Your Skin and Chronic Graft-versus-Host Disease (GVHD)

The skin is the most common target of chronic graft-versus-host disease (GVHD).  Learn the symptoms and treatment options.

Presenter:  Joseph Pidala MD, PhD, Associate Member of the Moffitt Blood and Marrow Transplantation and Cellular Immunotherapy Program, and Associate Professor
in the Department of Oncologic Sciences at the University of South Florida Morsani College of Medicine

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

Presentation is 45 minutes, followed by 15 minutes Q&A


Skin GVHD is the most common manifestation of chronic GVHD.  It's important to report any changes in skin, range of motion, nails or hair to your transplant doctor so that treatment can be started promptly.


  • GVHD affects the skin in approximately 70 percent of patients who develop chronic GVHD 
  • Skin GVHD affects different layers of the skin as well as connective tissue
  • Symptoms include skin thinning, changes in skin color, spots on the skin, thick and tight skin, itching, skin dryness and cracking, decreased range of motion, muscle cramps, hair loss or hair thinning and brittle, cracked or chipped nails.
  • The goal of treatment is to control symptoms, prevent organ damage, improve physical function and improve quality of life
  • Prednisone is the primary treatment and about 2/3 of people will see improve after 6 months of treatment
  • If prednisone fails, there are more than 20 second-line treatments that physicians can try
  • Patients with skin GVHD have an increased risk of developing skin cancer

Transcript of Presentation

00:00  Good morning. Welcome.

00:03  It's very nice to see all of you and actually see some familiar faces. Some of my own patients are here and that's a very special experience to see you all here so welcome. Thank you for that introduction.

00:21  Today we're going to talk about chronic graft-versus-host disease. I'll abbreviate it as GVHD as an abbreviation for graft-versus-host disease and we'll focus specifically on that of the skin and connective tissue.

00:37  Overview of talk:  By way of a quick outline, first, just to lay the foundation I'm going to talk briefly about chronic GVHD in general. I know there was a general chronic GVHD session delivered by Dr. Marcie Riches earlier on in this meeting. Next, we'll then zoom in on GVHD of the skin and connective tissues. We'll then talk about chronic GVHD treatment and a couple of important principles therein. We'll move into aspects of supportive car, and then importantly, I'll conclude with how I believe you can partner with your doctor and clinical team to help to achieve good outcomes in GVHD therapy.

01:13  First, we'll talk a bit about chronic GVHD in general and I'm going to pose a few questions and then answer them to give you some context. The first is how common is GVHD and how do we do in preventing it with commonly used GVHD prevention strategies?

01:31  30-50% of patients who have a transplant with cells from a donor develop acute GVHD: I'm showing you here some information just importantly from two major what are called BMT CTN trials. This is our national cooperative group so the Blood and Marrow Transplant Clinical Trials Network. For example, we're conducting clinical trials at our own center, as are many other transplant centers, but then we partner in this national effort in this cooperative group to answer important questions in the field.

01:53  I'm only sharing this with you to indicate that both what is called acute GVHD and then subsequently chronic GVHD are common problems despite our conventionally used prophylaxis approaches. What this indicates to you is that the 0402 trial was focused exclusively on sibling donor transplants where someone has a transplant from a completely matched sibling and the 0201 trial on your right was an unrelated donor transplant trial. I'm just showing you these results to kind of capture those commonly used approaches and what you can see here for acute GVHD is that it's about 30-50% of people that are affected. What I was sharing is just that under conventional practices there is an ongoing burden of acute and chronic GVHD and I'm just showing you some representative information from two major national trials that capture our usual practices.

02:44  50% of patients who have a transplant with cells from a donor develop chronic GVHD: This is showing you information on acute GVHD and then this is showing you information on chronic GVHD. You can see here both in the context of sibling donor transplants and also unrelated donor transplants, that it is a very common problem and it's about half or greater of people that are affected by chronic GVHD. This illustrates the point that it is a common problem, we need to do better to prevent it, but until we can affectively prevent it in all people, we need to focus on effective treatment strategies for this problem.

03:16  Using peripheral blood stem cells instead of marrow increases the risk of GVHD: The other key problem I want to highlight for you is just that the use of what is called peripheral blood mobilized stem cells or PBSC which is an overwhelmingly utilized strategy to get stem cells for a transplant. It is the majority of transplants that are done using peripheral blood stem cells. That does contribute to the risk of chronic GVHD. Using that type of approach instead of a bone marrow harvested stem cell product increases our chances of seeing chronic GVHD. This illustrates the point that it is common and one major feature of our practice actually contributes to this issue.

03:52  In summary, on this section, the major point is that both acute and chronic GVHD are common and I pointed out, the use of peripheral blood mobilized stem cells result in more chronic GVHD. What you should do ultimately is moving forward, from early post-transplant onward, you should always be cognizant of new symptoms or new problems that are developing and report them in a timely manner to your doctor. The good news, which actually is not the focus of this talk, this talk is focused on treatment of established skin GVHD, the good news is that there are many new promising GVHD prevention strategies that hopefully will dial down the overall burden of both acute and chronic GVHD. Hopefully our research will more effectively prevent these issues.

04:43  Chronic GVHD is an immune system disorder: The next topic is how does chronic GVHD present? How do we recognize that it is present? A quick word about chronic GVHD. This can be called an immune mediated disorder or IMD. That means that your donor's immune system can see your body as different and cause a reaction against you. That is the underpinning of what we see clinically as GVHD. Importantly, chronic GVHD as I mentioned before is very common and it affects the majority of transplant patients and it usually first presents around six months after transplant. This means while that early recovery period is important, we're unfortunately not completely out of the woods. We can actually then enter a period where we're at risk for chronic GVHD.

05:29  Chronic GVHD can affect many parts of your body and one unique thing about chronic GVHD is it's more complex. Acute GVHD really is more simple in a sense that it only affects your skin, your GI tract, and your liver and in certain obvious ways. Chronic GVHD not only affects more organs, but also can affect each one of them differently. It can present in many different ways, so it's a little bit more complex and we need to be mindful of that.

05:58  50 percent of people who have an allogeneic (donor) transplant develop chronic GVHD: This is just information to share with you. What is the expected burden of these problems under usual practices? This comes from a very large national effort which was a prospective study where over 900 people were enrolled in an observational study from transplant moving forward and we observed how likely were they do develop these various problems and how did things go for the patients afterwards. One major conclusion here is you can see that on the second row down that it is about 50% of people that were affected by chronic GVHD and on average that occurred at about seven months after their transplant, but there are a couple of other important features here which is that besides chronic GVHD in general, there are a few other important categories of GVHD that can occur late.

06:49  Bronchiolitis obliterans syndrome: One of them is something that is called late acute GVHD and this just means that that same problem that can happen early after transplant can happen late and so we need to be mindful of that and then also this shares with you what is the overall burden of specific types of chronic GVHD that we think are especially important. The first one is BOS which means GVHD of your lung. This is something called bronchiolitis obliterans syndrome. You can see while the overall risk of developing that is low, it may be about five percent of people in total, the important this is that it's a serious problem and it happens later. The average onset time is about a year after transplant.

07:30  Cuteaneous sclerosis of the skin: Also, another specific type of skin GVHD is this thing called cutaneous sclerosis or sclerotic chronic GVHD. That may bear some resemblance in your mind to something called scleroderma. You may have heard of people that actually have an autoimmune condition where their skin gets hard and tight. There are some parallels between that disease and this type of chronic GVHD. It kind of may ring true in your mind about that issue. And importantly, while also that is a relatively rare problem happening on the order of about 10% of people, again, it's a serious and difficult to treat problem that occurs late with an average onset time of about a year after transplant.

08:10  Skin is the most common organ affected by GVHD: This just shows for you that when we rank order proportionally, how much are each of these organ sites affected by GVHD when you look at large populations of patients. You can see immediately that skin is certainly one of the most important things. It's one of the most common organs affected by GVHD. Hence why we need to be mindful of changes in the skin and also highlighting the relevance of this discussion right now.

08:39  In summary, we distinguish chronic GVHD from acute GVHD by it's actual features, not just the time after transplant. You should know that acute GVHD can occur later. These are all things that your doctor is looking for in the late follow-up after your transplant. There are different subtypes of chronic GVHD. Some of the most important ones are those involving the lung or this more difficult to treat problem in the skin where it gets hard and tight, cutaneous sclerosis. Also, this illustrates that skin is a very commonly targeted site of this problem chronic GVHD.

09:14  How chronic GVHD can impact your life:  Next we're going to talk about what is the importance of chronic GVHD. How does it actually impact you and why should we care about it? This one slide summarizes a lot of things about why it's an important problem. First, it can cause troublesome symptoms. Certainly, chronic GVHD is associated with a symptom burden, but also can impair physical function leading to disability, as well it can affect your ability to return to work and return to normal roles and normal functioning. Also, both chronic GVHD and the treatments we use to manage it can increase your risk of infections and other complications.

There's been extensive research that shows that chronic GVHD adversely impacts your own reported quality of life and also importantly, chronic GVHD leads to prolonged treatment with immune suppressive medications. The people that stay on immune suppressive medications for a long time after transplant are those that are affected by chronic GVHD. This one slide summarizes what is the major impact on both the life and the well-being and the quality of life of people affected by the syndrome.

This one slide focuses on quality of life. These things, a PCS and an MCS are just physical and mental summary scores of a commonly used quality of life instrument. What this illustrates for you is just that people with more severe chronic GVHD report impairments in their quality of life that are actually on par in the physical domain with extremely serious chronic physical conditions like congestive heart failure and chronic lung disease and cancer and other problems. In this comparison it just lets you know that the impact on their quality of life is sizable and it's on par with other very serious diseases and also the way it impacts their self-reported mental quality of life or their mental and emotional well-being actually is on par with major depression. This just summarizes for you one aspect of that impact. Why is this such an important problem?

11:29  Two-thirds of patients with GVHD continue to have the disease 5 years after diagnosis: This is information from a recently published study which shows that after a chronic GVHD diagnosis, when you move out about five years after that diagnosis, it's only about a third of people that are successfully free of their GVHD and off their immune suppressive medications. This illustrates the point that I raised earlier which is that when you have chronic GVHD it impacts the total amount of time that you spend on transplant medications.

12:00  How GVHD manifests itself on the skin: That's a bit of an introduction. We're now going to zero in on chronic GVHD of the skin and connective tissue specifically. This cross-section of the skin is meant to indicate that your skin is multi-layered. There's the most obvious part that you can see, but there are deeper layers of your skin and soft tissues all the way down into the fascia and the muscle that all can be targets of chronic GVHD. What this slide summarizes is that depending on which part of this is affected you will see different types of manifestations of GVHD in your skin.

12:33  Just to show a contrast here, for example if you had GVHD only targeting the top layers of your skin, you may just see things that are abnormal appearing like change in the skin color, or an obvious rash. Let's say it looks abnormal but it feels normal and it is not hard or tight. That can progress through the deeper layers of the skin, the fascia, and below and that can translate into things on that spectrum of what we call cutaneous sclerosis which means the skin and soft tissues are hard and tight and inflexible and it can impact your overall joint mobility and your range of motion. This illustrates that the way GVHD can affect your skin is diverse and how it affects your skin will translate into the type of GVHD you're facing.

13:23  Pictures of skin GVHD: I wanted to point out a couple of types of chronic GVHD of the skin just so you've seen a picture of them. You should know that common red-pink rash that is seen in acute GVHD can also happen in the context of chronic GVHD and it can look just the same. What is called skin erythema or redness can happen in chronic GVHD but I'm showing you a couple of examples of types of chronic GVHD rashes or problems that are distinctive. They happen in chronic GVHD and they do not happen in acute GVHD. That's the major point here.

One thing is called Poikiloderma and this just means that the skin is thin and the pigmentation is varied so there are lighter and darker areas. Next you can see this thing called lichen planus which actually is a raised, purple-red spot that can have a silvery or shiny appearance to it. This is another distinctive manifestation of chronic GVHD of the skin. Another is called lichen sclerosis which is a raised, gray-white plaque or spot that can have a rough or leathery consistency. This is another unique feature of chronic GVHD of the skin. Importantly, this is meant to indicate to you the range of problems that can happen with cutaneous sclerosis.

It's useful to think about this problem as kind of a spectrum. It can range all the way on the easier side of just your skin is not as pliable or pinchable, but it can range all the way into a more dramatic end of the spectrum which is the skin is not only not pinchable but the deep tissues are extremely hard, tight, rigid, inflexible, or even what is called hide-bound which just means you can't move it all, it's just completely hard.

15:16  Skin GVHD can affect your range of motion:  On this spectrum is also the underlying problem called fasciitis which means it can impact your range of motion and your mobility. This is not meant to alarm or scare you, it's just meant to indicate that this is one feature of chronic GVHD that is critically important and it's something that we need to be really mindful of and treat aggressively that we can help to resolve that tightening and hardness.

15:43  Symptoms of skin GVHD: So what about symptoms? I just shared with you the way chronic GVHD affects your skin is diverse. How does it actually present, how do you actually know that you have a problem? Some of the more common symptoms that people report are itching, dryness or cracking, on that cutaneous sclerosis end, people may notice that actually they have hard or tight skin or that they newly cannot do things like their joints are stiff or they have decreased range of motion or there are certain things they cannot do. For example, let's say trying to get from a crouching down position to standing up is difficult. Or for example putting on a shirt or buttoning a shirt is difficult, or reaching for things is difficult. In other words, you may notice that there are certain normal activities that you used to be able to that you cannot do because of this problem.

Some other less common problems are things like muscle cramps or spasm, hair loss or thinning. This definitely can happen and there are many contributors to that. Finally, one of the more frustrating things for many people is nail changes. Nails can become brittle, cracked, or chipped and it can be extremely frustrating because once that happens it's difficult to make that better and also it gets in your way. It becomes a nuisance problem. These are all commonly reported skin and associated chronic GVHD symptoms.

In brief summary about this part of our talk, chronic GVHD can affect your skin in different ways, it depends on which part of your skin and tissues are affected, and the important point is that any of the following things require medical attention. You should be mindful of these things and then report them to your clinical team.

17:31  Routinely examine your skin for changes: The first one is if you see anything abnormal. I commonly recommend to people that they get in the habit of doing a once-over of their skin on a recurring basis like a head-to-toe, examine your skin and find out is there anything changing for the worse? Is anything not normal?

An abnormal appearing rash or spots could be an issue. Abnormal texture of your skin, namely tightness or hardness could be an issue, then as I mentioned, difficulty moving your joints or difficulty doing tasks that used to be normal for you. Any of those things are of potential concern and you should definitely promptly report them to your clinical team and I keep stressing that because what we think is that the earlier we jump on those things and the earlier we treat them, the more likely we will be able to safely make them better and that's our goal.

18:24  Treatment goals for skin GVHD:  We're next going to move on to the topic of chronic GVHD treatment. Before we get into the specifics, I'd like to point out what are the major goals of our treatment. This is definitely true of treating any type of medical problem, but this definitely rings true in the context of chronic GVHD and specifically chronic GVHD of your skin.

We want to provide benefit and we want to minimize harm. On the benefit side, we hope that our treatments can control symptoms, they can prevent or manage damage that is occurring from the GVHD itself, that they can hopefully improve physical function when that's limited due to chronic GVHD, and hopefully the treatment can improve quality of life. These are all of the desired outcomes of any type of treatment we implement in chronic GVHD.

Of course we want to minimize harm. We certainly want to minimize potential side effects of the treatment and also we want to be attentive to and prevent and manage infections that can come about based on the immune compromise of immune suppressive treatments and also we want to try to minimize other complications. In grand total, these are our major objectives in treating skin chronic GVHD.

19:45  Treatment strategies for skin GVHD:  A bit about what we do to treat chronic GVHD and what do we expect in terms of outcomes. This will look a little bit complicated but I will actually walk you through this figure. First, we'll talk about primary treatment of chronic GVHD which means you have not yet been treated with any type of what is called systemic medication for chronic GVHD, meaning you've not yet seen prednisone or other related medications specifically for chronic GVHD. In that context, when we start those medications we call it first or primary therapy.

20:18  Prednisone at a high dose and then tapered is considered still the gold standard for primary therapy of chronic GVHD. This pertains to chronic GVHD in general but also specifically when we think skin chronic GVHD is bad enough that it requires this type of treatment. I mention that just because sometimes people can do well with only lower intensity or only topical medications. For example, if you just had a minor rash and we said, "You know what, maybe you can do okay with a topical steroid" that would really be great. If you can get away with that and you don't require these higher intensity treatments, that would be perfectly fine. It is very common that when GVHD is significant, we do need to implement these higher intensity therapies.

As I mentioned, prednisone is the standard of care in the first line setting and I'm citing a number of different clinical trials in the bottom right and the point here is just that there have been multiple clinical trials in this space where investigators have tried to outperform prednisone. They've added prednisone together with other medications and in randomized studies compared prednisone plus something to prednisone only as initial therapy for chronic GVHD. Actually I can summarize all of those trials by saying that none of them met that mark. It does not appear that any of those combination therapies are more effective than prednisone alone. That leads us to believe that this still is our gold standard.

When you look at all those trials and you look at the clinician reported response rates, meaning the person treating that patient reports how well had they done with the treatment, it's about two thirds of people that have achieved some type of good response, they've responded in some way by six months of therapy.

22:04  Treatment failure: However, I want to show you a plot here, the big figure on your right. This is a concept that's been developed by someone Yoshi Inamoto and Paul Martin, these are individuals from the Fred Hutchinson in Seattle, and they've pioneered this concept of treatment failure. It's an outcome that is called treatment failure and I'm sure that has some intuitive meaning, when something fails it's not done enough for you. What it really means is it's a composite or there are multiple things that contribute to this outcome and those are treatment change, meaning you've not done well enough with the prednisone and you have to graduate onto something else or things that we don't want to see which are transplant-related death or relapse of cancer. When you sum all those up, those are all negative outcomes and as a combined package, they're called treatment failure.

I only highlight this for you, not to be negative but only to say that you can see the driving force here is that some people are successful but those that fail are primarily because the first line treatment was not good enough. Their GVHD has not responded well enough and their doctor says, "We must move on to the next line of therapy." The major point here is just that it's common that people require multiple lines of therapy to treat.

23:24 Second-line treatments for skin GVHD:  This becomes even more significant when you move into what is called secondary therapy or second line therapy and beyond. Again, this is a study that I'm showing you here where again it's presenting that information of treatment failure. What you can see here is that between this figure that treatment change is the real problem, but you can see here that it's an even bigger problem here in the second line therapy. This just illustrates the point that it is very common that people do not get enough benefit from one line of therapy that we need to move on to the next one to adequately control the syndrome and to achieve all of the major things that I mentioned before, meaning provide benefit and minimize harm.

24:10  In the second line and beyond, this is where things get a little bit challenging because there actually are many therapies that are available. I'm going to share some examples with you but truly in the second line therapy and beyond, many different types of treatments are used and it's very common that people need to change. That's the major message here.

24:33  Goal of GVHD therapy is to wean people off the drug without GVHD flaring up again:  This figure illustrates a nice point which it's meant to indicate on the left hand side that you're starting at a certain amount of immune suppressive treatment like prednisone or other immune suppressive medications to treat your chronic GVHD. Ultimately the end goal over time, moving from left to right is that you've achieved this thing that we call clinical tolerance which means you no longer have signs of GVHD and you're able to come off immune suppressive medications. That is definitely our long-term goal with everybody with GVHD is to make it better, taper things down, get them off the medication, keep them free of transplant medications. That is the desired end goal.

25:13  Treatment of GVHD isn’t a straight line process: If that's the starting point on your left, and that's the end goal on your right, this figure illustrates a nice point just to help you to understand how this commonly goes which is it is not always a seamless process. In fact, it's very common that it is an up and down step-wise process where the GVHD can get better or worse over time and commonly that improvement or worsening is dependent upon the intensity of the treatment that we're using. Let's say we get good control of it, we taper down the therapy, the GVHD sometimes can declare to us, "that's not okay." The GVHD can flare up and then we have to increase the therapy again. Commonly it does look like this where it's up and down for a bit before you are decidedly better.

25:59  This could look like going up and down on a prednisone dose, it could look like coming off medications and then having to resume them, it could be doing well for some time but then requiring a new line of treatment, so I just want to share this with you to illustrate that this is actually a normal and expected process. While you're going through it it's definitely challenging and I'm sure frustrating, but the key points are that you're not alone. This is an expected process and that the end goal is achievable. Those are the two positive aspects of this figure.

26:35  There are many different treatments that can be used after steroids. You can see here that this list is very long and this is not a completely comprehensive list but it's meant to just illustrate that there are many treatment options that are available. What I've done here is I've actually underlined several of them such as ECP or photopheresis, sirolimus, others. My point in doing that is just to illustrate that these are pretty commonly used. If this is a giant menu of options, I highlighted some of them that are some of the more usual things that we use.

27:13  Imbruvica: The other thing I've highlighted and starred there is something called Ibrutinib or Imbruvica. The reason I've done that is that that actually, based on a prior clinical trial, has actually been FDA approved for use in chronic GVHD. That one stands out among all of these medications because it is the only one that actually bears that designation. You should know that there are a number of immune suppressive medications that we use in transplant that are not specifically FDA indicated for that in particular.

27:45 Extracorporeal photopheresis ECP: I also wanted to point out, in part because it's a unique thing, but also in part in the development of this talk, I got a lot of feedback from many involved that actually reviewed these slides from the organizers of this meeting that they wanted me to specifically focus on the concept of photopheresis or ECP, that that would be especially important. I totally agree. It's its own unique thing and so we should spend some time on it.

28:09  In brief, the major difference about ECP is that it is a procedure. It is not a medication that you take. It is rather a procedure that you undergo. It's a procedure where you actually require a certain type of port to facilitate the process and you, on a recurring basis, come back to the transplant center and have a process where your blood is removed and treated and then returned to you. That type of treatment actually helps to dial down the activity or the aggressiveness of your immune system to help to dial down the overall burden of GVHD. It's actually a procedure that treats your blood and helps to alleviate the GVHD.

28:51  It's something that's pretty commonly used and also we use it very commonly when people have skin and soft tissue GVHD. We use it very commonly in that problem that I mentioned before, the cutaneous sclerosis and in fact it can be helpful and actually it has been very well studied in that context. There have been important trials that have systematically studied how well does ECP work in the setting of cutaneous sclerosis. We actually have a good evidence base in that context.

29:21  Benefits of ECP: The other really good thing about it is that it has a very nice risk and benefit profile. Remember we talked before about we want to provide benefit and not cause harm? ECP does provide benefit over the long term. It requires some time and most people do extremely well with it. It's very infrequent that it causes side effects. Sometimes people feel fatigued after having ECP and then the other issue is just that you can have complications related to the port itself. For example bleeding or bruising or a clot associated with the port itself or even a port infection. These are all things that can happen but overall the ECP actually has a good risk and benefit profile.

30:04  Downside of ECP: If all of that is great, what is the major downside of ECP? Well, the major down side is just that it is logistically demanding. It's commonly only done in certain transplant centers and if you live far away from the transplant center, it's difficult to get back and forth repeatedly for this and in fact it demands several hours on a machine. Each time that you are getting it, you're spending a couple of hours doing that. Plus, you have labs and maybe a visit and each time you're at the center doing ECP, you may spend multiple hours. It may consume a large part of your day. That is difficult, and then the other challenging thing is just that we usually start it at high intensity where we're doing two sessions of ECP two days of the week per week on a recurring basis. It means you're there twice per week on a weekly basis getting this.

Over time we actually taper the frequency to maybe two sessions every other week and then in people responding we will continue to taper it, but in grand total may people will spend on the order of 6 to 12 months receiving ECP. I'm highlighting all of this just to characterize what are some of the unique features of this therapy and I would say the major details are that it has a good risk and benefit profile, it's major challenge is just the logistical demand associated with it.

31:28  How do doctors decide which treatment option to offer patients? With all of those options, how do we make a decision? How do we choose? There are many considerations. Again, what I'm talking about here is if someone has been treated with the standard of care, first line therapy, namely that steroid therapy, and they've had to graduate onto next lines of therapy because they need more help to make the GVHD better, and if we have this range of options in front of us, how do we make decisions on a case by case basis?

At the top of the list in terms of considerations, you can see I've emphasized here available clinical trials. While we have a range of options available to use, things we can prescribe outside of a clinical trial, there are all kinds of shortcomings of each one of them; none of them are perfect. As I showed you in that figure before, it is relatively common that people need to graduate through multiple lines of treatment to make it better. Anything we can do to make this more effective certainly is worth studying and therefore we should always consider are there clinical trials available that you could participate in? That is absolutely a number one consideration.

Moving beyond that consideration, there are a couple of other important factors. One is what medications are you currently taking? Also what is your prior treatment experience? Generally speaking, if you've already been treated with one of those options and we think we need to move on to a next option, it's not very common that we're revisiting old things. That's not meant to say that you cannot do that, sometimes we do that, but generally speaking, both for patients and for doctors, we generally think, "Let's move on to something that is distinctly different. What we've tried before has not worked, let's move on to something else that may provide a different avenue of controlling this."

Again, one consideration is clinical trials, the next is your past and current treatment history, another is are there unique things about you that limit your ability to tolerate certain medications? Everybody is different and we need to pay attention to the whole picture. Sometimes let's say for example your kidney function is not good and we don't want to risk making that worse with certain medications. Or let's say your white count or your platelets or hemoglobin, let's say those are already in a position where they're dangerously low. We may not want to challenge you in ways with medications that may make that worse. There are a number of other considerations but your own ability to tolerate medicines will impact what we choose.

Finally as I mentioned before, there are logistical considerations. What is the time and commitment involved, what is the overall burden of the treatment? This especially true with ECP but it's also true across many of those treatment options I just mentioned. Many people do not live real close to their transplant center and we could be managing this issue over the course of multiple years so we need to be very attentive to how reasonable is this? Are we asking too much from someone?

To summarize this part which is focused on treatment, the major point in sharing all that was not to alarm you or to make you concerned, it was just to share with you a reality which is that both in the first line and the second line and beyond, our treatments are imperfect. Therefore it's common that people need to graduate through one therapy and into the next.

I want to point out something that I've not mentioned before which is that many treatments do work in skin and connective tissue chronic GVHD, specifically the focus of this talk, however we really do not have good evidence to call any of our currently available treatments skin-specific. It's tempting sometimes to say that but in fact many of these treatments have activity across multiple different sites of GVHD involvement and many of them have evidence for working in the skin. As you saw before, skin is an extremely common issue. It's very common that people have skin GVHD but to hand-pick therapies because we think they're preferentially active in the skin is not truly fair to say that.

35:38  Good news is our understanding of GVHD and its treatment is improving: Actually, I want to counter some of the more sobering aspects of what I just shared with you with some good news. The good news is that our understanding of what drives chronic GVHD is rapidly improving. Our actual understanding of what is the underpinning of the immune reaction that is causing GVHD, that has been improving by leaps and bounds and it is constantly getting better. Already one new drug, which in part is based on some understanding of what is mechanistically driving chronic GVHD, has been FDA approved. That is actually a major landmark in terms of that end and also there are multiple other promising treatments that are currently being studied in clinical trials. The major good news is that our understanding is improving and with that there is a massive groundswell of clinical trial activity that is offering a number of new promising treatments for chronic GVHD.

36:39 Supportive care measures that help with skin GVHD:  Let's move on to the topic of supportive care, because actually so far everything I've mentioned to you is medications and therapies. We certainly should not ignore this next part of the talk. First of al,l sometimes, as I mentioned, it's okay to just use topical therapies but even in those people that are receiving systemic therapies like prednisone and other systemic immune suppressant drugs, topical treatments can certainly be helpful and we're commonly using them together. As your skin is immediately accessible and amenable to topical treatments, we are commonly using skin agents like topical creams. One major component of your treatment could be topical steroid creams or other topical therapies to treat skin GVHD.

37:30  Moisturizers help with dryness:  Also many people find it helpful to moisturize their skin to generally treat dryness. Sometimes you can get stuck in a bad cycle of dryness, itching, cracking, scratching; it can be kind of a vicious circle. Moisturizing can help to alleviate that sense of dryness which may help to combat some sense of itching or other symptoms and those should be safe to use with your other medications.

37:56  There are medications you can take for itching:  The other thing is that sometimes if significant itching is a problem, you have unrelenting itching that is distressing to you, there are medications you can take by mouth to actually combat the sense of itching. Some of the commonly used ones are Benadryl or Atarax. These are medications that can be used. The important thing is that they're all sedating so finding a good balance of managing the symptoms but not being too sleepy, that's an important consideration.

38:25  Physical therapy helps with skin GVHD: The other major thing is physical therapy. We as a community and also I personally am a very strong proponent of this. It is extremely helpful. What could be helpful about physical therapy? Number one, globally for anyone, it can help to improve your strength and your conditioning irrespective of whether and how significant you are dealing with skin GVHD. Specifically for people that are deal with that problem of impaired range of motion like their joints are not moving correctly, physical therapy can be extremely helpful to target those areas and work on improving range of motion and flexibility. That can be helpful globally versus specific targeted areas.

39:12  Massage helps with skin GVHD: Another thing that is commonly used and I also endorse this, I think it is helpful for a number of reasons, is massage. I think this can be helpful for the skin, I think it also can be helpful for your overall well-being. Things like massage or yoga or other practices certainly are useful adjunct. They can help you overall.

39:32  People with skin GVHD have a higher risk of developing skin cancer:  Now we're going to talk about a specific aspect of what we need to be mindful of in the skin and that is unfortunately the risk of skin cancer. It is true that anyone is at risk for skin cancer. We live in a state where we get a lot of sun exposure but we also need to be mindful that people that have gone through a transplant may be at greater risk for developing skin cancers in comparison to the overall population. Also it may be the case that those especially that are affected by chronic GVHD of their skin and also the immune suppressive medications that we give them to treat that problem may also increase the risk of developing skin cancers.

The best practices are really about vigilance, ongoing monitoring. We would definitely recommend at least an annual dermatology exam. That would be a dermatologist who's expert in this area doing a head-to-toe examination to look for cancer or precancerous lesions. I would definitely recommend in parallel monitoring yourself. You have a view of your own skin and how it is changing on a daily basis and so you can definitely be your own advocate in monitoring your own skin.

40:50  Protecting your skin against the sun is important:  Then finally we should definitely focus on skin protection. This would be first, minimizing sun exposure to the extent that you can, trying to cover up more of your skin as you can, and also wearing sunscreen. All of these things are things you can do to help to prevent this problem.

41:12  Skin issues patients should report to their doctor:  Finally, I'd like to talk about specifically what you can do. Obviously, your doctor and your clinical team are going to be focused on everything they can do to help you but this is definitely a partnership and you should definitely be involved in your own care. There are multiple things that you can do to advocate for your own well-being. The first one is, as I've mentioned a few times, you definitely want to monitor your own well-being globally but also specifically keep an eye out on your skin. It's actually relatively simple. You just want to look for things that look different. You don't have to know the specific details, but if you see things that are appearing that look different like a rash or new spots or new changes, that could be an issue and you definitely want to report that to your doctor.

Some of the time some of our patients do something which I think is extremely helpful and I definitely support this which is let's say they live four hours away, they'll email us and say, "Hey, I've got this new problem coming up, let me send you a picture." They'll take their phone and they'll take a picture of their rash and they'll send it to us. That can be one very helpful way to make a decision. Is this okay, is this not okay, how quickly do we need to see them? That's a totally reasonable thing to do.

Another is things that feel different. If your skin feels not pinchable or thick or tight or hard, those could all be signals of that problem I mentioned before, cutaneous sclerosis. As soon as you notice that you definitely want to report that. Then also if you notice changes in your joint range of motion. For example as I've mentioned, you can't move them, if they're stiff, if they're inflexible, if you're finding either new challenges to your day to day activities, those are definitely things you want to notice and then report.

43:06  Track how you feel and respond to treatment:  The other thing is, that's all about diagnosing or sort of recognizing new problems, but you are also a key member of your own treatment team. As you are undergoing treatment, you should also pay attention to what's happening during your treatment. I would definitely recommend that you track how you feel you are responding to treatment and also how or if you're experiencing any new treatment side effects. You're going to know that before your clinical team does so you want to be your own advocate. If you feel like you're responding well to a treatment, that's definitely something you want to let your doctor know. If you feel like things are getting out of control, either you're just kind of plateaued and you're not making meaningful improvement or things are obviously getting worse, you definitely want to report those to your doctor. Also, any new side effects of any type you always want to report them and that's all.

So the key message here is that you are a key advocate for your own well-being, both in terms of recognizing new problems and also tracking your own progress as you move forward.

I'd like to acknowledge all of the patients and families and members of our own team at the Moffitt Blood and Marrow Transplant and Cellular Immunotherapy Program and also I want to acknowledge that I've actually shared some information in this presentation from the Blood and Marrow Transplant Clinical Trials Network. Those were those first few slides I shared with you. Also I've shared some data with you briefly that actually arises from this national effort called the Chronic GVHD Consortium which we participate in so I want to just acknowledge that I've shared some information from those sources. I'd be happy to take any questions. Yes?

Question and Answer Session

44:56  That's a good question. I'm sorry, you said itching and?

45:05  Question about distinguishing skin GVHD from other medical problems:  Okay. Okay. I think that's one of the most important things, as I've mentioned here, is being aware of your symptoms and reporting them. I think that's the most critical thing that is your responsibility. I think it is really up to your doctor and your clinical team to be able to distinguish, "Is this coming from this problem or that problem?" I can tell you that the overlap between neuropathy symptoms and chronic GVHD symptoms is usually not great. They're usually pretty distinct. For example, people with peripheral neuropathy commonly complain of things like they can't feel the bottom of their feet very well or they can't feel their fingertips real well or there's numbness or pins and needles sensation or even pain. Those are most of the time attributable to peripheral neuropathy and not related to chronic GVHD of the skin, just as an example.

I think that there are multiple things that can potentially overlap that are attributable to GVHD versus attributable to other medical problems or even side effects of certain treatments so I think that you definitely want to be aware, you definitely want to share that information. You definitely want to participate in finding the solution, but I think ultimately the onus is on your doctor and your clinical team to be able to say, "We believe this is related to this and not related to this for this reason and this is what we're going to do about it and this is how we're going to track your progress."

I have to tell you, the care of any one person after time after transplant is definitely a continuum. That's one of the key features of what we're doing all the time is that continuity. Managing things over time and observing how they change for the better hopefully. I would say that is how I would approach it.

47:13  Question about community healthcare providers not knowing how to treat GVHD: Your point is very well taken, meaning I feel for you and I'm sorry you're having a hard time with that. You're highlighting something that can be true which is no one will have the same level of expertise pertaining to your transplant care as your transplant center. There are many oncologists and other doctors in the community that are truly excellent that we routinely partner with, especially for those people that live relatively far away.

For example, sometimes we'll set up a pattern where let's say, I'm just making this up, but let's say I will see you every three months and every intervening about half way between each one of our visits we'll have you follow up with your local doctor and we'll have an ongoing communication with that local doctor saying, "Can you check these labs, can you check this tacrolimus level, can you do X, Y, and Z?" A lot of the time it works really well. I am aware though that sometimes it doesn't work really well and sometimes people without specific knowledge in the domain that the transplant are either afraid or unwilling to engage because it's out of their skillset.

I think part of it is communication. Part of the responsibility is on us, the transplant doctors, to have communication with other doctors involved in your care and based on how much we think we can delegate to them versus how much we have to handle ourselves, we need to understand that very well. The way that shapes up for any given person may differ dramatically. Let's say we think we need to locate all of your care in our clinic or let's say we think we can partner with your doctor back home, that would look different.

You're highlighting something that's very important which is your care can span a long period of time. It may be difficult to come back to the transplant center all the time and you may be dealing with doctors that are not immediately familiar with all the things. If you don't mind me giving some advice, I would just say, based on the question you posed, I think if you feel like your needs are not being addressed there, then certainly I would recommend coming back and we could reevaluate, think about what we need to do, think about creating a network of doctors that can care for you.

I've many reactions to that. My major reaction is my advice is yes, of course you're welcome back. Yes, he is no longer seeing patients, but there are many of us there that would be capable of helping you. By all means, I would recommend scheduling a follow-up visit with us. Yeah, we can definitely do that.

50:12  Question about Jafaki:  Okay. Okay. These are also very good questions. The first one was about Jakafi. It's one of the medications I cited there. It's called Ruxolitinib is the name of it, but it's called Jakafi. You're right there's a lot of buzz about that medication. I think one thing we need to be cautious about, meaning it may be helpful. It's one of the major options that we have and it may ultimately be approved. It may ultimately earn an FDA indication for treatment in this space, but the thing we need to be mindful of it's actually currently being studied in a major clinical trial. There's a major clinical trial that's been ongoing that actually is a very large study that's intended to understand the benefit of that medicine versus other commonly used medications in chronic GVHD.

51:07  Drugs being studied on clinical trials are not always available to patients off-trial:  The only note of caution I'm sharing is just that when things are actively being studied in clinical trials, we should not jump to conclusions before those trials are finished but what you probably are seeing and what is happening is that things tend to kind of bleed into each other in a sense that that medication's actively being studied in a major trial and yet people are sometimes getting it approved to be prescribed outside of a clinical trial. Sometimes it can be a battle with the insurance providers. Sometimes they say, "No, this is not something you can get." Sometimes we repeatedly ask and they will give it to us, meaning allow us to prescribe it but my only note of caution is before we say that that is something that is truly helpful, we should at least wait until we have the mature results on that clinical trial to fully understand it's benefit. Until then, I think yes, it is one of several options that are out there.

What I can share with you is it can be helpful, just anecdotally, I've seen it help some people. It is also not risk-free. There are some certain complications of it that can happen. This gets back to the point of we need to be very careful about providing benefit and minimizing harm.

52:26  Your second question was about are there aspects of GVHD that are permanent? I think it's more useful to think about it as a spectrum of easily resolved versus more difficult to resolve. There are some things that come and go quickly.

For example, when you develop a red rash and we use steroids and it cools off, that's a good example of something that it happens, we treat it, it gets better, it's obvious. There are other ways that GVHD can affect the skin where it's much more difficult to make it better and, also, the overall time course is longer. Some of those things are for example the cutaneous sclerosis I mentioned but also as you just mentioned when the skin has changed its pigmentation.

For example there's something called hyperpigmentation which mean it's darker than it should be in certain ways. Yes, that can be more difficult to resolve and yes, I have seen people have that kind of indefinitely for multiple years and it doesn't seem to be very sensitive to their treatment being up or down. I think it may not be fair to call it permanent but it would be justifiable to call it more entrenched and more difficult to make better and less treatment responsive let's say.

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