And so, the GI tract is really a primary site of activation for GVHD. You can then see how the GI tract easily becomes this central focus and a commonplace location of one of the first symptoms of GVHD.

(04:58): Roughly 70% of patients with grade two-to-four acute GVHD will have GVHD in the GI tract. The lower GI tract is also harder to treat than skin or upper GI acute GVHD, and we know that when the lower GI tract is involved, patients are at higher risk of mortality. We know then that treatments also don't work as well. And 73% of patients with severe acute GI GVHD can stop responding to the frontline treatment of steroids or don't show a response to steroids within two weeks. We do take it much more seriously when a patient does show initial signs of potential GVHD and are always then questioning our patients about any diarrhea or new GI symptoms.

(05:44): Having GI GVHD is very significant and so we will often make what's previously an uncomfortable topic to ask about diarrhea and stool output, something very commonplace within the clinic.

(05:59): Symptoms of acute GI GVHD include loss of appetite, heartburn, nausea and vomiting, and  weight loss. To assess for acute GI GVHD, we ask about your appetite, if you're getting full earlier, if you're having heartburn, feeling nauseous or vomiting or perhaps if you're losing weight because any of these symptoms could be signs of GI GVHD. We also ask about abdominal pain and any signs of diarrhea, as it signals that patients are not absorbing water and nutrients. This can lead to dehydration and malnutrition. We really have to stay ahead of diarrhea and this is why we always ask patients to call immediately at initial signs, even if it turns out to not be graft-versus-host disease.

(06:45): To gauge how severe the GVHD is, we do what is called staging. We assign the stage of severity by if there is persistent nausea or vomiting ,and how much diarrhea or how many stools a patient is having every day. More diarrhea signals more advanced disease. We combine the staging calculation with that of the skin and the liver and we determine an overall grade of acute GI GVHD. But for chronic it's a bit different.

(07:17): Chronic GI GVHD commonly involves the mouth, esophagus and GI tract, whereas acute GVHD rarely involves the mouth or the esophagus. Although patients can have mucositis from their chemotherapy, that seems to blend into it.

(07:37): With chronic GI GVHD, patients will complain of oral dryness, mouth ulcers, blistering or sensitivities to food. In particular, I have patients that often complain about tomatoes or tomato sauces or Italian foods, essentially foods that are more acidic. They might also complain about difficulty swallowing and feeling like food is getting stuck because there is a narrowing of the esophagus that blocks the food transit down to the stomach.

(08:06): Other chronic GI GVHD symptoms mirror those of acute GVHD when it involves stomach and lower GI tract with nausea, vomiting, diarrhea, and potential weight loss. These symptoms vary in severity and we use the symptoms to grade the severity. Since we're talking about mouth esophagus and other, it's a little bit more broad than with acute GVHD.

(08:33): The severity of chronic GI GVHD is assessed by how difficult it is to eat, whether there is narrowing of the esophagus, whether there is weight loss, and its impact on daily activities. For chronic GVHD, in the case of mouth symptoms, we interpret severity based on how much the GVHD limits the patient's ability to eat. So that can be very subjective initially, but it's really important to dig into the details with your provider and make sure that they're aware of how much change has happened for you. If you're eating less or if you're not able to keep food down or if you feel like it's just too painful for you to eat or swallow, or if your mouth is too dry for you to be able to produce enough saliva to be able to swallow.

(09:09): For the GI tract, we mark the symptoms including if there is an esophageal stricture or narrowing of the esophagus. We consider more severe GVHD to be that which leads to more weight loss, reduces the ability to get enough nutrition, requires a procedure for you to undergo or if it's affecting your daily activities. So not as objective of a scale than we use for acute GVHD.

(09:34): To fully evaluate for all these GI symptoms for acute or chronic GVHD, multiple tests are ordered. We might include stool studies to rule out infection. We might perform an endoscopy of the upper and/or lower GI tract. An upper endoscopy is also called an EGD, and a colonoscopy is obviously through the rectum, but could also be a flexible sigmoidoscopy, which is a shorter view of the GI tissue closer to your rectum.

(10:14): Additional blood work may look at blood counts and chemistry panels to check your kidney and liver function, looking for other signs of other organ involvement. GVHD biomarkers can be sent and blood markers of nutrition like your vitamin levels or your mineral levels, to signal whether you've had more malabsorption or are having other signs of malnutrition. Sometimes imaging studies like with a CT scan or MRI are also ordered to rule out other issues or to see if there's actually been improvements or worsening of your GVHD

.(10:47): These are example images of an upper endoscopy or EGD  from a patient with liver GVHD. You can see the images are taken with the forceps or cryotherapy tools that the GI doctor uses to take biopsies or to treat certain areas. In this case, they were used to stop bleeding.

(11:07): Biopsies are sometimes used to diagnose GI GVHD. GVHD is a clinical diagnosis. That means we diagnose based only on symptoms, but it does not mean we do not still try to  get more specifics about the diagnosis or potentially to confirm it, when it's possible to get tissue biopsy. Biopsies are not always required. Patients may be started on treatment based solely on how much diarrhea or other symptoms they're having, but biopsies can be very helpful. Besides the amount of diarrhea someone is having, biopsies can tell us how severe the damage is to the GI tract. It also allows us to do tests to rule out an infection, and[confirm] that there's actually no GVHD.

(11:52): Biopsies may need to be repeated after some time if symptoms change, particularly if symptoms get worse despite treatment. You then might need to rule out that there wasn’t an infection there before, but there could be an infection now. And it can help us assess whether a patient is responding or not responding [to treatment[ because there could be other causes of diarrhea.

(12:31): GVHD in the liver can lead to cirrhosis and impaired liver function. The second organ system we're going to talk about today is the liver. The liver has many different functions, so the list here is not all encompassing. The liver filters blood and removes toxins, makes bile that helps us digest food, makes proteins that keep us from bleeding. It helps us balance fluid, regulates our bodies, and importantly, metabolizes and processes medications..

Damage from any particular disease, but particularly from GVHD, can lead to scar tissue formation or scarring within the liver which eventually leads to cirrhosis. When that happens, the liver is functioning less well, and these important responsibilities start to falter. That's when patients might start to show more symptoms.

(13:28):  Patients with liver GVHD may initially have no symptoms. Oftentimes our initial suspicion that a patient has liver GVHD is when there are no symptoms is based on lab values that we're routinely checking. Rarely, a patient might also be jaundiced. We regularly check chemistry panel sat follow-up visits soon after transplantation including your alkaline phosphatase, your AST, ALT, and your bilirubin numbers. We'll talk a little bit more about those going forward. This is the same for chronic GVHD where it's often the labs that tip us off initially that something is off.

(14:22): Signs and symptoms of more serious liver GVHD may include jaundice, swelling in the legs and abdomen, increased bleeding from the nose or rectum. Signs and symptoms of more serious or severe GVHD in the liver are not specific to graft-versus-host disease, but these include jaundice, which is yellowing of the skin and eyes, swelling and other signs of fluid overload, particularly in the abdomen and the legs, and any signs of increased bleeding symptoms, particularly from the nose or from the rectum or any increased bruising. If advanced patients can have confusion and dark urine.

(14:56): Because the clinical signs and symptoms can vary between patients and do not accurately reflect the severity of the disease, our scoring for acute and chronic GVHD is based off of the lab values. Here we show the scale that's used for chronic graft-versus-host disease that uses the total bilirubin, the ALT and alkaline phosphatase numbers. These are all results on a comprehensive metabolic panel or CMP that is routinely ordered by your provider.

(15:31): Chronic GVHD in the liver is more common than acute GVHD in the liver The incidence of liver GVHD is more common in chronic than acute GVHD. These ranges, as you're seeing them here, six to 15% for acute and five to 31% for chronic do overlap. Most reports would say that rates of acute liver GVHD are near the lower end, towards 6% , whereas chronic liver GVHD tends towards the 30% higher end. We'll go into that a little bit more.

(16:00): Roughly one third of patients with chronic GVHD have GI involvement and roughly 50% have liver involvement. Over time, looking at all the cases of chronic GVHD and breaking it down into the main organ systems, roughly 50% of patients (over time from 1995 to '99, 2000, 2003, 2004 to 2007) have liver involvement. Weight loss is also relatively stable, 39 to 41 to 34%, it's about one in three, and then you can see for mouth above as well.

(16:35): So while the incidence of GVHD in other organ system have changed over time, the liver and GI tract have stayed pretty stable. Things like the skin, though the rate has increased. it's probably not that the rate of skin GVHD has increased so much as that we are diagnosing it more readily and making that number seem higher. But generally, the organ system breakdown is pretty stable over time, and roughly one-third have chronic GVHD symptoms or have GI involvement and one-half of patients have liver involvement.

(17:07): Liver GVHD can occur as late as two years after transplant. Other facts about liver GVHD in general is that it appears about two months to two years after transplant. There's a wide range when it can first show signs or symptoms, which is why it's important to continue to have routine follow up with your provider even well after you've completed your stem cell transplant and even after you've been weaned off of immunosuppression. And this liver GVHD can affect up to 75% of all patients by some reports.

(17:41): Liver GVHD typically presents with a cholestatic pattern. Cholestasis means there is decreased flow through your liver and so that backup of flow causes the symptoms of the bilirubin accumulating, which is why you develop jaundice or yellowing of the skin and eyes. But it can also show up as a hepatitis, which is inflammation of the liver where it causes increases in your lab work for your liver transaminases like your AST or ALT numbers that are routinely seen on your metabolic panel. So you might have an increase in those numbers, AST and ALT, but not have an increase in bilirubin.

(18:34): Imaging with ultrasound, CT or MRI is not diagnostic, but it can help identify if there needs to be a closer examination, especially to determine if you need a liver biopsy.

(18:48): AST and ALT elevations, alkaline phosphatase, hyperbilirubinemia, which is where your bilirubin numbers are higher, may warrant a liver biopsy. Even if you do pursue a liver biopsy and it even shows scar tissue, this does not always mean that it's GVHD. It could be, but there are other complications, even before or after stem cell transplantation, that have carried over and it can be very broad.

(19:26): Infection and drug-induced liver problems can mimic the symptoms of liver GVHD. There are common mimics to graft-versus-host disease such as drug-induced liver injury. It, could be a medication that you received that, for whatever reason, had side effects that damaged your liver. Or you may have had an infection. We do check hepatitis B and C prior to stem cell transplantation but should be routinely checked to make sure that that is ruled out. It could also be a CMV or cytomegalovirus, which is something that we commonly check and routinely make sure it's not reactivating after stem cell transplantation, causing liver issues. It could be an adenovirus or even a fungal infection. And so these other causes that can mimic GVHD can be difficult to distinguish, even with a biopsy. So, it has to be a very educated decision that this is most likely chronic GVHD or acute GVHD.

(20:25): Sinusoidal obstructive syndrome (SOS), iron overload, a severe infection and a fatty liver can affect the liver and be confused with liver GVHD. There are other causes listed here of liver abnormalities such as veno-occlusive disease or sinusoidal obstructive syndrome (SOS). Even iron overload can do this. If you've received many transfusions over time, having elevated levels of iron can also damage your liver. If you had a very severe infection and you were septic, then you can actually have a similar cholestatic picture just from being septic. Steatohepatitis and steatosis, or if there's an underlying malignancy in your liver, can mimic GVHD as well. Steatohepatitis and steatosis refer to the deposition of fat in your liver that can cause more inflammation, which is increasingly a problem.

(21:08): Keep in mind, though, that it could be liver GVHD AND one of these other things. Just because you have one of these diagnoses, such as steatosis, does not mean you can't also have liver GVHD. So, this further complicates the diagnosis of liver GVHD. Getting all the information, lab values, potentially tissue biopsy and imaging helps us narrow and make an educated decision about how to proceed.

(21:39): To sort all this out, your healthcare provider would order these studies. In addition, a referral to a liver specialist (hepatologist) can be helpful to make sure that we're ruling out other potential liver-specific complications or liver-specific causes that we might not be considering. So, it becomes a multidisciplinary care team quickly when there's liver GVHD involved.

(22:10): Without a liver biopsy, patients may be diagnosed and treated for liver GVHD when they actually don’t have it.  As I mentioned, a liver biopsy can be very important and I do want to take a minute to discuss the importance of biopsy, information that I think is important for the patient to understand. It might be surprising, despite me talking about how difficult it is to diagnose liver GVHD, that it's more an exception than a rule that we actually obtain a liver biopsy, despite its utility and its helpfulness to narrow or confirm the diagnosis.

(22:39): Oftentimes, getting a liver biopsy is deferred or delayed or not done just due to the perception that there's an increased risk of bleeding or complications that make it not worth the benefit. But an NIH cross-sectional study that was published last year looked at 315 patients that were diagnosed clinically with liver GVHD, based on lab values alone. And these lab value cutoffs that they used were when your ALT or bilirubin were three times normal and had no other explanation.

This resulted in half of the patients (150-160) having a clinical liver GVHD diagnosis, but only 32 of those patients actually had a liver biopsy or liver tissue from an autopsy. Liver tissue from these 32 patients showed that only 60% of them actually had liver GVHD.

(23:46): Unfortunately there's not a lot of tissues to be able to look at, but even from the ones that they did have, when patients were diagnosed with liver GVHD just based on labs, only 60% of them actually had liver GVHD. 41% of these samples had no liver GVHD. This can have major implications - patients on treatment with immunosuppressive therapies when they might not actually need it, or they might have an underlying condition that is not GVHD that we're not recognizing.

So, there's, of course, the caveat that the biopsy is also 1not 00% diagnostic. Just getting a biopsy doesn't mean that we're going to have all the information that will definitely guarantee that we do know, or do not know, if you have liver GVHD because we don't have specific features that definitely tell.

(24:36): All this information has to be used in a very educated manner with your clinical team to to say that this is much more likely to be GVHD and should proceed with treatment versus not. But you can see that it's important to always take a closer look.

(24:57): The timing of biopsy is also very important. As I just mentioned, the biopsy can be very helpful, but if you do it too soon, this can actually result in a false negative. And if patients have been on treatment and then we do the biopsy, then the biopsy might be negative because the treatment has actually already started to help. So, you have to be judicious about when to ask for the biopsy.

(25:31): Liver biopsies can actually lead to a change in treatment. This slide shows additional data showing that 50% of biopsy results led to a change in treatment for this series of patients who had undergone liver biopsies. And if you look across the published studies, biopsies actually led to a change in treatment for up to 95% of cases in one report. So roughly half of patients, up to most patients, actually had a change in treatment because of what was found on the biopsy.

(26:07): What is involved in the liver biopsy? Where is it done and by whom? Typically, it is done through an interventional radiologist team. This can be done either transjugularly, through the jugular vein in your neck, or it can be done percutaneously, which is through the skin over your liver. It is a short outpatient procedure. Obviously, you need some moderate sedation, not general anesthesia, but moderate sedation to do the procedure, depending on if they're going transjugular or percutaneous, or through the neck versus through the skin.

(26:46): It's a similar procedure to having your tunneled line placed and it is done by the same team. The pain associated with the procedure varies for each person, but most patients come out of it with discomfort similar to what you would have with a tunneled line placement and the recovery time is just a few days.

(27:14): In a study to assess the safety of doing transgenic or percutaneous liver biopsy, there were no adverse events in the majority of patients (92%), and of the patients that did have an event, pain was the most common. You can have a small hematoma or blood collection at where they enter the neck and very, very rarely (0.0015%), the bleeding was so significant that a patient needed a transfusion.

(27:47): So, in general, a liver biopsy is very well tolerated, low risk, but obviously not without any risk. And when you look at other concerns such as whether a patient had a significant hematoma or a pneumothorax, which is where they actually puncture the lung and have a lung deflation issue, that's less than 3% of patients.

(28:13): Steroids are the first line of treatment for GI and liver GVHD. So now that you have a diagnosis after all this, whether it's acute GI GVHD, chronic GI GVHD, acute liver or chronic liver GVHD, what is the treatment? So, I put clinical trial here first because clinical trials for me, are always the gold standard. The reason is that the first line of treatment is steroids, and I don't think I have to elaborate on the side effects and toxicity of steroids. While they can be very effective at suppressing the immune system and dampening inflammation very quickly, they also can very quickly cause side effects such as high blood sugar, high blood pressure, fatigue, muscle loss, bone density decrease, et cetera.

(29:02): So, we're constantly, as academicians within the GVHD community, trying to find something that's better than steroids but that works just as well, and just as quickly. I always encourage consideration of a clinical trial, if one is open near you, for your type of graft-versus-host disease.

(29:23): If steroids don't work or stop working, then we'll talk about these next two agents - ruxolitinib and belumosudil. I do feel like I should say that there is another FDA-approved agent, ibrutinib, which I'm not going to discuss because it is not used commonly in practice because of side effects. I think at any treatment change opportunity, a clinical trial, if available, should be considered.

(29:57): GI or liver GVHD tend not to respond as well to treatment with steroids as do other organs.  When we look at patients that have acute graft-versus-host disease, and we want to get an idea of how well steroids work, we have a very well-done review that was published in 2015 where we looked at patients who had different stages of acute GVHD, which involves the skin, lower or upper GI tract and the liver. When you break up the different types categories of organ involvement that patients have when you have GI involvement, particularly the lower GI tract, which is in the box in the bottom four rows, there is a decrease in the response rate four weeks later. Four weeks later is just an arbitrary marker at this point, but we know that patients will not respond as well if there is lower GI involvement.

(31:01): If there is more severe lower GI involvement, where it's more advanced with more diarrhea, you can see that those numbers that had been the 60%s, 70%s, are now 50% and down to 35%. The most difficult to treat, least responsive organs are when have liver involvement and the most severe manifestations of lower GI tract involvement. So, GI tract involvement and/or liver involvement of acute graft-versus-host disease is a signal to your provider and your care team that, while of course we can give you frontline steroids, you're less likely to respond. And so consideration of next-line agents or clinical trials should be heavily weighed.

(31:50): The response rates when you look at liver involvement, dropped from where you were in the 50%s, 60%s before, down into the 30%s, 40%s.

(32:02): The first medication that I wanted to look at for acute graft-versus-host disease, aside from steroids, is ruxolitinib (Jakafi®), which is FDA-approved. Ruxolitinib is a JAK inhibitor that dampens inflammation by blocking the JAK pathway or JAK-STAT pathway.

(32:29): When we're specifically looking at lower GI responsiveness, we have no specific numbers because the study was not designed to have a direct comparison. But they did share data can give you an idea of how bad the staging of lower GI tract involvement was before the patient received ruxolitinib, and then four weeks later.  And then the same information on the right for patients on that trial who received best available therapy - there were a number of different therapies besides ruxolitinib that were studied.

(33:08): You can see the patients in the first bar versus the third bar are where a patient started initially with treatment. And then you look at the second bar and the fourth bar, you see that the staging might be, if it's lighter colored, less severe with the ruxolitinib than with the best available therapy. It seems like the lighter colors reflect that there's less severe graft-versus-host disease and had lower stages after four weeks with treatment with ruxolitinib.

(33:45): For the liver, this is roughly the same but harder to tell because the numbers were fewer, but it appears that the liver GVHD did slightly better with ruxolitinib than the best available therapy. Again, no firm conclusions can be drawn from this. The study was not powered specifically to look at this, but just important information to know when we're trying to personalize the decision on how to treat a patient with GI tract liver disease from GVHD.

(34:18): When we look at chronic GVHD, and see specifically how the mouth, esophagus, upper GI tract, lower GI tract and liver respond to ruxolitinib, the response rates are high. This is seen in the second and third column versus best available therapy, which is the fourth and fifth columns on the right. So, you see a baseline involvement and then the organ response. For the mouth, patients had baseline around 58% to 60% and then with ruxolitinib about a 50% response versus 25% with best available therapy. So significant difference with improved responsiveness with mouth.

(35:03): The esophagus, about 10% were involved at baseline and then there was about 50% response with ruxolitinib versus 30% versus for best available therapy. Upper GI tract, 12% at baseline and then 40% responding in both best available therapy and ruxolitinib. For the lower GI tract, about 6% to 10% involvement. And then a 53% response rate with ruxolitinib and about 30% with best available therapy. And liver, similar responses for ruxolitinib and the best available therapy.

(35:45): The next treatment that I wanted to review is belumosudil (Rezurock®) for chronic GVHD. Just to take a step back, there is no other FDA-approved agent for acute graft-versus-host disease besides ruxolitinib. So, if a patient is not responding to ruxolitinib, that’s when I would consider a clinical trial. But for chronic GVHD, if you have failed two prior therapies, then you can consider belumosudil, which is FDA-approved as well. In the study called the Rockstar study, response rates are shown here by organ system for belumosudil. There were higher response rates in the lower GI and upper GI tract, and also the esophagus, and a lower response rate in the liver.

(36:40): But this is not compared to anything else. This is just the response rate. This is just comparing it to itself. You see higher response rates in the GI tract than you do in the liver. But still notable response rates in general.

(37:17): Summary. So, in summary, the GI tract involvement in acute GVHD is common. About 70% of patients with grade two or higher GVHD have GI tract involvement. Liver involvement in acute GVHD is significantly less common, but it is very common in chronic GVHD. That might be because we are diagnosing it based only on lab values and not commonly getting liver biopsies. So, it is worth the conversation with your provider to discuss whether or not any of your lab abnormalities are due to medications or potentially GVHD.

(37:56): GI tract or liver involvement increases the risk of mortality in patients with acute GVHD. Interestingly, it does not increase the risk in patients with chronic GVHD. Chronic GVHD is thought to be more chronically treated and more of a slow persistence or slow progression.

(38:14) A liver biopsy is helpful in diagnosing acute and chronic liver GVHD. Biopsy is helpful in liver GVHD in acute or chronic GVHD and to confirm the diagnosis throughout other causes and to monitor for progression.

(38:23) Steroids, ruxolitinib and belumosudil are potential treatments for GI and liver GVHD. And the treatments that we've reviewed include steroids, which the responsiveness can be lower if your disease is more advanced. We also considered ruxolitinib and belumosudil as treatments. But I do still, again, highly recommend that you consider clinical trials for treatment as long at any stage or any juncture for your GVHD management. And that concludes the presentation that I have prepared. I'll take any questions at this point. Thank you.

Question and Answer Session

(38:56): [Anna Stensvaag]:  Thank you, Dr. Choe, for this excellent presentation. We will now begin the question-and-answer session. Our first question is "I am two years from my bone marrow transplant. I just started having GI issues and I'm seeing a GI specialist, not a GVHD specialist. They're conducting many of the tests you mentioned. Do I need to see a GVHD specialist?"

(39:36): [Dr. Hannah Choe]:  So, I would highly encourage you to follow up with your transplant provider who obviously will have a high suspicion for graft-versus-host disease as well. If you have not seen your transplant provider, then I would schedule with them because depending on the GI specialist’s history or experience with graft-versus-host disease, they may not be considering it and they may not be looking for the markers that we would consider important. And if GVHD is in fact the trigger for all of these things, then the treatment would not be through your GI specialist, it would be through your transplant provider or transplant specialist. So yes, I would encourage you to follow up with your transplant physician.

(40:36): [Anna Stensvaag]:  Okay, thank you. The next question is, "My allogeneic stem cell transplant was in 2018. The oral lesions have improved, but my intestinal cramping and increased peristalsis persists. I cut back on fibrous foods and noticed I do better with fatty foods, meat and exercise, improved symptoms. What causes this? I had colitis when I was taking the conditioning treatment. Could this be part of it?"

(41:06): [Dr. Hannah Choe]:  Yeah, so that's really tricky because the symptoms can be very nonspecific and there's also so many different other GI conditions that can be causing the symptoms instead of GVHD. Without seeing your tissue biopsy or knowing your inflammatory markers, I don't know how much of it could be GVHD. You have to think about other GI conditions such as pancreatic enzyme production or irritable bowel syndrome or I'm assuming you don't have inflammatory bowel disease, but making sure that all of these things are being checked appropriately because it might not just be your GI tract if it's digestion. As I mentioned, it could be liver involvement too, but usually they see that based on liver enzymes. But these things should all be considered.

(42:11): So it's hard for me to say without seeing you myself, but you can have responses in one organ like your mouth, but not have improvement in another. And that would not be uncommon for GVHD. So it may be that whatever treatment you're on for your graft-versus-toast disease has worked to a certain level. And if this is, in fact, your graft-versus-toast disease that's continuing to cause these symptoms, you may be in a position to consider whether or not another line of therapy would be more appropriate.

(43:07): [Anna Stensvaag]:  Okay, thank you. The third question is, "Why do I have random flare-ups in my gut that last about a week causing pain, indigestion, nausea and fatigue? I have become sensitive to certain foods such as wheat, oats, and shellfish to name a few. These foods trigger a reaction in my mouth and often spur a sour or gurgling gut. Is it still safe to eat some of these foods?"

(43:33): [Dr. Hannah Choe]:  Yeah, so as I mentioned, it's not uncommon for patients to have certain food sensitivities with graft-versus-toast disease. So, this could be your graft-versus-host disease that's triggered by certain foods that you're eating, or the sensitivities that you're having from graft-versus-host disease are then triggering these symptoms. So, I can't advise whether it's safe or not to eat these things without knowing the details.

(44:00): But I would recommend seeing your GI specialist, evaluating whether you need to have repeat scopes done, and then making sure we're identifying what other organ systems besides the GI tract to look at for signs or symptoms of progression of GVHD, to help make an educated decision. So, I can't speak specifically to your needs, but it's not uncommon to have food sensitivities. And the persistence of those sensitivities might signal, if in fact due to GVHD, that your GVHD is not well controlled. So, I would follow up with your provider about that.

(44:42): [Anna Stensvaag]:  And the next question is, "How do I best support my wife who constantly feels nausea due to GVHD?"

(44:55): [Dr. Hannah Choe]:  Well, thank you first of all for asking on behalf of your wife because caregivers are so important with managing chronic GVHD. In regard to nausea, it depends on what the trigger for the nausea is. There are many different types of nausea medications. I think that it's important to understand what is triggering the nausea and if it can be managed by medications alone or if it's GVHD that's not controlled. Does she need treatment for the GVHD to help with the nausea? For nausea in general, a lot of times when we're thinking of upper GI GVHD, we will go to topical but non-absorbable steroid. Something like budesonide is commonplace, obviously anti-nausea medications are commonplace.

(46:04): And then if the endoscopy or EGG does show that the GVHD is not responding, then different GVHD therapies may be considered. I'm trying to think if there's anything that I wanted to touch base about. Oftentimes we'll use beclomethasone in addition to the budesonide. This might involve using a compound pharmacy to obtain these medications. And you might also consider whether other medications are also contributing to her symptoms as well.

(46:39): GI GVHD, being pretty non-specific, it could always be a medication that's causing the nausea or something else that's causing the nausea rather than the GVHD.  In that case, an endoscopy could be helpful. I would follow up with your provider to make sure all these things have been considered and done.

(47:04): [Anna Stensvaag]:  Okay, great. The next question is about a 65 year old male, 10 months post-transplant for MDS. He is having ECP treatment for skin GVHD. So far, no GI GVHD. Is there any chance of getting it from this point forward?

(47:22): [Dr. Hannah Choe]:  Unfortunately, yes. Obviously, I'm glad that he's on treatment for his GVHD, which should hopefully prevent further progression. But patients can stop responding to treatments and that's one of the limitations. And one of the things that we're trying to improve is the duration of response or how long a patient will respond to treatment because when a treatment does stop working, then we have to consider the next line or consider what else might be a way to treat their graft-versus-host disease. It's somewhat rare to have what's called a complete response to any of these therapies. While we might have a high number of patients respond, rarely do we actually get patients to respond completely where their GVHD goes away completely.

(48:24): And then when we do wean patients off of therapies, there's always unfortunately the chance of that graft-versus-host disease coming back. And when the graft-versus-host disease comes back, it could come back in different organs. So, I can't say absolutely that he or she will never develop a GI tract GVHD, but it sounds like he or she's receiving active therapy for it. So hopefully it should prevent it as possible.

(48:58): And it's obviously being monitored then for those symptoms. But yes, I think you should always be vigilant for new symptoms that are GI tract or those liver abnormalities that given his history of GVHD of the skin, that could be GI tract or liver GVHD, but would still need its own workup.

(49:20): [Anna Stensvaag]:  Okay. Thank you. Do you consider chronic GI GVHD as a process that can  "burn out” or one that needs to be managed with medication for life?"

(49:35): [Dr. Hannah Choe]:  That's an interesting question. We don't completely understand how GVHD occurs and whether we can stop treatment or if it can just phase out on its own. Do we see rare patients who can stay off therapy? Yes. But most patients have, at a low level, some form of mild symptoms that persist, even if they have been weaned off treatment. I still highly recommend ongoing routine continued to monitor for early signs or symptoms of a recurrence of graft-versus-host disease in all organs, including the eyes.

(50:36): Once a patient has been diagnosed with graft-versus-host disease, even if it doesn't involve the eyes, I always refer a patient to the ophthalmologist to look for early signs or symptoms of GVHD of the eyes and have them continue to follow up yearly at a minimum to have that checked. Because what you want to do is be in a position to prevent and detect early any other manifestations of GVHD that might affect your quality of life. The immune system is very unpredictable. I don't know if I believe in burnout necessarily, but I think that you have to always be vigilant for recurrence.

(51:33): [Anna Stensvaag]:  Okay, thank you. Any recommendations for management of acid reflux with chronic GI GVHD? Any guidance, for example, in the long-term use of Omeprazole?

(51:59): [Dr. Hannah Choe]:  Omeprazole. So, we have not, to the best of my knowledge, studied long-term use of proton pump inhibitors, omeprazole or pantoprazole in patients with GI GVHD. There are studies with this class of medication just in general with malignancy, but not specifically for GI GVHD. But it is one of the most effective medications, if not the most effective medication, for managing acid reflux. And so, if symptoms require it, then your hands are tied, the patient should be on it.

(52:44): But in that sense, I would defer again to that multidisciplinary care team and talking to your GI specialist to see if there are other causes of the persistence of that heartburn, such as with infections. For example, making sure that there's no H. pylori coinfection or something like that. Making sure you're crossing out all the other potential causes and leaving you with the need to just stay on that long-term. So regular and routine follow-up, if symptoms are persisting, is necessary. And if that requires repeat imaging or repeat endoscopy, then I do think it's worth it because it's obviously affecting quality of life.

(53:28): [Anna Stensvaag]:  "I am almost four years from my allogeneic transplant and have minor/moderate chronic GVHD, dry eye, dry mouth, mouth sores and esophagus stricture. I'm taking tacrolimus for these GVHD symptoms. Is ruxolitinib or belumosudil a better approach?"

(53:59): [Dr. Hannah Choe]:  Hard to answer as I don't know your specific case and your details, but things we have to keep in mind for ruxolitinib and belumosudil is that they are not without their own side effects. Your provider is most likely weighing the risk and benefits of those side effects versus how well you're tolerating tacrolimus. If you're having very mild symptoms perhaps they could give you better control potentially. So, this is something to discuss with your provider.

(54:42): I don't know if ruxolitinib is the right thing for you., depending on your counts, because ruxolitinib can decrease your blood counts. So, if that's a concern, then that might not be an option. Belumosudil does not have that as a side effect, so that could potentially be an option, but it depends again on the severity, and the balance of the risk benefits of each of these drugs, but it's certainly a consideration.

(55:08): [Anna Stensvaag]:  This will have to be our last question as we're running out of time. "Unlike liver GVHD, is it possible or common for GI tract GVHD to present itself with a distended stomach absent the more common symptoms that accompany GI tract GVHD - nausea, diarrhea, lack of appetite, weight loss, et cetera?"

(55:35): [Dr. Hannah Choe]:  A distended abdomen or a bloated abdomen, in this case, I want to make sure that I'm understanding it properly because you can have abdominal distension or enlargement of your belly or swelling of your belly from gas, or you could have it from fluid accumulation. And for the latter, if it is fluid accumulation, as I had mentioned, abdominal swelling or ascites fluid accumulating, that is a sign or symptom of liver dysfunction, so that possibly could be related to the liver.

(56:12): If it is due to the GI tract causing a lot of bloating, et cetera, that again, could be a different GI process entirely. Could it potentially be GVHD? Yes, but it'd be worthy of a thorough physical examination, potentially even abdominal imaging, which could be CT or MRI, or potentially ultrasound as well, to evaluate the actual  cause. It could actually be your liver rather than your GI tract. But yeah, I would follow up with your provider about that specifically.

(56:52): [Anna Stensvaag]:  Okay. We have time actually for one more question because you were very efficient in answering that, so thank you. "Can GVHD affect bladder causing pain, frequency, urgency?"

(57:08): [Dr. Hannah Choe]:  I can never say never with GVHD because we have classically always said that GVHD can affect any organ system in the body. I have personally not seen bladder involvement. But what can happen with GVHD is that the treatment that we're giving you with suppressing the immune system can put you at higher risk of infections that can cause those symptoms.

(57:33): So when you say that to me, I'm thinking automatically is this BK virus, for example. BK virus is a virus that will reactivate in patients that are immunocompromised and can cause those exact symptoms or it could be the symptoms that you're having could be a side effect of a medication. So unclear. I have personally not seen bladder graft-versus-host disease. Vulvar GVHD is very common or vaginal GVHD is very common, but bladder specifically I cannot speak to.

(58:05): [Anna Stensvaag]:  Okay. Well, thank you so much, Dr. Choe, for sharing your time and expertise. On behalf of BMT InfoNet and our partners, I would like to thank Dr. Choe for a very helpful presentation. And thank you the audience for your excellent questions. Please contact BMT InfoNet if we can help you in any way and enjoy the rest of your symposium.