Introduction to Chronic Graft-versus-Host Disease (GVHD)

Chronic graft-versus-host disease (GVHD) is a common side effect of a transplant using donor cells. Learn who's at risk and treatment options.

Presenter:  Marcie Riches MD, MS, Professor of Medicine, Director of Clinical Research and Data Quality - BMT, and Clinic Medical Director of the BMT and Cellular Therapy Program at the University of North Carolina Lineberger Comprehensive Cancer Center.

This is a video of a workshop presented at the 2019 Celebrating a Second Chance at Life Survivorship Symposium

Presentation is 44 minutes, followed by 16 minutes of Q&A

Summary:  Chronic graft-versus-host disease (GVHD) s the most common long-term complication after a transplant using donor cells. It can affect virtually every organ of the body. Most of the patients have mild or moderate chronic graft-versus-host disease, if they develop it. Treatment options vary, depending on location of GVHD and severity.


  • There are two types of graft-versus-host disease:  acute and chronic.  They vary by time they occur, symptoms and organs they affect.
  • Approximately 50% of patients who have an allogeneic transplant (transplant using donor cells) develop chronic GVHD
  • Chronic GVHD most often affects the skin, eyes and mouth, but it can affect virtually any organ in the body
  • Most people experience only mild or moderate GVHD, but in some cases, chronic GVHD lasts for many years
  • There are two types of treatment:  systemic, which affects the entire body, and topical, which only affects the area where GVHD is active
  • Steroids are the mainstay of systemic treatment and have many long-term side effects

Transcript of Presentation:

00:01  It's a great pleasure to actually be here today and talk to everyone about chronic graft-versus-host disease. This is something that unfortunately we see frequently in our transplant patients who receive allogeneic transplantation. And so we're going to go through a little bit of an overview, but I would also direct your attention to the fact that there are multiple symposia throughout today and tomorrow. They're going to focus in more detailed areas such as eye GVHD, mouth GVHD, skin, et cetera.

00:34  Overview of Talk: In terms of an introduction and overview, I'd like to talk to you about what is chronic graft-versus-host disease, how common is graft-versus-host disease, and how long does it last, which is a common question that my patients ask me. What are the treatments that we do have available to help manage chronic graft-versus-host disease, and what are the complications of chronic graft-versus-host disease, and more importantly also the complications of its treatment. This is a huge topic and I'm going to try and condense it down into about 30 minutes so that that leaves about 30 minutes for questions.

01:13  There are two types of GVHD - acute and chronic: The first thing is that we need to talk about what is different between acute graft-versus-host disease and chronic graft-versus-host disease because these are different entities and the symptoms are a little bit different; although some of the organs that are involved with the symptoms are the same.

01:32  Acute graft-versus-host disease is very much of an inflammatory reaction and it's a very rapid onset of symptoms, and it usually is very early after transplant, in the first three months or so. I'll show you kind of a diagram of timelines on the next slide. It's driven by what we call mature T cells. So everyone has heard in here, I suspect, the term stem cells, and stem cells are what help grow into adult cells. T-cells, or mature T-cells specifically, are an adult type of white blood cell. And even when we're doing a collection of stem cells, we actually will have some mature T-cells in that collection product, and those can help contribute to this as well as the rapid development and expansion of these adults T-cells early after the cells have been infused. But as I said, it has a really very abrupt onset of symptoms and things can happen pretty quickly.

02:32  Chronic graft-versus-host disease on the other hand is a much subtler, slower, and can be an insidious process. And it's something where we have really two different manifestations. We have scarring manifestations, where there's a development of fibrosis and drying manifestations, which we also term sicca. It, however, is also driven by T-cells, but there's also an interaction of another type of white blood cell called the B-cell. And those also are the cells that are developing from the stem cells and going in causing wreaking havoc in the patient by attacking the patient's healthy organs. And this can result in tissue destruction overtime with scarring or with the drying process that I talked about.

03:26  When each type of GVHD occurs: As I mentioned, this is a timeline. Actually what you can see here on this timeline is that there's a lot of overlap between acute graft-versus-host disease and chronic graft-versus-host disease. Day zero, the day that the cells are infused through day 100 is really our greatest period for acute graft-versus-host disease; but we can have some chronic graft-versus-host disease symptoms that start earlier, often in patients who've received more of a reduced-intensity conditioning regimen.

But as you can see there's some similarity in the organ involvement for acute and chronic graft-versus-host disease with the GI tract, the skin, and the liver being common organs that can be involved. But when we get to chronic graft-versus-host disease, we really have to think about every potential organ that can be involved with this, and this can include the eyes, the mouth, the joints, genitalia, lungs, all of those have the potential to have manifestations of chronic graft-versus-host disease.

04:28  Approximately 50% of patients will develop chronic GVHD after a transplant using donor cells: Unfortunately, chronic graft-versus-host disease remains one of the most common long-term complications that patients have after allogeneic transplantation. It occurs in anywhere between 30% and 70% of patients going through transplant. And that's a wide number because of changes that have happened over time in terms of how we treat patients for conditioning regimens, the medicines we use to help prevent graft-versus-host disease. So these have really developed over a wide period of time have some manifestation of chronic graft-versus-host disease. For most of those patients, when they develop it, it is going to be in that first year after transplant; but there are a small number or small percentage of patients who will develop it not early, but even later beyond a year after transplant.

05:31  Chronic GVHD most often affects the skin, eyes and mouth: As I mentioned, it's the most common complication we have; and most commonly it affects the organs of the skin, the eyes, and the mouth. The benefits of it being there, if we have to say that there's a benefit, is that a lot of those are areas that we can treat topically. I can use eye drops, I can use mouth rinses, I can do things where I'm not having to necessarily increase the amount of immunosuppressive drugs that a patient is on.

However, there are liver changes that can occur that we see relatively commonly as well- and it's a little bit harder to put a cream on your liver. And so we're not able to treat that topically and we'll have to use medicines that we call systemic medicines, things that people take or ingest.

06:19  Risk factors or developing chronic GVHD: There are multiple risk factors for chronic graft-versus-host disease. The most common risk factor is the fact that you had to have a donor stem cell transplant. Unfortunately, that's not one we have a whole lot of control over- and frankly a lot of these we don't have a whole lot of control over in terms of what we've got in those risk factors. They're not things that we can necessarily change. And so, receiving a transplant from an unrelated donor increases your risk for chronic graft-versus-host disease. That increased risk may only be a couple percentage points of an increased risk, but it's there. But if you don't have a perfectly matched sibling donor, then we don't really have a choice. We need to use that unrelated donor if we're going to do the transplant.

07:07  A mismatched donor increases the risk of developing chronic GVHD: Mismatched donors, worse with unrelated versus related mismatch donors are also risk factors. Again, we don't choose to use a mismatched donor unless we have no other option.

07:19  Female donors for male patients increases the risk of chronic GVHD: Use of the female donor for a male patient, and that gets into the fact that we know that there are minor differences that occur between the patient and the donor and one of those that's very commonly known is that women have two X chromosomes, where men have an X and a Y chromosome. So that woman's immune system, when it goes into that male donor, it's going to recognize the Y chromosome as being different and try and attack it. And so that's why that percentage is a little bit different if we have a female donor for a male recipient.

07:56  Use of peripheral blood stem cells versus bone marrow increases the risk of chronic GVHD: Use of peripheral blood stem cells. There have been studies in both related donors and unrelated donor transplants that we have more chronic graft-versus-host disease when we use peripheral blood stem cells than when we use marrow stem cells. But there are different limitations with using marrow stem cells including whether or not a donor can do that, or is willing to do that. It doesn't have a difference in survival outcomes though. The change is really in the development of chronic graft-versus-host disease.

08:30  Age of patient and donor affects the risk of getting chronic GVHD: The age of the patient, the age of the donor with being older ages can also increase risks for chronic graft-versus-host disease. We can't affect what our age is when we need transplant. If we have a sibling donor, we can't really affect that their age is going to be substantially younger than ours. When I have an unrelated donor option that I'm using, because I don't have a sibling donor, then that unrelated donor, I tend to choose a younger unrelated donor to try and help mitigate that. But if I don't have that option, I don't have that option. And so again these are risk factors we know about, but they're not necessarily things that we can change.

09:10  Acute GVHD is a risk factor for developing chronic GVHD: The other major risk factor for development of chronic graft-versus-host disease is that you've already developed severe acute graft-versus-host disease. And again, we do all the things we can to prevent that from happening, but there's not a switch that we can turn on that.

09:30  National Guidelines for Diagnosing Chronic GVHD: When we talk about the diagnosis and severity of chronic graft-versus-host disease, there is a large group of transplanters that have worked to develop consensus criteria through development of an organization through the NIH consensus criterion and chronic GVHD consortium,. And these are really used to help us score the organ systems for organ involvement and really determine an overall severity of the disease.

What we end up doing is looking at each individual organ and assigning a score to that organ to then come up with a composite score to say how severe is the graft-versus-host disease. And so we're looking at those main organs that I talked about, and then there are some other features that we'll look for as well, including things like neurological changes, is there peripheral neuropathy or numbness and tingling in the legs or feet, fluid collections such as effusions (effusions mean that there's fluid maybe around the lung or around the heart), kidney changes and changes in blood counts because we know that chronic graft-versus-host disease can also cause a drop in the blood counts that people have because it can attack the marrow.

When we're looking at this and I say we score each organ, it's a relatively generic system that we're using, but it's scoring from a zero to three. Zero being no signs or symptoms of graft-versus-host disease in that organ system, up to three, where it is severe signs and symptoms. We also have to take into account any signs or symptoms that were present prior to transplant or may have another cause contributing to them.

For example, I have a patient of mine who's hitting around four months after transplant and I was kind of running through all these questions that I asked to ferret out any signs or symptoms of graft-versus-host disease, and we talked about dry eyes and she said, "Well, I have problems with dry eyes before I ever got my leukemia, and I used to take fish oil for that. So I don't know if it's that coming back that I'm paying attention to or if it's new." And so it's one of those things that I know I need to keep an eye on it, but okay let's go ahead and restart your fish oil that worked before transplant and before your leukemia diagnosis because I don't know if that really score that system at this point. And that's why I talked about it being kind of subtle on its onset.

12:04  Grading the severity of chronic GVHD: But when we’re scouring this, if patients only have a score of one in one or two different organs, that's going to be mild chronic graft-versus-host disease. Moderate chronic graft-versus-host disease ends up being having three or more organs. So if you have five organs with a score of one in severity, mild symptoms, then that's going to still be moderate chronic graft-versus-host disease. But if you have an organ system even just one that reaches our criteria for a moderate score or a score of two, you automatically fall into that moderate chronic graft-versus-host disease criteria.

12:47  The lungs are a separate situation because it is a much more severe manifestation in general; such that even with mild chronic graft-versus-host disease of the lungs, a score of one, we would actually still call you having moderate chronic graft-versus-host disease.

13:06  Pictures of GVHD: I did put some pictures up for some different manifestations of chronic graft-versus-host disease, and these include things that we consider to be diagnostic findings that don't necessarily require me doing additional biopsies to prove that those changes are there.

13:23  Pictures of skin changes with chronic GVHD: What you see in this panel, the first three are all skin changes, but you can see that they're all very different. This is something that we call lichen planus, and it's really sort of purplish bumps and they're often very itchy. We can have patients who have inflammation. You can see the red rash on here, but the hand is swollen and there's inflammation of the tissue underneath the skin, and that's called a fasciitis.

Thickening of the skin or scarring of the deep layers of the skin are something that we can often see as well, and that's that scarring or sclerosis or fibrosis are the terms that I've used to describe this. But this is lichen planus of the skin, this is lichen planus of the mouth. And again, it's more of a white lacy pattern that occurs in the mouth and there may be some irritation along the linings of the mouth; and in some cases, patients can develop some mouth sores or mouth ulcers as well.

14:29  Most people experience only mild or moderate GVHD: What I want to point out is that most people end up in that mild to moderate range. It really is only about a third of patients that fall into the development of severe chronic graft-versus-host disease. What you can see here is again, like I talked about, the skin, the mouth, the eye, the liver tend to be the most common organs that are involved. And again, that's the same over here as well as even in the severe category, skin is one of the most common areas with manifestations. The issue is whether or not they're skin changes that I can treat topically or they're deeper skin changes that are going to require me to do something more systemic for treatment of that.

This information, these data came from a study that was done across the U.S. in about nine different centers and conducted by the Chronic Graft-versus-host Disease Consortium that is trying to investigate sort of how does that scoring system we developed work, where do patients fall, and some other data that I'll present to you today as well.

15:46  Chronic GVHD can last for many years: How long does chronic graft-versus-host disease last? Unfortunately, the reality is that for some patients, it does last for many, many years. It's something that is a hard thing to hear because a lot of times these symptoms are ... they're chronic for a reason because they don't necessarily go away, and we work to control the symptoms associated with that.

16:18  How long does treatment for GVHD last?  Treatment, in terms of actually needing to treat the chronic graft-versus-host disease symptoms, can be a very prolonged period; and for most patients, it's a year or longer of treatment focusing on that chronic graft-versus-host disease. The risk factors that results in us needing prolonged treatment are some of the same risk factors that increase the risk of developing chronic graft-versus-host disease in the first place.

16:52  Chronic GVHD long-term can affect quality of life: Obviously, having something that you're going to have potentially long-term may have significant impacts on quality of life. We're going to talk about how that compares a little bit to people who have other chronic diseases, such as chronic lung disease from smoking changes, or diabetes or other different diseases that we think about differently in our mind because we didn't go into needing a treatment where we traded one disease, your cancer, for another disease, chronic graft-versus-host disease.

17:32  Again, there was a lovely study that was done from The Chronic GVHD Consortium, where they actually went and got patient-reported outcomes. They talked to the patients and had them score their symptoms: how did it impact their lives, so that we have this information to help our patients regarding that. 
What was interesting, frankly, was very interesting to me, is that the mental health component, sort of the conscious sense of well-being, issues with depression or anxiety or things like that, actually were fairly similar to what we see in patients with other chronic diseases. It wasn't particularly worse, and in some cases, it was actually better. My hypothesis, is that while we've traded one disease for another, we've also hopefully had your cancer cured by doing this. So I think that gives you a different sense of, "Okay I'm going to deal with this because ... " That's my take on this. I'm not the person that's gone through this though. I'm the one on the other side.

18:51  Physical health changes due to GVHD create a "new normal" for patients: Physical health and feelings of sort of living a completely normal life however are impaired. You may not get back to where you were prior to your diagnosis of cancer and needing transplant. You develop a new normal. That can be a difficult adjustment as well. What was interesting is that those patients with mild and moderate chronic graft-versus-host disease had very similar senses of how they were doing, whereas those with severe chronic graft-versus-host disease certainly had a much more negative impact on their quality of life.

I truncated this figure a little bit. There is a very long table, and I wanted it to be large enough for people to be able to at least get a sense of what's going on here. This is an interesting statistical technique that we do in terms of plotting this. So I'm going to spend a couple of minutes trying to go through this. But what this shows you is these yellow lines here in the middle, and I hope the yellow projects well, are what would be expected for the normal population. So somebody who has no medical issues, living their life, that's where we call normal in that regard for the scaling system. These top four rows are all related to graft-versus-host disease patients. And so this top row is sort of all of the chronic GVHD patients together; whereas the next three rows are looking at the different severities: mild, moderate, and severe.

You can see in the sense of mental well-being that actually there's a tendency for there actually to be an improved sense of general mental well-being for patients with mild chronic graft-versus-host disease compared to a general population. Moderate is almost exactly the same as it is for the general population; whereas there are some impairments in patients with severe chronic graft-versus-host disease similar to people with ongoing depression or ongoing chronic lung disease. I find that to be an interesting scenario. But I think it also gives you a sense that there are a lot of different things that play into how somebody feels as they're going through life.

The physical components, however, are real and there are going to be physical limitations, particularly if we have more severe forms of chronic graft-versus-host disease. You can see that the severe GVHD physical impairments are similar to somebody who's had a heart attack or lives with congestive heart failure. It's just different symptoms that somebody is experiencing.
I point out this line here, which is people with diabetes, and then people with vision impairment simply from the standpoint that those patients are also people that have cataracts, and that provides an impact their physical well-being. They may not be able to drive. And so all of those things are a chronic manifestations. It doesn't negate the symptoms that you're having, but sometimes it's very important to realize that you're also not alone in having all of those impacts and thoughts about the symptoms that you're having and how it is affecting your life. Because unfortunately, it does and for some people, it's a significant impact on life.

22:41  There are two types of treatment for chronic GVHD - topical and systemic: I'm going to switch now to talking about treatment. Again, this is a very broad overview. Treatments are split up into two different sort of broad categories. We have topical treatments, something I can put on the eyes, I can put in the mouth, I can put on your skin. But we also has systemic treatments. So those are the pills that you ingest or an IV medication that you need to take.

23:10  Topical treatments do not suppress the immune system: With topical treatments, we really have very minimal absorption, which means there's really minimal effect in terms of increasing your risk for infection because it's not suppressing your overall immune system. There's also a lot of supportive topical treatments that we use that aren't treating the graft-versus-host disease, what's causing it. They're not treating the T and B cell reaction, but they're helping to control the symptoms that you may have so hopefully it results in less impact in your quality of life. As I mentioned, they may work well and be sufficient for patients who have mild chronic graft-versus-host disease or manifestations that are really just limited in the eyes, the mouth, or the upper GI tract.

24:01  Systemic treatments have more side effects: Systemic treatments, unfortunately, just like with every medication we give to somebody, have potential side effects. They have potential drug interactions. And more importantly, when we have medicines that are trying to blunt an immune reaction of the donor attacking the healthy body, we increase risk of infection.

24:23  Topical steroids for skin GVHD: I'm going to go through some of these treatments and some of the drugs that we can use from a topical therapy perspective. Topical steroids are generally one of the most common things that we use, and they have different strengths and different potencies. We can have them sometimes in more of a gel or ointment form, sometimes more of a cream form. They can be compounded at a pharmacy to mix the steroid with a Eucerin cream to try and help provide moisturizer in addition to the steroid therapy. And so we have a variety of those that can be used.

25:01  Topical steroids for the mouth GVHD: For the mouth, we have steroid rinses. We also have topical paste that can be used. So if somebody has just one small area in the mouth that's more bothersome, you can actually use a little bit of paste and dab it on there. Some of my patients, they say it stays for about an hour or so. I think for most of them, it's probably more than about 10 to 15 minutes, but enough to treat that area for the time and to try and help provide some benefit.

25:30  Topical steroid for GVHD in the GI tract: There is one pill that we use that is a steroid that you swallow; but it isn't actually absorbed very well. And that's a medication called budesonide, and that's something that we can use to sort of topically treat the GI tract. It is something that, although you're swallowing it, your body doesn't absorb it from the intestines. And so this is all just one giant tube from mouth down and so it's treating it topically that way.

26:01  Topical tacrolimus and cyclosporine to treat chronic GVHD: We do have calcineurin inhibitors. I suspect most people are familiar with the drug tacrolimus. Tacrolimus and cyclosporine are calcineurin inhibitors, but we also have topical formulations of tacrolimus and cyclosporine. Tacrolimus has an ointment that can be used on the skin. There's also a mouth ointment that could be used if necessary. There's an eye drop called Restasis which is a cyclosporine eye drop. I would suspect most everyone has seen at least one commercial on TV for Restasis because lots of people have dry eyes, and Restasis is used for dry eyes whether or not the cause of that is chronic graft-versus-host disease. These are things that we have that are available to use.

26:52  Systemic prednisone and tacrolimus to treat GVHD: From the treatment of systemic therapy, initial treatment is unfortunately still prednisone. That is the go-to therapy that we have for our patients. Tacrolimus can be added or continued. The reason we would add or continue tacrolimus is to try and help get people off of the steroids. We do have multiple second line options of therapy, but the reality is that the overall response to any of the second line therapies that we have ranges between 20% and 70%. It's very dependent on the patient and their manifestations. And for us as physicians, it's a lot of trial and error. I'm going to look at what your symptoms are and pick which one of these I think is going to be most likely to be beneficial, that's also not going to necessarily negatively impact your other diseases that you have or other medical problems that you have, or the other medicines that you need. And so there is a lot of trial and error when we're talking about it not responding to steroids.

28:00  There truly is no optimal second-line treatment. In fact, there's only one drug that has been FDA-approved as second-line treatment, and we'll talk about that in a minute.
From the standpoint of systemic therapies, we're going to talk a little bit about each one of them but very briefly in overview with some talk about toxicities.

28:22  Systemic therapies can increase your risk of infection: The one thing that's important for patients and their doctors to remember is that any of these second-line systemic therapies or any of the systemic therapies that we use will increase your risk for infection. They're immune suppressant. They block your body's ability to well fight infections.

28:42  Steroids can cause bone loss: Steroids have some specific things including bone loss, so it can hasten osteoporosis or osteopenia. When I start my patients on steroids, I generally also start them on a calcium supplement. Our practice at our program is to get a DEXA scan to look at people's bone density within about a month or so after the transplant itself. And then depending on what's going on, if we need to start steroids, we may also start other medications to help keep the bones stronger besides just calcium.

29:18  Muscle weakness is a major toxicity of long-term steroid use; and the muscles that are most commonly affected are the ones that we call proximal muscles or girdle muscles. So the hips, the thighs, those quad muscles, your shoulders. And so people will say, "I have trouble getting up from a chair." And a lot of that is from the muscle weakness that can develop from the steroids that we've got. And so I will counsel my patients on starting certain exercises to try and help keep those muscles strong as we're starting steroids.

29:53  Unfortunately, steroids also can contribute to the development of diabetes or worsen diabetes, if people already have that. And they can cause increased cholesterol and increased triglycerides, which are important things for us to remember as well, because we don't want you to also subsequently develop coronary artery disease because we weren't paying attention to some of those other manifestations. Weight gain and the moon faces. So sort of those chipmunk cheeks are steroid face that people develop is another manifestation that we can see.

30:27  Side effects of tacrolimus: Tacrolimus, which most everybody gets, does have its own toxicities and side effects: and that can include things like high blood pressure, it can be hard on the kidneys (that's why we monitor level so frequently), it also can contribute to poorly controlled blood sugar or diabetes. A lot of people will complain of a tremor, "My handwriting is not as neat as it was." And a lot of that can be from tacrolimus, but steroid muscle weakness can cause that as well. And then tacrolimus has significant drug interactions with two medicines that we used to help prevent fungal infection called voriconazole and posaconazole. So we have to adjust the number of pills of tacrolimus you take to get to the right level when we also need to have you on voriconazole or posaconazole.

31:16  Ibrutinib is approved by FDA for GVHD patients who have failed other treatments: I mentioned that there's one drug that has been FDA approved for treatment of chronic GVHD; and it's approved only for those patients that have already failed one or more other treatments: and that would include failing steroid treatment, not having as good a response as we would like to see. It may also allow us to get people off of steroids with the steroid toxicities that we worry about maybe just a little bit faster; but it has its own risk and toxicities.

31:46  Side effects of Ibrutinib: Ibrutinib is actually chemotherapy drug and it has some of the side effects that chemotherapy does in terms of fatigue. It can contribute to diarrhea or muscle spasms. More concerning complications are that it can increase risks of bleeding and it can also increase your risk of developing a heart abnormality or an arrhythmia called atrial fibrillation. And so if I have somebody who already has an underlying atrial fibrillation, I'm not going to choose ibrutinib necessarily, even though that's the only drug I've got that's FDA approved because I may make things worse for them. Again, drug interactions are common.

32:30  Side effects of sirolimus: Sirolimus is another drug that we have. It's approved for use in kidney transplant, but not stem cell transplant. And it can impact your triglycerides and your cholesterol so that we need to monitor those frequently and may need to start you on medications that can help to keep those problems under control. It also contributes to high blood pressure, and a lot of our transplant patients end up on blood pressure medications as well.

33:00  Side effects of ruxolitinib: Ruxolitinib is actually a chemotherapy drug that we use to treat a bone marrow disorder called myelofibrosis. Myelofibrosis is scarring in the bone marrow. So it's been investigated for scarring types of chronic graft-versus-host disease, and it has shown to have some benefit. But it also can impact blood counts causing low blood counts and people may need to be on growth factor support. It can cause weight gain and it again has drug interactions.

33:34  Baracitinib is being investigated to treat GVHD in joints: Baricitinib is a similar agent, but it is FDA approved for the treatment of rheumatoid arthritis, which is an autoimmune disease that affects the joints. And so it's something that we've also investigated in treatment for particularly joint manifestations of chronic graft-versus-host disease; but it can increase risk of developing blood clots. And so if I have somebody who has a history of having blood clots, that's probably not going to be my go-to second agent because of that history. It's also difficult to use in patients who have kidney or liver damage for whatever reason including the things that we've done to patients from a transplant perspective.

34:16  Rituximab is sometimes used to treat chronic GVHD: Rituximab is a chemotherapy drug that attacks B-cells. It specifically attacks a marker called CD20 (and there are two other CD20 targeted agents). Those drugs have all been used to treat certain cancers that are B-cell cancers like CLL or lymphomas. Rituximab is FDA approved for treatment of rheumatoid arthritis. And it's because of the manifestations of it being an autoimmune disease, and since graft-versus-host disease is very similar except it's somebody else's immune system attacking you, it's something that we use often to try and treat graft-versus-host disease. Again, all of these will have potential implications and infectious complications. Rituximab can cause something that we call delayed neutropenia. Meaning the white blood cells, the neutrophils, go down, but it may be three or four months after you've received the drug.

35:21  IL-2 has shown benefit [in the treatment of chronic GVHD]: These are often subcutaneous injections or IV administrations. It's actually a drug that's approved for treatment of kidney cancer or melanoma that have spread widely or metastatic. It's major toxicity is really, really bad flu symptoms. And this is a drug that's administered usually three times a week. And so people often feel like they chronically have the flu. And so for a lot of people that's worse than some of the symptoms that they're having from graft-versus-host disease. In higher doses, it can cause drops in blood pressure as well.

36:03  Proteasome inhibitors are sometimes used to treat chronic GVHD:  Proteasome inhibitors are, again, chemotherapy drugs. They're drugs that we use to treat patients who have multiple myeloma. And that's a cancer that we often do transplant for. So a lot of patients are familiar with these drugs. But there's three of them: bortezomib, carflizomib, and ixazomib, and they have their own different toxicities. Bortezomib is notorious for causing peripheral neuropathy. And for some people, that can develop into significant painful neuropathy, but I've also told you painful neuropathy can be a manifestation of graft-versus-host disease. When someone's getting that, it's hard to know is it their GVH or is it the drug were using. Cardiac and GI issues are also manifestations.

36:51  ECP or extracorporeal photopheresis is used to treat chronic GVHD:  ECP or extracorporeal photopheresis is something where actually you have a special port or an IV line and the blood flows into a machine and its treated with a medicine called psoralen and then ultraviolet light is applied to that which kills the T cells that are in that blood, and then it goes back to the patient. It's a very effective way to treat graft-versus-host disease, but it does have some time consuming issues. When we start that therapy, it's generally two days in a row every week for four weeks, and then every other week for eight weeks, and then once a month, two days in a row for another at least four months. And for people who live very far from a transplant center, that can sometimes be very prohibitive to that kind of a treatment as well. There are cellular therapies that are very early in study that are being looked at as well to try and help treat manifestations of chronic graft-versus-host disease.

37:57  Supportive treatments are important to manage chronic GVHD:  I mentioned a lot of supportive treatments: and these are important to help treat the symptoms. Skin moisturizers, anti-itch medications. I generally recommend things like Zyrtec or Claritin that are available over-the-counter that act as antihistamines. Avoiding the sun, which is always a difficult thing to do in Florida, but the reality is that sunscreen is your friend. We know that the sun can trigger inflammation which can then trigger graft-versus-host disease, not to mention the fact your increased risk for skin cancers.

38:32  For the mouth: you want to use good oral hygiene. Brush your teeth two to three times a day and make sure you're keeping things clean. There are salivary stimulants to help make saliva. Sucking on hard candy is a good way to do that. There supplements that can be used as well. I'm sure a lot of people are familiar with biotin.

38:51  The eyes, artificial tears are a great friend. Refresh, Systane, generic equivalent, all of those. You can use those and use them as frequently as you need them. There are night time ones that are thicker that you can apply, and those can help as well. Sunglasses, make sure you're keeping those eyes covered.

39:13  Genital GVHD: There are supportive treatments. I didn't get in too much about genitalia manifestations of chronic GVH, but it's often again more of those scarring manifestations and drying manifestations. So lubricants and topical estrogen for women can be very beneficial to try and help minimize the symptoms. 

There are enzyme supplements that we can use for patients that help to supplement the pancreas enzymes that may not .... Your pancreas may be having some scarring and not making what you need. And so we can provide those to patients, that will help to minimize risks of of urgency of bowel movement after we have eaten. Ursodiol is a medicine that a lot of people get as they're going through transplant, but it does help to decrease bilirubin and help your body get rid of that, which bilirubin being high can impact also skin itching type manifestations.

40:05  Bronchodilators are used to treat lung GVHD:  And then for lung GVHD, we have medications, we call them bronchodilators. What they are is they're inhalers or other medications that help to keep those airways open wider so you're not necessarily feeling short of breath. Pulmonary rehab is critical. I think it's an important thing to learn how to work with the lungs that you have subsequently developed.

40:29  There are medicines we can use to help treat symptoms of neuropathy: so duloxetine, which is also called cymbalta or gabapentin, also called neurontin can sometimes help the symptoms of neuropathy. Some people have more benefit from it than others. It doesn't make the neuropathy better in a sense of making the nerves grow, but it certainly does help a lot of patients with symptoms.

40:57 It’s important to get re-immunized after transplant:  Immunologic: I talked about a lot of things that increase your risk for infection. You're going to likely be on multiple antimicrobials: things to treat bacterial, fungal or viral infections to help prevent them. Immunizations are critical. It's important to get re-immunized after transplant. 
Unfortunately, for most of my patients with chronic GVHD, I can't give them live vaccines like the measles, mumps, and rubella, which is really pertinent in today's society, when we're having one of the largest measles outbreaks in 25 years. And so then it becomes just trying to avoid exposure in those situations. And I mentioned, growth factor support as well.

41:40  Physical therapy is important [for patients with GVHD]. You can have joint contractures or tightness. The skin manifestations can be very tightening as well. And so anything that you can do that's causing, that's stretching out those joints and the skin tissues can be beneficial and physical therapy can do that; but it can also help you build up that strength in those girdle muscles that can get weak. And so those are important things to be participating in. And bisphosphonates and calcium supplements are also very useful to help keep and minimize osteoporosis and breaks.

42:15  Nutritional supplements for GVHD: General health and well-being: nutritional education I think is very important. I talk to my patients about nutritional supplements, particularly if you're having a lot of GI manifestations where you're not absorbing as well.

42:30  Exercise helps patients with GVHD:  Exercise: I mentioned core-strengthening to help those girdle muscles, but even going out and making yourself do that walk for 30 minutes every day is really important. It helps to build the lungs, it helps to keep the muscles strong. And so it's something my patients hear from me on the day of the first consult is: I expect them to, as I say, "Do the do." I got that from my nurses actually at Moffitt Cancer Center, which is drinking two liters of hydrating fluids a day, eating well, good nutritional, small amounts, frequently throughout the day, and walking. And so my patients, that's one of the first instructions they get from me during their consultation.

43:13  Psychosocial support is important:  And then psychosocial support. This is tough. This is a difficult thing; and I'm constantly amazed by my patients as they go through all of this, and maintain an amazing attitude going through this. But you need support. And that support can be individual therapy to talk about, are you adjusting to your new normal? It can be group therapies of other people going through it. It can be symposia like this, where you get to talk to other people that have gone through the same kinds of things.

43:45  Summary: In summary, chronic graft-versus-host disease is the most common long-term complication after allo transplant. It's something people are likely going to deal with when they go through an allo.

It has multiple different signs and symptoms and can affect virtually every organ of the body. Most of the patients have mild or moderate chronic graft-versus-host disease, if they develop it.

And treatments can be topical or systemic. The toxicities of treatment are very broad but they can be managed. And we pick the drugs that we choose based on some of your other medical conditions or other medicines that you're needing.

I think the supportive measures to improve symptoms and overall well-being are critical, and a lot of those are the things that you all as patients and your families can help you do everyday that are as important, frankly, if not more important than some of the things that I can do with the pills that I've got.

44:46  There are more than a hundred clinical trials right now investigating treatments for chronic graft-versus-host disease. That means we don't know how to do it well yet, but we're continuing to learn. And it's an area of very active research. And so it's something that is important to talk to your doctors about too is, "Are there are there any trials that I could be eligible for because these things haven't worked?" And those are important things to know.

The last slide that I have is just some of the references that I cited, and most of those are related to the NIH consensus criteria. I'm going to actually go back to this slide here and stop there to take questions. I can bring it around to you so you can speak into the microphone.

Question and Answer Session

45:48  Question about the measles. Unfortunately, I have had to do some traveling because I'm back to work some. And I'm on a lot of planes. I won't be getting the measles vaccination for probably a couple years. What happens if I get the measles?

[Riches] You will likely end up being hospitalized would be my guess, to try and help do all the supportive management to have that run its course. My recommendation, and I have certainly had my own patients ask me these questions, I recommend when you're traveling on a plane, that you're wearing an N95 mask. Most transplant centers, and I thought I saw somebody with an N95 mask earlier., I see some of the lighter paper mask, but the N95 mask is a little bit harder mask. And that mask is going to be a much better protectant for you. Take with you hand sanitizer and you touch something, you hand sanitize. Because the key is to try and avoid exposure. And those are going to be the things that you can do to help you try and avoid exposure.
I think realistically knowing that if you have an abnormal immune system at this point, it sounds like you're still fairly early in these things, would be really trying to see if from a job perspective, you can avoid going to the areas where they have been hardest hit. Obviously, New York City has been very hard hit in the Orthodox Jewish community. And then a lot of the places in the upper northwest. And so the key would be trying to avoid exposure.

47:35  Are less drugs more when treating GVHD?  Secondly. Probably everybody that's had a transplant has some type of this. From your presentation, I kind of got maybe the less drugs you are on and the more kind of tolerable you are and you feel alright to try and avoid as much treatment for this disease.

[Riches] It's a double-edged sword. There are certain scenarios where we're seeing organ damage because of the chronic GVH and we absolutely have to treat it, even if you don't have a whole lot of necessarily symptoms. But I think if we can do treatments that are mild or topical therapies, that is better for you in a general health well-being sense because you're not going to be necessarily increasing your risk for infection.

audience] But when your liver and your kidney function is going well then just ...

[Riches] And it's hard, it's hard to realize that you may not be symptom-free. But if we're having dry eyes or dry mouth and I can treat it, and I apologize for pointing at you, I saw you using your eye drops a few times in here, using your eye drops frequently, if that helps keep you controlled and you don't need to be on Prednisone, that's a big deal.

49:04  Question:  Is it equally as important to wear the mask in the airport as well as on the airplane?

[Riches] I would actually recommend wearing it in the airport and the crowded areas because we know that it's been spreading in part through travelers. I think that, that is a very reasonable thing to do when you have an abnormal immune system. We're trying to prevent infection and those are airborne infections. The common cold has multitudes of different viruses that cause it, and they can have varied levels of severity and impact on a patient. My patients get very annoyed because I encourage them to wear their masks until they are off immune suppression for at least a month. I never tell them not to.

49:55 Question about second line drugs:  Hey, I've got a question with the medication. I guess you would call it your second line. We're just trying Jakafi now. But we also have heard something coming down from the recent conference in Germany couple months ago, KD025. What is that? Is that a Jakafi partner?

[Riches] It's one of the drugs that, again, are early in development. When they have a number like that, they're still in early phase or on trials. All of these, it's going to be one of those 100 clinical trials that are actively being looked at for treatment. It's certainly not made it to mainstream at this point.

50:43  Question about muscle cramping:  I saw a muscle cramping on your slide, but I missed anything that you suggested to do for that.

[Riches] Unfortunately, a lot of times with muscle cramping there's not a whole lot of medications that work well for it. There are certainly the wives tales of a little bit of mustard or a little bit of vinegar, but a lot of doing things like massage therapy are going to be some of the things that help the most with that. And that's where it gets into that physical therapy kind of aspects of things as well.

51:17  Question about steroid toxicity:  In your experience, how long have you seen patients develop toxicity to steroids or to tacrolimus?

[Riches] It's variable. If I have a patient who has you know already has high blood pressure, and they're getting their tacrolimus to start even for prevention of graft-versus-host disease, I may end up having to start them on a new blood pressure medication within three or four days. For things like diabetes, if somebody is not diabetic, but is now needing to be on steroids, it could be two or three weeks after they've been on steroids or even a month or longer after they've been on steroids before they can develop some of that. Because these things can happen doesn't mean they're going to happen to everyone; but they are things that can happen that we need to watch out for.

52:18  Question about how to find clinical trials:  Is there any type of clearing house that we could go to to follow these clinical trials?
[Riches] Actually the website is actually where all of the trials are there. Where I was getting my number for more than a hundred, actually I went to the day I made this slide, which was about five weeks ago, and typed in chronic graft-versus-host disease and can look and see how many trials there were. And that website will also give you information about what sites are participating in different clinical trials. If there are early results that have been published, those maybe are supposed to be posted on there as well.

53:07  Question about whether you get enough immunity to measles from your donor’s cells:  I live outside of Detroit, where they identified patient number 0, who brought the issue from Israel over, and I frequent those areas. And I'm now through almost four years. But do I potentially get the measles resistance or you know from my donor: does that transfer?

[Riches] There's no clear evidence that we get that transfer. That's why we re-immunize all of our patients after a transplant because there is no evidence that you will develop that. And in fact, people who have an autologous transplant, they're getting their own cells back, we re-immunize those patients as well. Because we're starting with stem cells to develop that immune system, and so we don't know that that immunity has truly been transferred.

[Audience]  Can I follow on that? If you have [inaudible 00:54:15] can you do?

[Riches]:  No, you can't. What that does is basically it's going to help ... And a lot of people do need a booster to the MMR, so most of us that were immunized between sort of the in the mid '60s, actually the booster is recommended at this point with the new outbreak. Because what you're going to do is just generate immunity to it. It's kind of like when you get a flu shot, you may develop symptoms in the sense of a little bit of aching or fever, which is actually your body reacting and having immunity and generating immunity to what you're being immunized against.

55:01  Question about prednisone taper:  When going through a prednisone taper, I know you mentioned tacrolimus, you increase that. Is there anything else or maybe I misunderstood you?
[Riches]:  So a lot of times, we'll try and have patients on tacrolimus while they're on steroids, or other medications while they're on steroids, to be able to do a little bit hopefully more rapid steroid taper to get people off of steroids. That works for some people, it doesn't work for others. But a steroid taper generally has to be a slow process and it depends on if you have a flare of symptoms as we're trying to go down on the steroids. And so hopefully the goal is if we have another agent on board like tacrolimus, that we may be able to get somebody off of steroids a little bit more quickly.

55:54  Question about calcium supplements for bone density:  You know as a young woman as myself, you talked about calcium supplements for our bone density, and stuff like that. Is there anything you recommend?

[Riches]  Generally, there are lots of different calcium supplements that are available over-the-counter. I generally have my patients take the equivalent of 1200 mg of calcium with Vitamin D. If they've already got osteopenia or some bone loss, usually two to three times a day. If we're just trying to kind of prevent that, at least once a day.
I would talk to your doctor. I don't know if you've had a DEXA scan to look at what your bone density is and you could certainly ask about something like that. Chemotherapy in general will decrease bone density to begin with. And then if we have to add things like steroids, that can make that happen even more quickly. For women, our loss of estrogen from going through menopause or early menopause can hasten that bone loss as well. And so those kinds of things from that, not knowing whether or not you're still having menses, whether or not you're where your bones are, it's hard to say what would be the exact right amount for you. But probably starting at least at 1200 mg of calcium a day would be reasonable. And make sure it's got vitamin D. Caltrate D is a well absorbed one. Some people prefer the Viactiv, which are fine, which are those sort of calcium chews. It just depends on what works for you. Calcium supplements can cause some constipation sometimes; and so sometimes playing around with which one works better for you [is necessary]. But always make sure when you start those things, you let your doctor know what you've added to your regimen.

I'm happy to stay for a couple minutes after, if people want to come up and ask me additional questions.

57:50  Leukemia and Lymphoma Society Clinical Trials Help:  Hi. This is more of a comment. I'm with the Leukemia and Lymphoma Society and one of the question was on clinical trials. We now have a center for clinical trials. We have nurses that will help you investigate clinical trials. If they find one that looks like it's suitable for you, they'll send you back to your doctor to talk about it, and then they'll actually help you enroll in the clinical trial. So that's through the Leukemia and Lymphoma Society, so they can maybe help you find something.


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