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

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

Wednesday, April 21, 2021

Presenter: Karamjeet Singh Sandhu MD, City of Hope Medical Center, Duarte, CA

Presentation is 37 minutes long plus 14 minutes of Q & A.

Summary: Graft-versus-host disease occurs when a donor’s cells attack a transplant recipient’s organs and tissues. GVHD can occur throughout the gastrointestinal system as well as in the liver. This presentation describes how GVHD can attack the mouth, esophagus, stomach, large and small bowels and liver.

Highlights:

• Transplants from unrelated donors and those that use peripheral blood stem cells, instead of bone marrow, increase the risk that a transplant recipient will develop GVHD.
• Acute GVHD typically occurs in the first 100 days after transplant and typically affects the skin, GI tract and liver. Chronic GVHD typically occurs after day 100 and can affect many additional organs.
• It can be difficult to distinguish GVHD of the GI tract from other infections and diseases.A team of multi-specialty experts can provide the most accurate diagnosis and treatment.

Key Points:

(03:38) Several factors contribute to GVHD including donor source, preventive medications, conditioning regimens, and the health of the patient’s microbiome.

(06:24) Several medications and T-cell manipulation techniques may prevent or minimize the severity of GVHD.

(09:36) GVHD can affect the mouth, esophagus. stomach, bowels, and liver and cause a wide variety of symptoms.

(11:02) GVHD of the mouth can cause oral ulcerations, oral pain, dry mouth, and tooth decay.

(12:00) GVHD of the esophagus can cause difficulty swallowing and a narrowing of the esophagus that may be treated with dilation procedures.

(14:53) GVHD of the stomach can cause abdominal pain, weight loss and loss of appetite.  It may be treated with steroids, other immunosuppressive therapies, and dietary modifications.

(17:03) GVHD of the small and large bowel can cause abdominal pain, nausea, vomiting and weight loss and can often be mistaken for or confused with other diseases of the lower GI tract.

(23:45) GVHD of the liver does not usually occur alone, but when other organs are also affected by GVHD.  There may be no symptoms. Liver enzyme abnormalities may indicate GVHD but also have many other causes like medications or transfusions.

(28:04) Intestinal microbiota play a valuable role in promoting the immune system. There are several clinical trials underway to learn how to modulate gut microbiota and improve treatment responses.

(36:09) Treating GVHD is a team effort involving multiple practitioners, clinical trials and new treatments that hold promise for more effective remedies for GI GVHD.

Transcript of Presentation:

(00:01) [Marla O'Keefe]     Introduction. Hi. My name is Marla O'Keefe. Welcome to the workshop, chronic graft-versus-host disease of the gastrointestinal tract and liver. It is my pleasure to introduce today's speaker, Dr. Karmajeet Sandhu. Dr. Sandhu is an assistant clinical professor in the Department of Hematology and Hematopoietic Cell Transplantation at the City of Hope. He is also a member of the GVHD Committee and the leukemia disease team at the City of Hope. Dr. Sandhu is investigating novel strategies to prevent GVHD after transplant. Please join me in welcoming Dr. Sandhu.

(00:42) [Karamjeet Singh Sandhu]      Overview of Talk. Hello everyone. This is Karamajeet Sandhu. Thank you for this introduction and I'm thankful to the BMT Infonet for providing this opportunity to interact with all of you at this platform.

I'll be talking about graft-versus-host disease of gastrointestinal tract and the liver. We'll be discussing some basics of graft-versus-host disease, potential causes, how it presents, how it [it is classified]. And lastly, we'll talk about potential treatment choices. Then I will be open to take some questions from the audience.

(01:21) How to optimize transplant outcomes for patients. We all know that hematopoietic stem cell transplant is an immunotherapy with the primary goal to eliminate malignancy or recovery of the bone marrow function for some other benign diseases. It is always a challenge for us to optimize patient disease or treatment related variables with outcomes like choosing an optimal donor and strategies to prevent graft-versus-host disease, and balancing that against the risk of developing graft-versus-host disease, relapse, infections and mortality. [In addition], prior transplant co-morbidities contribute to transplant related mortality [are taken into account when recommending transplant] to the patient who may be able to tolerate the intensity of the treatment. Intensity of the conditioning regimen may be contributing to the organ toxicities, so balancing it with the patient comorbidities with the risk of relapse. Hence, there's overall fine balance that we have to optimize for each of the given patient.

(02:18) Patients who have had graft-versus-host disease have a lower risk of relapse. The slide here reflects on the role of immune system in eliminating the disease. The bar that is going above is the probability of the relapse, and one that is below reflects the time period. And lower curves over here reflect less relapse whereas the upper curves represent the increased risk of relapse.

So one can appreciate that the patients who had immune complications of the transplant like acute graft-versus-host disease and chronic graft-versus-host disease have relatively lesser risk of relapse compared to the patients who received [stem cells from an identical twin] or where [the stem cells] were depleted of T-cells to prevent graft-versus-host disease. So this confirms the concept of immunotherapy as we have discussed in our previous slide.

(03:08) Graft-versus-host disease is actually an immune reaction which is triggered by non-self or donor cells reacting toward self or recipient cells, recognizing them as foreign. Several immunosuppressive approaches are applied to prevent this reaction while waiting for the donor cells to have tolerance for foreign cells, allowing safe taper of these immunosuppressive therapies.

(03:38) Factors contributing to GVHD. There are several factors known to contribute to graft-versus-host disease. It can be even seen in fully matched donors although [it is seen more frequently] in patients with a mismatched donor, which could be either at the HLA or because of gender.

(03:52) Trials of the graft-versus-host disease preventive medications may impact the severity of the graft-versus-host disease. Conditioning regimen intensity plays very important tool in treating this process.

(04:07) Patients receiving bone marrow rather than peripheral blood stem cells [from the donor] have lesser risk [of developing GVHD]. And lately there has been expanding literature on the impact of the microbiome on transplant outcomes, including graft-versus-host disease.

(04:20) Some of you may be asking what is microbiome? So basically the microbiome is a collective genetic material of the microbes and decomposing bacteria, fungi, viruses that live inside and on the human body. It is believed that we have more microorganisms in our body than the number of cells.

(04:46) This slide reflects role of various factors as discussed in previous slides, which played a role in graft-versus-host disease.

(04:53) Stem cells from an unrelated donor increases the risk that the transplant recipient will get GVHD. The graph on the left side describes incidence of acute graft-versus-host disease among sibling donors which is about 39% here, and whereas the one on the right side describe incidence among those who receive unrelated donor graft and was roughly about 60%. So there was definitely about 20% increase in graft-versus-host disease if you had received unrelated donor transplant.

(05:23) Patients transplanted with bone marrow, rather than peripheral blood stem cells, have a lower risk of developing GVHD. In both of these graphs, the lower curves represent less graft-versus-host disease and the top curve represents more graft-versus-host disease. And in both of these curves, you can appreciate that patients who did not received radiation and received bone marrow as the stem cell source, have less graft-versus-host disease compared to the patients who received radiation or had received the peripheral] stem cells.

(06:07) Similarly, as on a previous slide, this slide shares the incidence of late acute graft-versus-host disease, which is about 10%, and the chronic graft-versus-host disease, which is about 50% among the transplant recipients.

(06:24) Several medications may prevent or minimize GVHD. There are several approaches or combinations of approaches in practice to prevent graft-versus-host disease. The top two here, tacrolimus and methotrexate, post-transplant cyclophosphamide, tacrolimus, and mycophenolate are one of the most common. And there is currently an ongoing randomized trial, which hopefully should be finished this year, and will give us some insight into the best approach to prevent graft-versus-host disease with currently available information.

(06:49) Tacrolimus and sirolimus are our go-to combination at City of Hope, although participation in the clinical trials is highly encouraged when available. Furthermore, depending on the patient's comorbidities, regimens could be optimized as in the fourth one, where tacrolimus is switched with sirolimus, perhaps with the hope that it will cause less toxicity to the kidneys or the nervous system.

(07:15) Manipulating t-cells may lower the risk of GVHD. T-cells play an important role in the pathology of graft-versus-host disease. Therefore, T-cell manipulation techniques have been part of graft-versus-host disease prevention for more than two decades now. Initially we used to deplete all T-cells from the donor cells, but lately, only a subset of T-cells are being depleted among the Orca graft recipients, which is currently [being studied] in ongoing clinical trials, and has shown some very promising results.

(07:47) So as we talked about the role of the microbiome in the pathology of the graft-versus-host disease, and several trials are currently ongoing, actually in the pipeline, incorporating microbiota modification approaches.

(08:07)  Differences between acute and chronic GVHD. There are several differences between acute and chronic graft-versus-host disease which is not only the timing, but also the biology and the organ involvement. And this allows optimizing treatment approaches.

One of the factors that is considered is the timing. If the onset is less than 100 days, it is acute GVHD. If the onset is more than 100 days, it is chronic GVHD. Those who have the features of acute graft-versus-host disease, but the onset is after 100 days, fall in the overlap or late acute GVHD category.

 In acute GVHD, there is destruction as a result of inflammation T-cells processes, whereas in chronic GVHD there's tissue injury with abnormal repair, leading to fibrosis and scarring.

(08:53) In acute GVHD, the most common organs affected are skin, the gastrointestinal tract and the liver whereas in chronic GVHD, we can see several other organs that could be affected, including eyes, gastrointestinal systems, skin, joints, muscle, lung, liver, nervous system, genitalia.

I will be focusing mostly on the digestive tract and graft-versus-host disease of digestive tract, from mouth then going up to the esophagus, stomach, small bowel, transitioning to the colon, and we'll be also talking about liver.

(09:36) Symptoms of GVHD in the mouth. Well, how does it present with each organ? So mouth is generally involved in the chronic graft-versus-host disease, and patients will report oral dryness, oral ulcer, pain with oral intake, more often with spicy or citrusy food, gum bleeding. And going down from mouth to the esophagus, patients have difficulty swallowing, painful swallowing and some of the patients, some incidents of choking, even with pills. And again, this is present in chronic graft-versus-host disease.

(10:15) Symptoms of GVHD in the stomach.  Stomach could be involved both with acute and chronic GVHD. Patients present with abdominal pain, weight loss, loss of appetite.

(10:23) Symptoms of GVHD in the intestines and liver. Small and large bowel could be involved in acute and chronic GVHD, but is more common in acute GVHD. Symptoms are loss of appetite, abdominal pain, weight loss, diarrhea, bleeding, constipation. So we can have a full spectrum depending on what part of the gut, and to what extent it is involved.

(10:45) Liver involvement is seen in both acute and chronic GVHD. In most cases, there are no symptoms, but elevated liver enzymes. And if there were symptoms, those are likely related to graft-versus-host disease in other organs presenting concurrently.

(11:02) Pictures of GVHD of the mouth. This slide shows some pictures of patients with the oral involvement of the graft-versus-host disease. On the left side here, we can see some oral ulcerations. I'm not sure if everyone can see it, but there were some ulcerations in this patient. And on the right side, you can see these lacey findings, what we call as the Wickham striae, and if you look in the back, there are some mucoceles or vesicles in the back.

(11:47) Symptoms, as we discussed in the previous slide, will be oral dryness, a need for more water while chewing, oral pain and long-term consequences, could be tooth decay.

(12:00)  How GVHD affects the esophagus.  When the esophagus is involved with graft-versus-host disease, patients will present with difficulty swallowing, and not uncommonly, painful swallowing, or even choking on food intake. And this is all a result of the chronic scarring of involved musculature. And the diagnosis is based on the clinical presentation, but we do endoscopic studies and barium swallow studies to aid with the diagnosis. Very often, you will hear the terms like Schatzki ring or esophageal strictures, which represent different presentations of the graft-versus-host disease of the esophagus.

(12:36) Endoscopic gastroduodenoscopy to view GVHD in the esophagus.  This slide here represent a procedure of endoscopic gastroduodenoscopy which is primarily used to diagnosis upper gastrointestinal graft-versus-host disease. After numbing your throat and administering anesthesia, a scope is inserted into the mouth and then into the esophagus, stomach, and sometimes they can push into upper portion of the small bowel, including duodenum and jejunum. So this allows the gastroenterologist to assess the mucosa and whether the inner lining is healthy and at the same time, they can do a biopsy which can help in the confirmation of the diagnosis.

(13:23) GVHD in the esophagus can cause strictures which make it difficult to swallow. So this is a continuum of the graft-versus-host disease of the esophagus. You can appreciate in the first image, there's a semicircular stricture or narrowing of the esophagus. And on the third image here, you can see the full view of the stricture or the length. Second image here depicts a barium swallow study where patients swallow liquid contrast, and then the x-ray images are taken. Again, you can see this nice narrowing of the esophagus here. And forth image here represent longer narrowing of the esophagus. Cases like this are rarely seen these days with the availability of better diagnostic and treatment approaches. And management mostly is immunosuppressive therapy and the endoscopic interventions which are discussed on the next slide.

(14:18) So this is a representation of the dilatation procedure performed for the dilatation of the strictures as shown on the previous image. As you can see in the first image, a guidewire is passed and subsequently these dilators are passed with increasing diameter over the guide wire until the optimal results are achieved. So this is just a presentation of the concept, but there are several other form of dilators which could be used by gastroenterologist.

(14:53) Diagnosis and treatment of GVHD in the stomach. We now move on to the graft-versus-host disease of the stomach. Very often we see it early after transplant, during the acute GVHD phase but patients may also present [with symptoms] after seven months post-transplant in the chronic GVHD phase. Symptoms are mostly abdominal pain, weight loss, loss of appetite.

(15:13) Diagnosis very often will be clinical, but we work with gastroenterologists who can perform endoscopic gastroduodenoscopy to help with the pathologic confirmation. And depending on the severity of the symptoms, we can treat patients with a topical steroids, which often is not patient's favorite as it is mixed with the corn oil, so it has the specific taste to it. And if it is not tolerated or the symptoms are severe, we can often use other steroid formulations along with the steroid spreading immunosuppressive agents.

(15:43) Gastroparesis is one of the late complications of chronic graft-versus-host disease in the stomach. In gastroparesis, movement of the food from the stomach to the small intestine is stopped or delayed without any evidence of obstruction. Symptoms are mostly feeling full shortly after eating little food.

(16:15) Gastric emptying scans can be done to help with the diagnosis. Treatment is combination of several approaches, including immunosuppressive therapies, agents to increase the motility of the stomach and gut, along with gastric acid suppressants to help with acid reflux. And the surgical approaches could be considered in some refractory cases.

(16:37) It's not noted in the slide, but dietary modifications can actually help minimize the symptoms, which include low fat diets or soluble fibers. So we encourage working closely with multiple specialties, including a nutritionist. And avoiding carbonated drinks, along with alcohol and smoking, may also help with some of the symptoms associated with this problem.

(17:03) Symptoms of  GVHD in the small and large bowel. Now, moving down to the small and large bowel, we'll be discussing them together as there's a lot of overlap of the symptoms in both of them. Again, abdominal pain, nausea, vomiting, weight loss remain the primary symptoms with most gut-related graft-versus-host disease. But we will also notice diarrhea, and in advanced cases, we'll notice bleeding from severe inflammation or even paralysis of the gut making it non-functional, and presenting instead of of stool.

 One of the main symptoms is diarrhea, but that does not always mean graft-versus-host disease, even among the transplant patients. And for the sake of discussion, we'll be splitting it into infectious and non-infectious causes.

(17:51) Infections can cause symptoms  similar to those seen in GVHD of the small and large bowel. So infectious could be bacteria like C. diff, which most of you have heard about or Clostridium difficile. This infection is very common. Other cause could be campylobacter, Shigella, or salmonella, but GVHD has to be considered in the appropriate context. Very often we see reactivation of CMV, adenovirus or even EBV with the involvement of gut in immunocompromised patients. Rotavirus and norovirus could be acquired in the community. Cryptosporidium and mycobacterial could be other less common causes.

(18:31) Other diseases with symptoms that are similar to GVHD of the bowel. In the right context, especially when the patient long out after transplant without any evidence of graft-versus-host disease elsewhere, we consider inflammatory bowel disease like Crohn's disease or ulcerative colitis, also, in the differential diagnosis. The availability of an expert pathologist to aid with the diagnosis, who has seen a large volume of graft-versus-host disease cases, as you find in a transplant center, is very, very important. Therefore, whenever our patients are admitted to an outside facility with transplant related complications, we'll try to have them transferred to a cancer center when possible.

(19:09) Cord colitis is another unique pathology seen early among cord blood transplant patients. It is presumed to be caused by bacterial infection and responds very well to antibiotics. Therefore, a team with the knowledge to do a timely diagnose of this complication could be life-saving.

 (19:25) Graft-versus-host disease can often mask thrombotic microangiopathy syndrome because it basically is a destruction of red blood cells and consumption of platelets that leads to the blockage of the small vessels and in turn damage to the organs because of the dysregulated immune process.

(19:47) In the community, we see if this is as a result of deficiency of particular protein, but among transplant recipients, this could be very well be triggered by one of your medications. It can be treated by stopping the triggering agent or timely introduction therapies that help with that dysregulated activation of the immune system. Patients very often may relapse in the gastrointestinal system, which may cause diarrhea.

(20:17) GVHD and therapies can lead to pancreatic insufficiency. Over time, as a result of the disease and therapies, patients may have pancreatic insufficiency because the enzymes that help with the digestion of food are not being produced, and that, in turn, leads to diarrhea. Patients may have foul smelling stools, weight loss, bloating. So checking the content of the fat in the stool can help with the diagnosis. Replacing the pancreatic enzymes can help improve the symptoms.

(20:49) Small bowel bacterial overgrowth as the name suggests, is the colonization of small bowel microorganism, which otherwise should be in the large bowl. It can present in conditions where there's slow clearance of food and enzymes, as we talked about above in gastroparesis, and from some medications like antacids. In immunosuppressed patients with the decreased production of some immunoglobulins which keep the balance of the microorganism in the gut, it can be diagnosed with a breath test, checking for the content of the gases in the breath being produced by these organisms. And the treatment could be antibiotics, and sometimes dietary modifications can be helpful.

(21:34) Diarrhea is a common symptom of many infections as well as GVHD and requires multi-specialty expertise for an accurate diagnosis. Lastly which perhaps is one of the most common causes [of diarrhea] is medications and the chemotherapy agents that can cause diarrhea.

(21:52) So from previous slide it's perhaps clear that diagnosis of graft-versus-host disease requires multi specialty expertise, along with high suspicion in the right clinical context.

(22:03) Endoscopic procedures are an important diagnostic tool. So depending on the severity of the symptoms, we can proceed with lower endoscopic procedures which are sigmoidoscopy and oral colonoscopy. As you can see in this image on the right side which depicts passing up the scope into the colon, the patient would receive anesthesia and subsequently a tube would be introduced through the anus into the colon. Very often flexible sigmoidoscopy will suffice where the gastroenterologist would just go as high where my cursor is in the sigmoid colon. They will just visually look at the lining of the gut and at the same time will take the biopsy. And if it is inadequate or there is some diagnostic uncertainty, or there is a suspicion of other pathologies, gastroenterologists may go and look at the whole colon.

(23:01) The challenge with the colonoscopy is that it will often require prep for better visualization of the colon. Treatment when graft-versus-host disease of the gut is confirmed is, again, immunosuppressive therapy, including steroids and other nonsteroidal agents. However, more often than not, if the suspicion is high, we'll start treatment while waiting for the confirmation of the biopsy sample, since in serious cases, delaying the treatment could be detrimental.

(23:45) GVHD of the liver usually occurs with involvement of other organs and symptoms. We'll now move to the graft-versus-host disease of liver. Most often, patients will present with jaundice, but otherwise may not have any other symptoms from the liver standpoint, except that majority of the times, liver graft-versus-host disease will occur concurrently with involvement of other organs. Therefore symptoms, may primarily be of other organs.

(24:08) Liver enzyme abnormalities may signal GVHD or have other causes like medications or transfusions. One may have liver enzyme abnormality. It can present both in acute and chronic graft-versus-host disease. However, we have to be mindful of other causes of liver enzyme abnormalities, and very common among them is medications.

(24:25) Veno-occlusive disease, also called sinusoidal obstruction syndrome, is another complication among transplant recipient, which happens mostly within first month of transplant, and with patient complaining of right upper abdominal pain, weight gain. An ultrasound abdominal can help with the diagnosis. Defibrotide which is a blood thinner and works against certain portion of the clotting cascade has found to be a promising treatment.

(24:53) Fatty liver disease is more prevalent among a Western population and is a very common cause of elevated liver enzymes. And the patients who have been requiring frequent blood transfusions develop iron overload, and that can contribute to a rise in the liver enzymes.

(25:18) Infections - it's 's incompletely here - I should've mentioned viral hepatitis like A, B and C besides CMV, and adenovirus, can cause liver enzyme abnormalities. And obviously gallbladder diseases are other common causes of liver enzyme abnormality.

(25:40) How to diagnose GVHD of the liver. Diagnosis, again, starts with a clinical suspicion, but we have to rule out other pathologies which I have discussed in the previous slide by doing liver images with the ultrasound or the CT scan of the abdomen. HIDA scan is another scan which can be helpful in diagnosing any gallbladder issues ruling out the possibilities of the cholesterol status. Liver biopsy could be considered, but is very rarely used to avoid any major complications of the invasive procedure. Infectious blood work up to rule out major infections and obviously review of the medications can help, which can potentially be contributing to the rise in the liver enzymes. And once confirmed, treatment again is immunosuppression, which would be combination of steroids along with some non-steroidal approaches.

(26:33) Grading the severity of GVHD helps determine appropriate treatment options. So once we have the diagnosis, it is important to appropriately grade graft-versus-host disease, which is not only a prognostic tool, but also is useful in making treatment choices depending on the severity of the symptoms.

(26:46) Acute graft-versus-host disease mostly impact skin, liver, stomach, upper gastrointestinal tract, lower gastrointestinal tract. Therefore those are incorporated into the grading. Skin will be graded based on the body surface area involved, and liver again, based on the extent of the liver enzyme elevation, and upper gastrointestinal, depending on the severity of the symptoms like nausea, vomiting, and the lower gastrointestinal with the amount of the diarrhea. And especially, when you have severe abdominal pain, poor movement of the stool, and frank blood, it is already a stage four.

(27:29) And chronic graft-versus-host disease can impact relatively more organs, so that the grading is relatively complex compared to the acute graft-versus-host disease. And depending on the severity and number of organs involved, it can be divided into mild, moderate, and severe. I will not go through the details for the sake of the time, but you will have access to these slides. And if you have any questions, I will be available to answer.

(28:04) Intestinal microbiota play an important role in promoting a healthy immune system. I'd like to take a few minutes to go over a few slides related to intestinal microbiota, which has been gaining a lot of interest among transplant patients with malignancies and other diseases.

(28:13) We have previously discussed what is microbiota, and intestinal microbiota is all the microorganisms in the gut. It is now understood that it plays a valuable role in promoting our immune system. Several studies have been done in transplant recipients, which have shown that decreased diversity and the presence of certain microbial species have been associated with the increased risk of graft-versus-host disease, failure to response to treatment, and increased non-relapse related mortality. Therefore several clinical trials are currently undergoing to modulate gut microbiota to prevent and improve treatment responses.

(29:04) Fecal or stool transplants and capsules show promise in relieving symptoms of GI GVHD. So there are several approaches to modulate microorganism in the gut. And one of them includes a fecal or stool... So-called stool transplant. I'm highlighting two clinical trials which have already been published. The one on the top one, it was published in 2020. And it was from Netherlands. And these were the patients who failed to respond to steroids for gut graft-versus-host disease, and had no other suitable options. They received donor stool suspension about 300 to 500 cc, which is roughly about more than 50 gram of the stool through the nasal duodenal tube. So basically, nasal duodenal is a tube that is inserted through the nose, bypassing the stomach into the early part of the small bowel, which is duodenum.

(29:53) I think the responses are very impressive with 10 out of the 15 patients achieving remission, but it needs to be studied in a larger population at multiple centers. And I've heard about a phase three study that is currently in the works.

(30:10) And other interesting clinical trial was capsules filled with the stool microbiome suspension administered to the patient after their white blood cells recovered post-transplant. This study did confirm that diversity of the gut microbiome could be improved through this approach, although clinical benefit was not witnessed in the study, which is the decreased risk of graft-versus-host disease. I expect that similar clinical trials will be designed in the future to try to improve the clinical outcomes of transplant, or maybe it will be used with some other combinations.

(30:52) Numerous other treatments are now being studied in clinical trials to treat GI GVHD. There are several other non-stool transplant or non-fecal transplant trials, which could require a separate presentation. However, I will highlight only a few. There's a currently ongoing clinical trials studying a gluten-free diet in preventing graft-versus-host disease.

(31:10) There was a clinical trial with the probiotic in the form of the lactobacillus that was administered patients, but it did not show reduced incidence of graft-versus-host disease among transplant recipients.

(31:25) At City of Hope, we have recently finished a clinical trial using Clostridium butyricum which is CBM 588. Now this product has been around in Japan for actually more than 50 years, and there has been preclinical work revealing impact on the gut microbiota. They finished a clinical trial among lung cancer patients, and have noted that patients who were receiving CBM 588 responded favorably to immunotherapy.

(31:53) So analysis of our clinical trial among transplant patients is currently ongoing and we're seeing some positive signals. Hopefully we'll be able to share the results later this year.

(32:03) And similarly, we have opened another clinical trial this month where patients will be administered human lysozyme rich goat milk from goats, which was genetically modified to produce human lysozyme. And the lysozyme content in this milk is about 60% of what is expected in human breast milk. And the concept is replicating the benefits of breast milk, as breast milk has shown benefit among diarrhea illnesses in children. They have completed some pre-clinical studies in animals and have shown faster clearance of diarrhea and improvement in the gut health after administration of this product. We expect that consumption of this may help improve the gut health, which is severely impaired by the treatment. And that improving diversity of the gut microorganism may result in some transplant related outcomes, including graft-versus-host disease.

(32:58) Steroids remain the mainstay of treatment for GI GVHD but have side effects. There are several treatment options for graft-versus-host disease, but steroids remain the mainstay of the treatment. Unfortunately, the outcomes [benefits] come at the risk of several complications including raising glucose levels, some bone weakness, muscle weakness, suppression of the immune system, and difficulty sleeping. So they will be given along with other agents to allow safe taper once that response is achieved.

(33:22) After patients taper off immunosuppressive drugs, they may need to restart them if symptoms of GVHD return. Very often, depending on the severity of the disease, you will see that patients are either being continued on a previous immunosuppressant, including tacrolimus, sirolimus CellCept, or these drugs are being reintroduced if you have GVHD symptoms after the completion of the taper. And very recently Jakafi, which is an oral medication has been approved for patients who have failed to respond to steroids after acute graft-versus-host disease - this drug, and some sister drugs working on the same pathway, also have shown benefit in chronic graft-versus-host disease as well.

(34:00) Hopefully, we should see some of these results leading to approval, but in the meantime, we're often using these drugs off-label as well.

(34:08) And we are expecting an approval of Belumosudil later this year, which has shown promising activity among patients with chronic graft-versus-host disease who have failed multiple previous treatments. Ibrutinib was one of the first drug that was approved for chronic graft-versus-host disease. Infliximab and etanercept are given intravenously and are very often used among patients who have very advanced presentation along with other agents that are discussed above. And extracorporeal photopheresis, I will address in the next slide, but we highly encourage patients to participate in the trials, as that allow us to open several most promising options as has been the case over the past several years.

(34:59) Extracorporeal photopheresis is a safe treatment for patients with GVHD. Extracorporeal photopheresis, is perhaps one of the safest treatment used among patients with graft-versus-host disease who have failed previous treatments, and may be at risk off direct organ toxicities or immunosuppressive complications from several other immunosuppressive therapies. One of the limitations with this is that it does not work immediately. If you do not have good venous access, it will require intravenous catheter placement for the blood draw, and frequent visits to specialized center for the treatment, if it is being done on the outpatient basis. The patient's blood is drawn as you can in this image on the right side. In the machine, white cells are separated, and the plasma and the red blood cells are returned to the patient. And the white cells are then treated with the UVA radiation before being returned back to the patient. It modulates some of the quality of the cells to those which play a more of an anti-inflammatory and mitigating the graft-versus-host disease.

(36:09) Treating GVHD is a team effort with improved outcomes over the years.  Coming to my end of the talk, I would like to emphasize that graft-versus-host disease management is indeed a team effort. It is a complex disease and requires close communication with the team and patient compliance with the treatment plans. Over the years, our outcomes have been improving, with better understanding of the mechanism [of GVHD] and available treatments, along with improvement in the supportive care.

(36:33)  The role of clinical trials, nutritionists, and physical therapists. However, I always, as I have said before, encourage patient to participate in clinical trials where available after discussion with your transplant team. It definitely can take an emotional toll on an individual who is already challenged by the primary disease, and now with the complications of the transplants. It requires a lot of support both from family and your team at the transplant center.

(36:58) Nutrition is very, very, very important, and can understandably at times, with the gut involvement, become very challenging. So work with the nutritionist to find out the optimal plan, that can really help to keep up with the nutritional requirements.

(37:14) These treatments take a toll on one's physical ability, so working with a physical therapist, occupational therapist during admission, and then upon discharge to help you recover to your baseline can help. You can be on multiple drugs for the management of the disease, but sometimes these medications can contribute to complications, if not closely monitored. So there has to be close communication with the team in regard to the dosing side effects, et cetera. I never recommend that anyone start or stop any of GVHD medications without discussion with your team. Thank you. I'll be open for questions.

(37:58) [Marla O'Keefe]      Q & A. Thank you, Dr. Sandhu for this excellent presentation. We will now take questions. As a reminder, if you have a question, please type it into the chat box on the lower left-hand corner of your screen. Our first question is what does vomiting bright red blood mean?

(38:19) [Karamjeet Singh Sandhu]      One thing bright red blood means is that you have a bleeding somewhere in the upper gastrointestinal tract. It can be esophagus, it can be stomach, and there could be several reasons. Yes, graft-versus-host disease is an inflammatory process, but you can have as simple as gastric ulcers or the ulcers due to some infection in the gut or the stomach. So that would require an endoscopic procedure for the assessment and based on that, which the management will be guided.

(38:56) [Marla O'Keefe]     Thank you. The next question is, is an increase in formed bowel movements a sign of GVHD?

(39:16) [Karamjeet Singh Sandhu]      Actually not. Very often, the patients who have graft-versus-host disease of the gut in the past will have some sort of irritable bowel syndrome. So it takes months before the stools become regular. So as long as your stools are formed, it's less likely you have graft-versus-host disease of your gut. And it could be one of the other pathologies that we talked about.

(39:44) [Marla O'Keefe]      Next question. A liver biopsy shows I have GVHD six months post allotransplant. AST and ALT began to spike as soon as I stopped tacrolimus. Low-dose prednisone seems to be working at getting AST and ALT down. Will I always have liver GVHD or will it go away?

(40:10) [Karamjeet Singh Sandhu]      There's a good chance that with the time, it will go away, but it will require a very slow taper. The first and foremost goal is to achieve the best possible response. And once the response is achieved, then we wait for some time [to see if] that that response is durable, then we very gently try to taper off. And I've seen patients whom we have been able to successfully taper off, but it requires very close monitoring.

(40:41) [Marla O'Keefe]      Thank you for that answer. Can GVHD become an issue after CAR T cell treatment? If so, what are the side effects?

(40:52) [Karamjeet Singh Sandhu]      GVHD after CAR T, depends where we are getting the CAR Ts from. Are these CAR Ts from the donor or are these CAR Ts from the patient, your own self? So isif these CAR Ts are from the donors, hypothetically one can expect some immune activation or immune response. So it should not be any different than the graft-versus-host disease presentation, but I think it is very rarely seen.

(41:37) [Marla O'Keefe]      Okay. How does GVHD of the pancreas present? I developed exocrine pancreatic insufficiency seven months after transplant at the same time as I stopped immunosuppression. I wondered if it might be GVHD of the pancreas, but my doctor says this is extremely rare.

(42:02) [Karamjeet Singh Sandhu]      The graft-versus-host disease of the pancreas or the pancreatic insufficiency, what we see is more often is the pancreatic insufficiency. Basically impaired production of certain enzymes as we talked about. Graft-versus-host disease of the pancreas is not very well described. And more often than not, we see pancreatic insufficiency and all we do is the replacement of the enzymes that are being produced by pancreas. And they work very well if the diagnosis is confirmed.

(42:39) [Marla O'Keefe]      Thank you. Does iron toxicity put me more at risk for GVHD of the liver?

(42:47) [Karamjeet Singh Sandhu]     Not exactly. You maybe have a lower threshold for the rise of the liver enzymes with already compromised liver function, but to say that it plays role in the risk of graft-versus-host disease, it is not described.

(43:06) [Marla O'Keefe]      Next question. Do probiotics in pill form taken after transplant help or hurt with possible local explosion of microbes in the colon?

(43:19) [Karamjeet Singh Sandhu]     Actually, we don't have enough data, so I generally don't recommend patients to take them unless you have discussed it with your primary transplant physician. And currently, there are ongoing clinical trials, and hopefully in the next few years, we will learn more if taking this over-the-counter probiotic really helps with the healing of the gut or helping your immune system.

(43:50) [Marla O'Keefe]     Good answer. So we'll have to stay tuned for more information on that. Do you see any positive results with introducing a probiotic for GI GVHD probiotic?

(44:05) [Karamjeet Singh Sandhu]      As I talked toward the end of my presentation, there were three slides. For the patients who have failed the steroids, there have been clinical trials with the stool transplant and there will be a randomized phase three clinical trial which probably should come later this year or next year of the stool transplant to see if the patients who have failed the steroid for the graft-versus-host disease may benefit from the stool transplant. And similarly, there will be a lot more clinical trials which will be coming. So I think it should be studied in the context of the clinical trials and not taking probiotics or any other agents by yourself.

(44:52) [Marla O'Keefe]      Thank you. Why do we develop hyperpigmentation inside the mouth and lips and will it ever go away?

(45:02) [Karamjeet Singh Sandhu]      It definitely happens when the chronic inflammation and the scarring, and with time, it often decreases, but very often than not, patients will have persistence of it.

(45:17) [Marla O'Keefe]       Next question. Have you seen positive results with stage four GI GVHD and photopheresis? The patient has been on multiple drugs listed that have not helped. Medrol seems to be the only thing working, but trying to wean off of it due to the long-term effects.

(45:40) [Karamjeet Singh Sandhu]       Again, depends. You are talking about the stage four graft-versus-host disease with the photopheresis? I personally have not seen, if it is what you're talking about, stage four graft-versus-host disease, generally, when we use photopheresis, we use it in combination with other agents, especially when we are talking about stage four disease. Very often patients will have some other complications, either their counts are very suppressed, either they have organ injuries which limit the use of the systemic agents or other treatments that I discussed in previous slides. So that perhaps I'm presuming could be the reason that photopheresis is introduced to aid with some of the steroids or other less toxic approaches for the management of the graft-versus-host disease. But in my personal practice, I personally have not seen an improvement in the stage four graft-versus-host disease just by photopheresis itself. But yes, with the combination of other agents.

(46:55) [Marla O'Keefe]       Thank you. I am three years post-transplant and I have mild ocular and oral GVHD. For two and a half years, my liver enzymes were elevated, but now within normal limits since five months ago. I still get a crampy feeling after eating. Is it reasonable to stop the tacrolimus? I'm on one milligram twice a day.

(47:20) [Karamjeet Singh Sandhu]       It depends on how good the control of your ocular and oral graft-versus-host disease is. And I will probably discuss it with your transplant physician to come up with a plan, as they know your disease course better. And we'd discuss like the abdominal cramping, not necessarily... The liver graft-versus-host disease, very rarely has any symptoms and abdominal cramping may have nothing to do with your liver graft-versus-host disease, and may have some other pathology that needs to be investigated.

(47:55) [Marla O'Keefe]      Thank you. Next question is which one is better photopheresis or CellCept? I was taken off photopheresis and put on CellCept.

(48:08) [Karamjeet Singh Sandhu]      They have not been compared side to side. So I will not say that one is better than the other. It is again, there has to be a particular indication. So the photopheresis has its own profile of limitations. So if you don't have a good venous access, you need to catheter, and you're having recurrent infections, more frequent visits, or your disease is progressing, or not responding to the photopheresis which perhaps I assume, could have been the reason to switch to a CellCept. I think it is to be understood in the context of how advanced your disease is.

(48:58) [Marla O'Keefe]     Thank you. I just started receiving infusions of Entyvio for GI GVHD. Has this been found to be effective?

(49:23) [Karamjeet Singh Sandhu]     In my personal practice, I have not used this in any patients so far. And I know this has been in use for the management of some of inflammatory bowel diseases like ulcerative colitis or Crohn's disease. I assume there may be some clinical trial at this specific place where they're using this among this patient with the GI graft-versus-host disease.

(49:57) [Marla O'Keefe]      Thank you. Okay. This is going to be our last question. I am six years post BMT. Is it still possible to get GVHD?

(50:12) [Karamjeet Singh Sandhu]     The highest risk of getting graft-versus-host disease is during the first couple of years [after transplant]. So after that, the risk is fairly minimal of occurrence of any graft-versus-host disease.

(50:25) [Marla O'Keefe]      Okay. That's good. I think we might have time for one more. I have heard that a bone marrow stem cell donor might be better than a peripheral blood stem cell donor in terms of GVHD. Is that an option in any medical centers?

(50:40) [Karamjeet Singh Sandhu]      In majority of the transplant centers, they should be able to offer that. But this has to be, as I said in the very first slide we talked about, you have to balance various things. You have to balance graft-versus-host disease, risk of relapse, infections, your comorbidities. So all those have to be taken in the context before deciding if this patient will benefit from peripheral blood stem cells or bone marrow graft, and again, and the donor has to be available for bone marrow graft since bone marrow graft is more of an invasive procedure for donor, so they may not be interested in it.

 (51:26) [Marla O'Keefe]     Okay. We're going to have to wrap it up. Dr. Sandhu that was a wonderful, informative presentation. Thank you so much. And on behalf of BMT InfoNet and our partners, thank you for your very helpful remarks and thank you, the audience for your excellent questions.