Graft-versus-Host-Disease of the Gastrointestinal Tract and Liver
July 12, 2020 Part of the Virtual Celebrating a Second Chance at Life Survivorship Symposium 2020
Presenter: Zachariah DeFilipp MD, Transplant Physician, Massachusetts General Hospital
Presentation is 38 minutes with 22 minutes of Q&A. Download Speaker Slides
Summary: Graft-versus-host disease commonly affects the the gastrointestinal tract and /or liver in patients who have had an stem cell transplant using cells from a donor (allogeneic transplant). Treatment may require a combination of local therapies, systemic therapies, procedural interventions and/or various types of supportive care.
- GVHD of gastrointestinal tract can affect several organs including the esophagus, stomach, small intestines, large intestines, and colon.
- Symptom of GVHD in the GI tract may include diarrhea, abdominal pain or cramping, nausea, vomiting, poor appetite, and weight loss, although these can also be symptoms of other disorders. Difficulty swallowing may be a sign of chronic GVHD.
- When GVHD affects the liver, there are seldom symptoms. Liver GVHD is usually first detected by blood tests.
03:48 There are two forms of graft-versus-host disease (GVHD): acute and chronic. Both can affect the GI tract and/or liver, but differ in time of onset and, in some cases, symptoms.
09:24 80 to 85% of stem cell transplant patients who develop acute GVHD will have GVHD in the liver or GI tract. Of those who develop chronic GVHD, 50 to 70% of patients will have GVHD in the liver or GI tract.
16:05 GVHD is often a diagnosis of exclusion after tests rule out other potential causes for the problems such as infections, side effects from medication, reflux, a hernia or peptic ulcer.
21:53 If GVHD is suspected in the GI tract, an endoscopy may be needed to look at inside the patient’s esophagus, stomach and small intestines. A colonoscopy may be needed to look inside the large intestines and rectum.
25:54 Tests for GVHD of the liver may include blood tests, physical exam, CT scan or MRI and a biopsy.
28:47 Most treatments for GVHD of the GI tract or liver can be done in the outpatient clinic, but sometimes the patient must be admitted to the hospital.
30:00 Therapies for GVHD of the GI tract may include oral medications, such as budesonide, systemic steroids such as prednisone or other immunosuppressant agents, procedural interventions such as esophageal dilation and various forms of supportive care.
33:39 Patients with liver GVHD may receive Ursodiol to decrease liver inflammation, although it does not address the underlying cause of the liver inflammation.
35:09 Symptoms of GI GVHD such as ongoing nausea and vomiting can make a patient feel very weak. Physical therapy to build up strength as well as psychological and social support may be needed for both the patient and caregivers.
Transcript of Presentation
00:00 [Moderator] Welcome to the chronic Graft-versus-Host Disease of the Gastrointestinal Tract and Liver workshop. My name is Sue Stewart and I will be your moderator for today. It's my pleasure to introduce to you Dr. Zachariah DeFilipp. Dr. DeFilipp is a physician in the Blood and Marrow Transplant Program at Massachusetts General Hospital, and an assistant professor of medicine at Harvard Medical School. Dr. DeFilipp serves as principal investigator on multiple clinical trials on the prevention and the treatment of graft-versus-host disease. He's an active member of the American Society of Transplantation and Cellular Therapies and the Center for International Blood and Marrow Transplant Research. Please join me in welcoming Dr. DeFilipp.
00:51 [Dr. DeFilipp] Thank you, Sue. I want to start out by thanking the symposium organizers for the opportunity to speak today, and I want to thank everyone who's joining today's talk. I know that it's a beautiful summer day, at least in Boston, and I hope that everybody's having a happy and healthy summer. I want to thank you for taking time out of your day to come and learn a little more about graft-versus-host disease.
So, with today's lecture we're going to talk about the entity called graft-versus-host disease, but specifically we're going to talk about how this complication can affect the gastrointestinal tract and the liver.
So, this is the agenda. We're first going to take a step back and talk a little bit in more broad terms about what is graft-versus-host disease. Then we'll start to focus in on the symptoms of graft-versus-host disease, specifically when it affects the gastrointestinal tract and the liver. We'll talk a little bit about what's involved in the workup and how do we make a diagnosis of graft-versus-host disease in these areas. And then we'll cover ways in which we try to prevent graft-versus-host disease and ways to also try to treat it once it occurs.
Overview of graft-versus-host disease (GVHD)
02:24 So, we'll begin with the overview of. So, there is going to be a lecture, I believe, tomorrow where Dr. Corey Cutler will speak about graft-versus-host disease in more detail. But I think in order to be able to talk about the specific organs today, we need to first establish what graft-versus-host disease is.
So, graft-versus-host disease is a common complication that occurs in transplant recipients. It's important to note that graft-versus-host disease will only occur in patients who are undergoing an allogeneic transplant, which means a transplant where the recipient receives cells from a donor. What graft-versus-host disease is, it's a syndrome that can occur after the transplant where the donor cells, which we refer to as the 'graft,' recognize the transplant recipient's body, which we refer to as the 'host,' as being foreign, and this can lead to those donated cells attacking and causing damage to the transplant recipient.
There are two types of GVHD: acute and chronic
03:48 So graft-versus-host disease has two major forms in which it can manifest. There is acute graft-versus-host disease and chronic graft-versus-host disease, and I think it's important that we first start off by establishing a little bit of the differences between acute and chronic graft-versus-host disease. It's important to know that both the acute form and the chronic form of graft-versus-host disease can affect the gastrointestinal tract and the liver. But we can see a lot of variation in how graft-versus-host disease manifests in transplant recipients. Sometimes patients may only have one organ system that is affected by the graft-versus-host disease. Other times patients may have more than one organ involved, either at the same time or sequentially.
When acute and chronic GVHD typically occur
04:46 So this is a figure just showing a little bit of the timeline of graft-versus-host disease when thinking about these different forms. So, if you go back years or decades in transplant history, there used to be a definition of acute and chronic graft-versus-host disease made strictly by time. And that time point, which was somewhat arbitrarily elected was the day 100 post-transplant milestone. In this figure you can see the vertical line with the dashes right at day 100 there. And the way it used to be categorized was that if any graft-versus-host disease happened before day 100, that was considered acute graft-versus-host disease, and if it happened after day 100 it was considered chronic graft-versus-host disease.
But what we started to see in our practice was that this definition did not seem to be sufficient, that we really saw that acute and chronic graft-versus-host disease have a little bit of a different nature, a different characteristics in how they manifest. And then later there's been much, much research done that shows that the biology of acute and chronic graft-versus-host disease differs as well.
So what I'm going to highlight here is that still with acute graft-versus-host disease, we can still see that a lot of it typically happens before day 100, but you do have cases of acute graft-versus-host disease that can happen almost all the way out to a year after the transplant. At the same time, when looking at the chronic graft-versus-host disease, while it is true that the majority of graft-versus-host disease happens after day 100, you can see that sometimes it does occur even before that time period.
So, this table kind of comes... go on what we've established here that acute graft-versus-host disease, we'll just say, typically occurs earlier after transplant, while chronic graft-versus-host disease typically occurs later after transplant. I think one thing that is important to note is that there are different manifestations in the body of acute and chronic graft-versus-host disease.
Organs affected by acute and chronic GVHD
07:18 Acute graft-versus-host disease typically affects the skin, the gastrointestinal tract or the liver, while chronic graft-versus-host disease can affect a number of other organs. As you can see here the skin, the nails, the mouth, the eyes, the gastrointestinal tract, the liver, the lungs, the muscles and joints. But what I want to focus here today on is as you can see emphasized with these red boxes that both acute graft-versus-host disease and chronic graft-versus-host disease can affect the gastrointestinal tract and the liver. And we'll talk a little bit about what this looks like and how these can differ.
Organs that are part of the gastrointestinal tract
08:03 So, we've thrown around the term the gastrointestinal tract and the liver. This illustration really just comes so that we're all on the same page in regards what we're talking about. We'll start with the easy part, the liver refers to the organ knows as the liver, but the gastrointestinal tract can affect a number of other organs. So, we can see down the esophagus, which connects your mouth to your stomach, and then the stomach into the small intestines, which leads to the large intestines here or the colon, and then eventually to the rectum.
Then there's also an organ in there that contributes as well the pancreas, which we really won't focus too much on today, but just understanding that the gastrointestinal tract is long and involved, and there are different manifestations that a patient can, or different symptoms that a patient can experience based on which part of this long and involved gastrointestinal tract is being affected by the graft-versus-host disease.
Acute GVHD and chronic GVHD in the GI tract and/or liver are common after transplant
09:24 So this is a study that was published a few years ago, looking at changes in the care of acute graft-versus-host disease over time. And I just want to highlight one small table that was included in this paper just showing how common it is to have either gastrointestinal or liver involvement of acute graft-versus-host disease. So, in patients that had developed graft-versus-host disease over time they looked at whether the skin was involved, the GI tract or the liver, or combinations thereof. And what you can see here is that consistently over time, whether patients were transplanted in the late '90s or into the 2000s, it shows that about 80 to 85% of patients who develop acute graft-versus-host disease will have some involvement of either the gastrointestinal tract or the liver. So, these are pretty common manifestations.
This is a figure from a separate study specifically looking at chronic graft-versus-host disease, and the incidence of chronic graft-versus-host disease on different organs based on whether the transplant recipient received donor cells that came directly from the bone marrow or were mobilized from the blood. And my main take-home from here is that you can see that 50 to 70% of patients will have some liver chronic graft-versus-host disease involvement and 30 to 40% will have some involvement of their GI tract based on this older study. So, you can once again see that involvement of these two organ systems is quite common in chronic graft-versus-host disease as well.
So now let's move a little bit more into the presentation of graft-versus-host disease in these organ systems. So, we're going to look first at the gastrointestinal tract, and we'll look at the liver, and for each of them we'll look at acute graft-versus-host disease as well as chronic graft-versus-host disease.
Symptoms of acute or chronic GVHD in the GI tract or liver
11:42 So one thing that you'll probably notice is that there are many of the same symptoms in both of these columns. So, GI tract graft-versus-host disease can present with diarrhea, abdominal pain or cramping, nausea or vomiting, poor appetite, and weight loss. One presentation that is a little more specific to chronic graft-versus-host disease is difficulty swallowing where the reason for that difficulty is graft-versus-host disease that is involving the esophagus. So that's something that we usually see more with the chronic form, and not very often with the acute form.
When it comes to the liver, most of the cases of liver graft-versus-host disease, whether acute or chronic, is that they have no symptoms, so it's an asymptomatic manifestation meaning that a transplant recipient may go to their clinician and have lab work drawn, and there could be some abnormalities, some elevated readings of the liver function tests on the labs that may indicate that there is some evidence of graft-versus-host disease, but the patient does not experience any symptoms from this.
Sometimes if those liver function tests are elevated, specifically the bilirubin, patients can develop jaundice, which we'll see a picture of, it's like when the skin or eyes can turn a shade of yellow, and it can also be accompanied by dark urine.
I have a few pictures here. One thing that's a little difficult with this topic is there's not great pictures for some of the symptoms that patients can experience with gastrointestinal GVHD, but here you can see what on a x-ray, a esophageal stricture can look like. So, this is a picture taken from a patient, an x-ray that is, and you can see this kind of light vertical column is the esophagus, and the red arrow is pointing to an arrow where there's a stricture. And as you can may imagine, if a patient's trying to eat and food is coming down to that stricture and it feels like it's getting stuck, that can be a very distressing and problematic symptom.
So, the last picture was what it could look like more like on an x-ray. These are two examples of what it may look like in an endoscopy. So, we'll talk about endoscopy soon, but that's when a procedure's done, and a small camera is inserted through the mouth and down the esophagus. And one manifestation of chronic graft-versus-host disease can be an esophageal web shown here, where there's kind of a thickening of the mucosa in the esophagus that can cause things to get lodged or stuck. It's a little harder to really see in the picture, but the second picture here shows an area of sclerosis, so maybe there's an area in the esophagus that's just become a little bit hardened from the chronic graft-versus-host disease. It doesn't move as smoothly as it once did, and that can also cause strictures and difficulty with food moving down the esophagus into the stomach.
And this is a person of what jaundice can look like. So usually this would be when there's more severe liver inflammation and the bilirubin is elevated, but this is an example of what that yellowing in the eyes can look like in patients who have chronic graft-versus-host disease.
Diagnosing GVHD in the GI tract and liver involves ruling out other potential causes
16:05 So, now let's move to the diagnosis. So, I think one thing that becomes important, you'll hear today with this lecture, and you'll hear this in other times that graft-versus-host disease is discussed is that graft-versus-host disease is a clinical diagnosis. What that means is that there are a number of tests, and even biopsies, that can be done that can help support the diagnosis of graft-versus-host disease. But that ultimate determination of whether we're looking at graft-versus-host disease or not is it needs to be made by the clinical team.
In many cases, the tests and biopsies, rather than confirming the diagnosis of graft-versus-host disease, they can be used to help rule out other causes that could be causing those same symptoms that are not graft-versus-host disease. We'll talk about some of these here now, but these clinical scenarios can include infections, so viral infections, maybe a fungal infection, maybe a bacterial infection. There are other transplant-specific complications that can happen that are not graft-versus-host disease that can sometimes cause similar scenarios to what we see with graft-versus-host disease.
Transplant recipients may be experiencing a side effect from a medication and that could be the cause of their symptoms. And then there are other medical conditions, where they are preexisting to the transplant or new things that come up after transplants that may explain what's going on and be the alternative diagnosis rather than graft-versus-host disease.
Chronic GVHD can cause esophageal strictures or webs that cause difficulty swallowing
17:53 So just to kind of get a little more granular in what some of these scenarios could look like, we showed some pictures before of what esophageal strictures or esophageal webs may look like. The patient's having difficulty swallowing and the symptoms are related to graft-versus-host disease, but not every time that a patient has difficulty swallowing after transplant is it definitely graft-versus-host disease. Patients, it's very common to have esophageal reflux, maybe the patient has a hiatal hernia or sometimes there can be some rare infections in the esophagus that can give that same symptom of difficulty swallowing.
Nausea and/or abdominal pain can be caused by GVHD or other factors
When it comes to nausea and/or abdominal pain after transplant, once again, esophageal reflux disease, also peptic ulcer disease could explain a patient's symptoms. And I can say that out of personal experience, I had a patient that we were once concerned about having graft-versus-host disease in their stomach, and when we did the workup, they were actually found to have peptic ulcer disease and was treated with a different treatment because of that.
Gastritis is when there's inflammation in the walls of the stomach, and that can also cause some of these same symptoms like nausea and abdominal pain. Then we always worry about medications causing some of these symptoms as well. While we're thinking a little bit more about the lower GI tract and we think about diarrhea and abdominal pain, the two main things we think about are infections, so this could be a C. diff infection, which is a type of infection that can happen to transplant recipients, but also to other types of patients who are treated either with antibiotics, or are treated in the hospital for longer periods of time. And there can also be viral infections that can cause diarrhea, and once again, there are medications that sometimes have diarrhea listed as a side effect.
Liver inflammation after transplant can be caused by GVHD or other factors
20:09 And when we think about liver inflammation, whether it's earlier on after transplant or later on after transplant, there's some basic things to think about. The viral infections whether it's a hepatitis virus or a CMV virus, which you may hear about that can happen after transplant. Both should be evaluated in trying to find the true reason for the elevated liver inflammation. There can also be other issues going on with the liver, such as gallstones, that may cause elevation in those liver function tests. And once again, and quite commonly there are specific medications and/or combinations of medications that sometimes can lead to the liver function test being mildly elevated, and that can be difficult to separate out from chronic graft-versus-host disease.
Tests to determine if a patient has GVHD in the GI Tract
21:09 So what kind of testing might be done when working up these symptoms? We're going to first focus on the gastrointestinal tract, so everything always starts with the history and physical exam. That will be hearing the nature of the symptoms and how it develops, and in the context of that also being examined in the clinic, because this can often give us a lot of clues about what's going on and what the most likely diagnoses may be. Most workups will be accompanied by blood tests just to evaluate organ function and to see if there's any other abnormalities there are ongoing.
What I want to focus on here for the gastrointestinal tract is the idea of endoscopies. So, there is a colonoscopy, which is a procedure where an endoscope is used to visualize the large intestines and the rectum. This is usually considered for patients who are having diarrhea as a symptom. And then there's also upper endoscopy where an endoscope is inserted to look through at the esophagus, the stomach, and the small intestines. This can be used more for patients who have ongoing symptoms of nausea or vomiting, whether they have poor appetite, weight loss, or difficulty swallowing.
And it's important to know that biopsies are often taken during the colonoscopy or endoscopy procedures, but these are painless biopsies that are low-risk and done to help better characterize what we are seeing during those endoscopic procedures. So, this is just a figure of an endoscope where one end connects to the screen monitor. There's a control set that the usual GI specialist doctor uses in order to maneuver the scope, and then there is a long tube that has a small camera at the end.
And what you can see here, this is a portrayal of what happens during a colonoscopy, that the endoscope is inserted, it goes through the rectum, and then into the large intestines, and we're able to look for any signs of inflammation that may be ongoing. So, if a patient's having diarrhea, whether it's for graft-versus-host disease reasons or otherwise, sometimes the walls of the large intestines will look very inflamed. This is something that can be visualized with the camera that is at the end of the scope, and then small biopsies can be taken in those areas to help better understand is there an infection going on in that area or maybe there is graft-versus-host disease going on in that area.
And this is using the same type of endoscope. This is what a upper endoscopy looks like, where the endoscope is inserted through the mouth, then down into the esophagus, so it can look in the esophagus, but as well as into the stomach, and then into the upper part of the upper intestine. I do want to highlight one specific thing about endoscopy here, and this is the idea of esophageal dilation.
Dilators can be used to treat esophageal strictures caused by GVHD
24:50 So we showed some pictures earlier of what an esophageal stricture may look like where there can be a narrowing of the esophagus, and that's what you're seeing here in figure A, where you have a little bit of dilation in the esophagus and then it tightens here with the stricture. What can be done is there can be a physical dilation, so they can use a set of dilators that can be pushed through that stricture and manually open it up and loosen it so that the stricture goes away. And very often, patients who have an esophageal stricture and have this dilation procedure done during the endoscopy can very often quickly feel relief of their previous symptoms, meaning that feeling of food getting stuck or having difficulty swallowing can go away quite quickly with this procedure.
Tests to determine if patient has GVHD in the liver
25:54 Moving on to the liver. Some of the same things we talked about before, history, physical exam, blood test. I think something to focus on here is that sometimes you may have imaging done, whether that's an ultrasound or CT scan or MRI to better look at what the liver looks like with pictures, and then there can also be a liver biopsy done. A liver biopsy here is not done through endoscopy procedure, but it's done percutaneously meaning that a small needle is stuck through the skin to get a biopsy of the liver tissue, and then that is sent for analysis of what may be causing the inflammation that is seen.
Methods to prevent GVHD in stem cell transplant patients differs among transplant centers
26:46 So, a slide here about the prevention of graft-versus-host disease. I think one thing that is important to know is that there are no organ-specific approaches to preventing graft-versus-host disease. So when a patient gets a transplant that is an allogeneic transplant, almost all transplants will include some approach to prevent graft-versus-host disease, but this is not specific to one organ to say it will only prevent skin or gastrointestinal tract or liver, but it's a general approach to try to prevent any type of graft-versus-host disease from occurring, especially in a severe manner.
So, some of these approaches that patients can have early on with their transplant include standard combinations of immunosuppressive agents, so this would be sometimes referred to as your graft-versus-host disease prevention regimen. At some centers there is a procedure that's done that's a manipulation of the donor cells. So, some centers have an expertise in, for example, removing some of the T-cells from the graft to see if that might cause less graft-versus-host disease in certain situations.
But this is an evolving field and patients may be asked to participate in clinical trials where experimental agents are being combined with the traditional approaches to see if we can improve upon the development of graft-versus-host disease so that we see less graft-versus-host disease, and that graft-versus-host disease that does occur is less severe and more easily responsive to treatment.
Most treatments for GVHD in the GI tract and/or liver are done on an outpatient basis
28:47 So, what is the treatment of graft-versus-host disease? We've talked a lot about different aspects of it up until now. I think one thing that's important to know about graft-versus-host disease involving the GI tract or the liver is that almost all the cases where that is ongoing will require some type of intervention. Most of the treatment will be done probably in the outpatient setting, but some patients may need to be admitted to the hospital.
I think one situation that stands out to me that may require going into the hospital is that if patients have severe acute graft-versus-host disease of the lower GI tract. So there are times when patients can have large volumes of diarrhea that's related to graft-versus-host disease, and I think that is one of the scenarios that a lot of times patients do need to go in the hospital, sometimes for a shorter period of time, sometimes a little bit of a longer period of time in order to try and get that inflammation back under control.
Treatments for GI GVHD include local therapies, systemic treatments and procedural interventions
30:00 But when we're thinking about the treatments in general, I think there are a few categories. There can be local therapies, systemic therapies, procedural interventions, as well as supportive measures. So, for local therapies, the one that stands out would be a medication, it's an oral medication called budesonide, and what it is, it's a non-absorbed corticosteroid. So it's a steroid medication that really acts... although you take it by mouth, it really has its affect mainly just in the GI tract, and it can be very useful for patients who have nausea or poor appetite, and sometimes very useful for patients who are also having diarrhea.
When we're thinking about systemic therapies, the standard first-line systemic therapy, so systemic therapy is referring to a treatment that's going to be absorbed throughout your body, is prednisone. So that's also a form of a corticosteroid, and it is considered to be the first-line systemic therapy for both acute and chronic graft-versus-host disease. So many of the situations that we talked about earlier, a lot of those scenarios, if it felt that a patient would probably benefit from a systemically absorbed pill, the first treatment will probably be Prednisone.
Other options that are out there include ruxolitinib. So ruxolitinib is an oral medication that is FDA-approved for patients who have acute graft-versus-host disease that is not responding ideally to the Prednisone or the corticosteroids, and similarly, Ibrutinib is also an oral medication that is FDA-approved for the treatment of chronic graft-versus-host disease that is not responding in an ideal fashion to corticosteroids.
There are a number of other established agents in GVHD. Many of them are immunosuppressant agents, and I think one thing that's important to know is that there's a lot of variability between one center and another in which treatments they think about in the treatment of graft-versus-host disease at their institution. So, some of these treatments have a little bit of nuance to them, and certain centers have a lot of familiarity with a few agents that they feel they get a lot of success with, where there may be another center that prefers to use other medications and has success with those. So, there may be some differences in what each center uses, but there are a number of other agents that have a lot of history in treatment of graft-versus-host disease that are not mentioned in here.
And as I mentioned before, there also up-and-coming new treatments that are very promising, so sometimes enrollment in clinical trial might be brought up as an option.
When it comes to procedural interventions, we already talked about the one that I think really stands out, which was the esophageal dilation procedure. And then there are other supportive measures that may be added on.
Treatment options for GVHD of the liver
33:39 So, for patients who have inflammation of their liver, and their liver function tests are elevated when they get their blood work done, a medication called Ursodiol may be added. Many patients receive this medication early on after transplant. It's a medication that can help decrease the inflammation in the liver to a certain extent, but it's important to know that it doesn't address the underlying issue that's driving the inflammation. So more than just Ursodiol is needed in order to address a liver inflammation that's related to graft-versus-host disease.
Treatment for nausea and vomiting in patients with GI GVHD
34:17 If patients are experiencing nausea or vomiting, there are supportive medications that can help with those symptoms. For patients who have diarrhea, there are anti-diarrheal medications that should be used. In the cases of more extensive diarrhea, sometimes IV fluids are needed in order to help prevent dehydration. We're going to talk about nutritional support and dietary changes on the next slide. But I think it's also important to know that the symptoms of graft-versus-host disease that affect the GI tract and liver can be severe, and they can leave patients in certain instances feeling quite weak, especially if the symptoms progress or are persistent over a longer period of time.
Patients who experience prolonged nausea and vomiting due to GI GVHD may require physical therapy to recover strength and psychosocial support.
35:09 So sometimes patients will need physical therapy in order to try and build up their strength and their activity level. And I think it's also important to emphasize that it can be very difficult, not just physically, but emotionally, and that can be for the patient, but also for their family and their caregivers if they're dealing with bothersome symptoms over longer periods of time. So psychological and social support are very, very important in supporting patients who are dealing with symptoms of graft-versus-host disease.
Diet for patients with GI GVHD
35:47 So a slide here about diet. I think questions about what patients should be eating comes up quite often. What I would emphasize in general for bone marrow transplant patients is to try to follow a balanced diet. This plate happens to be super balanced. You don't have to be that balanced, but a balanced diet is usually a good thing. But specifically, when we're thinking about GVHD and how there can be inflammation in the GI tract, sometimes it's really good to avoid fatty or spicy foods because this can irritate your intestines. Sometimes patients, it'd be better off eating a bland diet to kind of see if their stomach and their intestines can cool off a little bit so to speak.
And then in certain very rare instances, if there's severe inflammation, probably talking a little more about those situations when people may be in the hospital, there may be a need to actually go on bowel rest, meaning not to eat for a little bit while get some nutrition supplement by vein and just let the inflammation cool off before resuming oral intake.
Summary of presentation
36:12 So to conclude here, graft-versus-host disease involving the GI tract and the liver is common in transplant recipients. Both acute and chronic forms of graft-versus-host disease can affect these organs. The diagnosis is made after evaluating for other potential causes of symptoms. Most patients will require some form of treatment, but it should also be important to emphasize here that the treatments and the outcomes of patients with graft-versus-host disease continue to improve.
So as a last slide here, after hearing about all these different symptoms which can be very common in a lot of scenarios after transplant, the question can be, "Well, do I have graft-versus-host disease right now?" And I think the overall recommendation would be to keep calm and to call your doctor. These are things that not every time you have these symptoms will it mean that you have graft-versus-host disease, but it's important to keep in contact with your treatment team so that they know if there are any changes going on with your medical care.
So, I want to thank, once again, the organizers. I want to thank everyone who's been able to join the call today for your attention, and I'm happy to address any questions.
[Moderator] Thank you very much, [Dr. DeFilipp]. That was an excellent presentation. We'll now take questions, and as a reminder, if you do have a question, please type it into the chat box on the left side of the screen. We'll try to get to as many of them as possible.
38:46 So let's begin with this one: "I am two years past the allo transplant. I have iron toxicity from past transfusions, which has been confirmed by MRI accumulated in the liver. Am I at higher risk of liver GVHD?"
[Dr. DeFilipp] So that's a really good question. One thing that can happen, and I didn't mention it here specifically, but this is a perfect example is that sometimes the liver can be a little bit inflamed for other things that happen with the transplant. And this transplant recipient is highlighting a perfect example of that, that when they received many blood transfusions, they have a high iron level. And one of the places that iron is known to deposit sometimes is in the liver.
I'm not aware of any specific studies that would indicate that having a high iron level in the liver increases the risk for graft-versus-host disease, but it is a good point of something to consider that there may be a little bit of an underlying level of inflammation that might put you at a little bit of a higher risk for graft-versus-host disease symptoms. One thing I would recommend is that you do speak with your treating team because there are things that can be done at the... but the timing needs to be right to try to lower those iron levels, which is also something that's going to be important in the long term for your health.
40:38 [Moderator] Next question: "Is a CT slide through procedure less invasive than a colonoscopy? If so, why aren't more CT slide throughs done?"
If I understand the CT slide through procedure, this would seem to be a little more of a non-invasive version of getting some information from a CT scan about what's going on in the colon as compared to doing the colonoscopy. You bring up a good point, which is that for any type of procedure, and I think transplant recipients know this very well, that you always have to kind of balance the potential benefits versus the risks of a procedure.
Colonoscopies or endoscopy procedures are in most instances thought to be fairly safe and done pretty routinely, but there are some scenarios where a patient may have a bit of a higher risk situation where maybe there'll be some higher level of concern or caution about doing the endoscopy procedure. The one thing that is beneficial about the colonoscopy or endoscopy procedure is that there would be an opportunity to do a biopsy, which can be very important for ruling out different types of viral infections. And then also may be getting some supportive picture for graft-versus-host disease. This is something that would not be able to be done in a non-invasive way.
42:23 [Moderator] All right. Next question: "Can you talk about using CellCept versus prednisone for chronic liver GVHD. My wife has been on prednisone for over two years and is seriously impacted by the side effects. If not CellCept, do you have any other suggestions?"
42:44 [Dr. DeFilipp] Sure. So that's a really good question. In general, as we kind of discussed before, the first-line treatment for patients with graft-versus-host disease that require systemic therapy is prednisone. And unfortunately, as I think your wife is experiencing, prednisone can have a lot of other detrimental effects. So, it can be good sometimes at reducing the inflammation related to graft-versus-host disease. However, it can cause many, many issues. It can wear on people's blood sugars; their blood pressure can be dysregulated because of prednisone. Their adrenal glands can be affected. It can make bones week. It can change people's weight and their muscle tissues and architecture. And these are things that we really want to be aware of and try to avoid as much as possible.
It seems that if her graft-versus-host disease symptoms are ongoing, and the prednisone is causing a lot of detrimental effects, it would definitely be correct to have a conversation with her treatment team about whether another medication could be added to help decrease the graft-versus-host disease-related inflammation and symptoms, and then hopefully also allow for tapering of the steroid, whether to a lower dose, or ideally maybe even all the way off.
CellCept is one of those immunosuppressant agents that's been around for a number of years, and I think many, many centers have experience with that. And it can be used as a GVHD agent as well as a steroid-sparing agent. Depending on the exact symptoms of her GVHD, whether acute or chronic, talking about the FDA-approved agents that were on these slides, one of them being Ruxolitinib, the other one being Ibrutinib, both of those are other oral medications that can be used in conjunction with steroid and sometimes can lead to a situation where the ongoing dose of steroids can be tapered to a lower dose.
45:22 [Moderator] Okay. Next question: "Ever since my transplant 12 years ago, my liver function readings have been elevated, although I have not had jaundice or the other symptoms you described. Could this to be due to other factors besides GVHD like radiation or something?"
45:42 [Dr. DeFilipp] This is another good question, and one that as a practicing bone marrow transplant physician I see a lot, which is in patients that are further out after their transplant, they have no symptoms, they have no other clear GVHD symptoms, and the liver function tests are whenever they get blood work are always a little bit elevated. They're not necessarily at an alarmingly high level, but they're not completely normal either.
I think that that's a situation that we have trouble with sometimes because I think we have to balance and say, "What's the potential harm in having a little bit of low level... You know, are these liver function tests, although not normal, are they going to cause any adverse problems to that patient?" Do they need treatment? Do they not need treatment? Do they need an expensive workup? Do they not need an expensive workup?
This could be a situation where maybe there's a little bit of mild inflammation that's a touch of graft-versus-host disease that's ongoing. Depending on what other types of medications you may be on, the question could always arise of whether some of the medications might be causing that to happen. And you also bring up other good points. Are there other things that have happened in the treatment history, whether it's the radiation or other situations that could be causing this mild elevation? I think it's something to continue to follow with your treatment team. I can tell you that in my practice I do have a few patients that have low level inflammation, and it's a situation that we've mutually decided that we're just going to continue to monitor, and as long as it doesn't go much higher, we've felt comfortable that we will continue the patient without further workup or change in treatment.
47:52 [Moderator] Next question: "Are you at greater or lesser risk of developing GVHD if you have a haploidentical transplant?"
48:00 [Dr. DeFilipp] So that is a great question, and one that is a little bit complicated. But what I would tell you is that the development of graft-versus-host disease in patients really depends on a few factors. There're going to be certain specific things about the transplant recipient, their biology, that will affect the development of graft-versus-host disease. Another major category will be what type of donor that you receive for your transplant, is it a fully matched, or in this situation a haploidentical transplant? And then the other category here that I would say is it depends a little bit about what the graft-versus-host disease prevention strategy is. We talked about some of the strategies for different types of transplants, different immunosuppressive approaches are being used.
Right now, the standard immunosuppressive approach for patients getting haploidentical transplants is a approach that uses a medication called cyclophosphamide. It's called the post-transplant cyclophosphamide approach where patients get doses of this after the transplant of this medication cyclophosphamide, and then they're on other immunosuppressive agents after that.
With that, the acute graft-versus-host disease incidence seems to be approximately what we see with other transplants, but it seems with the post-transplant cyclophosphamide, that the chronic graft-versus-host disease after transplant seems to be much lower than what we've seen previously. I would say that the risk for graft-versus-host disease is maybe a little bit less in this situation if you're using the post-transplant cyclophosphamide approach, but it may owe more to that approach rather than to the selection of the donor.
50:03 [Moderator] All right. Next question: "My husband is three years out from transplant. He's been coughing a lot after drinking liquids. Is this a sign of esophagus issues?"
50:19 [Dr. DeFilipp] So, it sounds like this is a new symptom that is now starting a few years after the transplant. And it definitely could possibly be a symptom of GVHD that is affecting the esophagus. Now, we also mentioned before there could be other things that are ongoing, not graft-versus-host disease in the esophagus. It could be... Sometimes patients develop difficulty with swallowing for other reasons that are higher up in their oral pharynx, so in their oral cavity, but I think this sounds like something that should probably be further evaluated. So I would definitely recommend that if you haven't yet, I would have you and your husband speak with his treatment team about these new symptoms and talk about the possibility of getting those symptoms worked up to get to the true cause of these new issues.
51:24 [Moderator] Great. "Is an MRI or CT scan better for imaging the abdomen and pelvis when investigating possible GVHD? The symptoms are weight loss, anemia, and abdominal discomfort."
51:41 [Dr. DeFilipp] So, the CT scan and the MRI can both be very useful tools in evaluating graft-versus-host disease symptoms. The CT scan is usually done before the MRI for various reasons. It's a quicker scan, it's easier to schedule, you're able to get the information back more quickly. And sometimes all the information that you need you can get from that CT scan. The MRI is used a little more in some specific situations. The MRI definitely probably gives better information about the liver, but once again, it can be used usually as a secondary test, not as the first-line test.
So with the current symptoms that you were reporting, I mean, it definitely seems like some of these symptoms could fall in the category of the things that we talked about today, but whether it's GVHD, it'd be hard to know at this point, and where that GVHD is affecting. Is it the upper area? Is it the esophagus? The stomach? The upper intestines? Is it a little bit the lower intestines? I think your treatment team might need a little more information, but I think we talked about some of the tests and some of the tools that can be used to be able to get to the bottom of what's going on.
53:17 [Moderator] Great. Next question: "Does GVHD affect recovery of your blood counts?"
53:26 [Dr. DeFilipp] So, GVHD definitely can have an effect on blood counts, but I think it's important to... I want to point one thing out that I didn't mention earlier. Typically when we think about graft-versus-host disease, we go back all the way how we defined it at the beginning of the talk, that you need donor cells that are going to then recognize the transplant patient's organs as foreign. Part of the definition is the donor cells have to have engrafted yet. There are very rare cases where sometimes people get some GVHD-like symptoms before their counts come up while they're still in the hospital waiting for that engraftment, waiting for the donor cells to have taken.
But most of the time, even the acute graft-versus-host disease will only really occur after that has happened. So, most patients have experienced their blood counts coming up, and most patients are usually outpatient. They're usually at home when these symptoms of graft-versus-host disease first start. Now, when graft-versus-host disease is ongoing, if you think about that syndrome, this syndrome of graft-versus-host disease, really just meaning that there's a lot of inflammation in the body that's happening. High levels of inflammation can definitely affect blood counts.
So there are sometimes we see that as the graft-versus-host disease is developing, patients can have a little bit of dip in their blood count, sometimes in their white blood count, sometimes in their platelets, sometimes in the other counts, once again, does not happen all the time, but it is something that we can see.
55:23 [Moderator] All right. "I had a balloon endoscopy. The findings were an extreme narrowing in the ilium believed to be from GVHD scar tissue. The doctor attempted to stretch it, but it still was only 10% of the normal opening. I eat low fiber, low residue diet. What are the chance that this section will stretch open with time?"
55:45 [Dr. DeFilipp] So this is another very tough case, and another very good question. So, one of the things that we see with graft-versus-host disease depending on the manifestation. Sometimes graft-versus-host disease symptoms kind of appear for a period of time, and then they kind of go away completely. Sometimes the symptoms of graft-versus-host disease kind of come up and then they kind of go down, and then they kind of fluctuate, they kind of flare sometimes. Sometimes they get better, sometimes they get a little worse.
There's another scenario that can happen sometimes where there's initially a little bit of graft-versus-host disease that occurs. And although the graft-versus-host disease we would say might have resolved itself, when the graft-versus-host disease was there and was active, it could cause some scarring, and if there is that scarring there, sometimes those types of situations, it's very difficult for that tissue to fully heal, it's like a scar.
Now, scarring, we're talking here about a case where that has occurred in the GI tract. Sometimes they go here, maybe at different points in the symposium with some of the other talks, it can sometimes happen in the skin and in the tissues of the muscles, in the soft tissues of the body. It's an unknown situation unfortunately. It's something that we have to see with time. There is hope that in certain situations that scar tissue can soften. And then with the softening of that scar tissue, whether that is just healing of the tissue on its own over time, or there now are some medications that are in development for patients who have graft-versus-host disease with some scarring that there is some optimism may be able to help certain patients in situations. We would be hopeful that that scarring could improve, but there are no guarantees.
58:00 [Moderator] All right. "What is the likelihood of a liver biopsy with a thin needle missing graft-versus-host disease?"
58:07 [Dr. DeFilipp] So when a patient gets the liver biopsy done, the usual feeling is that whatever is causing inflammation in the liver is pretty well spread out throughout the entire liver. In some ways it's almost analogous to what I think many transplant recipients have probably experienced at some point in their treatment, which is like a bone marrow biopsy. A similar kind of question of what's the chance that if you get a biopsy from the bone marrow, if you're only getting one small little snippet, how is that really going to be representative of everything else that's going on in the bone marrow?
We usually feel that the ability to identify inflammation in the liver is pretty good with the biopsies. I think where I as a clinician sometimes run into frustrations with the liver biopsy is that what the limitations of what the pathologists are able to tell us from it. So, it's not necessarily that the biopsy was unsuccessful. We're able to get a piece of tissue and send it for a viable piece of tissue for analysis. But sometimes, all that can really be described is that there is ongoing inflammation, and that they're unable to fully explain what that inflammation is from.
So sometimes they may be able to say, "It kind of looks like graft-versus-host disease." Sometimes the answer from the biopsy is a little more vague, and they'll say, "We see inflammation in the liver, and it could be consistent with either an inflammatory liver condition, or graft-versus-host disease, or effect of a medication." And in those situations, obviously those biopsy results can be frustrating for patients, families, and the treating team.
01:00:22 [Moderator] Thank you, Dr. DeFilipp, and with that, I'm afraid we need to wrap up this webinar, this webcast.
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