Chronic Graft-versus Host Disease of the Skin and Connective Tissues

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Chronic Graft-versus-Host Disease of Skin and Connective Tissues

Monday, April 19, 2021

Presenter: Badri Modi, MD  City of Hope Medical Center

Presentation is 42 minutes plus 16 minutes of Q & A.

Disclosures: Dr. Modi is a consultant speaker for Sanofi Genzyme and Regeneron, primarily with regards to high-risk skin cancers. He has also participated on an advisory board to discuss chronic GVHD therapies for a Kadmon.

Summary: Chronic graft-versus-host disease occurs in more than 50% of patients transplanted with cells from a donor. The skin is affected most frequently by GVHD. This presentation describes different types of GVHD of the skin. It also discusses the most common symptoms and promising treatments for this problem.

Highlights:

• There are four distinct layers of skin and GVHD. Depending which layer of skin is affected by GHVD, symptoms may be mild and easily treated, or more severe and long-lasting. 
• Severe cases of GVHD can affect the deepest layer of the skin, the fascia, causing scarring or thickening that restricts movement  and, in some cases, breathing.
• Skin cancers occur at higher rates for transplant patients (and especially those with chronic GVHD), so sun protection, self-monitoring and annual screenings are strongly encouraged.

Key Points:

(04:40) There are several  risk factors for chronic GVHD: prior acute GVHD, peripheral blood stem cell donors, older age of recipient, and poorly matched donors.

(05:48) GVHD of the skin can seriously affect quality of life for those with moderate to severe disease although successful treatment can improve the patient experience.

(10:18) The most common symptoms of GVHD include rash, itching, changes in skin color, sores, and ulcerations.

(15:05) When GVHD affects the deepest layer of skin (fascia), it may cause thickening of the skin or tautness, which can affect range of motion and in some cases, affect the ability to breathe.

(17:12) Some symptoms of skin GVHD, such as sclerosis, can be caused by non-transplant related factors as well, so careful diagnosis is required to establish and effectively treat the underlying cause of the problem.

(21:39) GVHD can cause hanges in skin pigment r and can be difficult to treat or reverse.

(26:54) Nail changes are common in chronic GVHD and are also hard to treat or reverse.

(31:03) Topical steroids and extracorporeal photopheresis can be an effective treatment for GVHD that affects the top surface of the skin. When GVHD affect deeper layers of skin, systemic steroids may be required.

(41:32) Early detection and appropriate treatment can improve quality of life for those with skin GVHD.

Note: In this presentation the speaker sometimes uses the terms “BMT” or” bone marrow transplant”. For purposes of this presentation, both of those terms also apply to patients who have been through a stem cell transplant.

Transcript of Presentation:

(00:00) [Michelle Kosik]     Introduction. Good afternoon. My name is Michelle Kosik. Welcome to the workshop, Chronic Graft-Versus-Host Disease of the Skin and Connective Tissues. It is my pleasure to introduce you to, Badri Modi. Dr. Modi is the assistant clinical professor in the Division of Dermatology at the City of Hope Cancer Center. His clinical care and research focus on high risk skin cancers, melanoma and skin effects caused by graft-versus-host disease. Dr. Modi, also co-directs the City of Hope Chronic Graft-Versus-Host Disease Clinic. Please joining me and welcoming, Dr. Modi.

(00:41) [Badri Modi]     Overview of Talk.  Okay. Thank you, Michelle, for that kind introduction. Just to reiterate, my name is Badri Modi. I am sitting in my office at City of Hope in Duarte, California. I want to first thank the organizers for inviting me to participate in this very important symposia. I feel honored to be able to speak to you all today, and I am very grateful for all of the efforts that organizers have put forward to making sure we have submitted everything on time, and also organizing this as a virtual event.

(01:26) This past year has been very challenging for everyone, and it's terrific that we can still continue to do these types of important educational events virtually. And it seems like we can potentially even reach more people. So with that said, let me see if I can progress my slides, there we go. So I'm going to spend the next 30 minutes talking to you about your skin and chronic graft-versus-host disease. I don't spend that much time speaking about acute graft-versus-host disease. My talk is primarily on chronic graft-versus-host disease.

(02:03) Just first is routine. I need to disclose any financial disclosures. I have participated as a consultant speaker for Sanofi Genzyme and Regeneron, primarily with regards to high-risk skin cancers. And I have participated in an advisory board to discuss chronic GVHD therapies for a company called Kadmon.

(02:25) Learning objectives. Learning objectives for today. We will review briefly the risk factors for developing chronic graft-versus-host disease of the skin. The majority of this talk is going to be reviewing the various manifestations of chronic graft-versus-host disease of the skin. And then we'll briefly touch on therapies available to manage GVHD of the skin. And finally, I was asked to speak a little bit about skin cancer after bone marrow transplantation, which is also a very important topic to our patients who undergo transplantation.

(03:05) So probably by day three now into the symposium, you've seen some version of this graph at some point, and you know that the number of bone marrow transplants is on the rise. So the number of transplants that are being carried out in this country are on the rise. And therefore, the number of individuals who will be dealing with chronic graft-versus-host disease is also expected to rise.

(03:32) Chronic graft-versus-host disease occurs in more than 50% of patients with a donor transplant. So what is chronic graft-versus-host disease? Well, in my opinion, it's the major barrier to an otherwise successful transplant. HSCT stands for hematopoietic stem cell transplant. In patients who have not had relapse of their disease, it occurs in, by some estimates, in more than 50% of patients who have undergone an allogeneic stem cell transplant. And patients with chronic graft-versus-host disease have a reduced quality of life and an increased risk of morbidity and mortality.

(04:07) It's a very important condition to be speaking on and know about. And I tell folks that it resembles, or the way I think about it, is that it resembles an autoimmune disease that may occur in patients who've never had a transplant. So as we'll go through the various morphologies of chronic graft-versus-host disease, are non-transplant-related correlates and non-transplant-related autoimmune diseases.

(04:40) Risk factors for chronic GVHD. So what are the risk factors for developing chronic GVHD? Well, these are the ones that we typically think of. So patients who had a history of prior acute graft-versus-host disease, patients who received a peripheral blood stem cell graft. Male hosts or male patients who received stem cells from a female donor are at a higher risk of developing chronic graft-versus-host disease. Patients who were older in age when they received their stem cell transplant. And finally, is folks who have a high HLA disparity between the recipient and donor, meaning that the match level between the host and the recipient wasn't very high, yet it was very important to get to transplant. These are some of the risk factors that are described.

(05:48) GVHD of the skin can seriously affect quality of life. I wanted to first, talk about what the patient experience with graft-versus-host disease is like. And this is an important study that came out of Seattle of around 1400 patients who completed just a patient survey about quality of life, symptoms, health status, and comorbid conditions and medications that they took. These patients, of the 1400, about 20% reported that they had mild chronic graft-versus-host disease. And 10% reported either moderate or severe graft-versus-host disease. About a quarter or 28% of patients, never had any chronic graft-versus-host disease. And about 20% of patients had chronic graft-versus-host disease, but it had resolved. And about 24% of patients did not complete the survey.

(06:45) Folks who developed the moderate to severe chronic graft-versus-host disease or reported that they had moderate to severe chronic graft-versus-host disease, they were more likely to report a worst quality of life, a lower performance status, and more likely to take prescription medications for pain, anxiety, and depression.

(07:07) And a hopeful point about this study is that the self-reported measures were similar between those who had resolved to chronic graft-versus-host disease and those who never had it to begin with. So treating and successfully treating chronic graft-versus-host disease does seem to improve the patient's experience with the syndrome.

(07:29) The skin is the most common place for GVHD to occur. Where does graft versus host disease manifest? Well, I'm a dermatologist, and so the skin and other cutaneous structures are near and dear to my heart. And the skin is actually the most common place where graft-versus-host disease manifests. You can see that the next most common area is the mouth. And beyond that, the eyes, gut, liver, these are all things that the other talks have probably covered today. We're going to focus mostly on skin today.

(08:03) Before we get started into the morphology of chronic graft-versus-host disease, I first like to show you how I think about chronic graft-versus-host disease. I'm a very simple-minded thinker. I like to think about things anatomically and that makes sense to me as we talk about how chronic GVHD manifests.

(08:27) GVHD can affect four different layers of the skin. So there are four major layers of the skin. There's the top most layer, which is called the epidermis and it's made up of skin cells that are rapidly dividing and flake off. And below that, you have the dermis, okay. The dermis is made up of, mostly, this amorphous protein called collagen that makes it the bulk of the skin. It forms the integrity of the skin. Also, you can see that in the dermis, you've got hair follicles coming in, you've got skin muscles, you've got nerves, you've got sweat glands and all are important structures.

(09:06) Below that is the subcutaneous fat, which is mostly... There's subcutaneous fat all over your body, including on the thinnest part of your skin, such as the eyes, or even on the thickest part of your body, the skin on the back, which is about 20 times thicker than the skin on the eyes. And below that you've got fascia, which essentially serves to tether the skin down and that's what attaches your skin to your body. And so you've got muscle underneath there, or perhaps bone.

(09:41) In graft-versus-host disease, you've got the donor's immune cells that come in and attack various parts of the skin and where it attacks and where it causes damage and thereby inflammation, injury and repair is really important in thinking about what type of morphology of graft-versus-host disease is going to develop. And so my talk, where I review the different morphologies, we'll really hone in on this anatomic diagram to help you think about the different subtypes of skin graft-versus-host disease.

(10:18) Symptoms of GVHD. So what are the symptoms that patients will mention to their doctors? So patients will say, "I have a rash". Or, "I'm feeling very itchy." They'll also describe perhaps, "I've noticed changes in my skin color." Or, "Doc, I've noticed that I'm no longer able to sweat as much." Or, "I've noticed that my hair's falling out." In other cases, patients will describe skin sores and ulcerations.

(10:52) Severe cases cause skin breakdown and reduced mobility. This column to the right is what we consider the more severe cases of chronic graft-versus-host disease. And in these cases, we'll see loss of the integrity of the skin that leads to these sores and skin breakdown.

We'll also see potentially some inflammatory processes that lead to thickening and scar-like development of the skin, which then can lead to reduced mobility of the skin. We don't really understand why some patients go on to develop this type of GVHD, where they're developing a tightening and thickening of the skin, whereas others, maybe simply develop discoloration, but we know it occurs, and we know that it can cause reduced mobility.

(11:42) Some of this mobility reduction may be noted around the mouth where patients may say that, "I can't open my mouth as much." Or, also very importantly, they'll notice there's a reduction in movement around joints, primarily around the shoulders, elbows, wrists and even ankles. Some patients may describe some dimpling or rippling of their skin which is commonly called cellulite, or maybe more appropriately called pseudo-cellulite. And I'll show you some photographs of that. And concerningly, some patients may describe difficulty with taking a deep breath because there has been some tightening of the skin around their chest trunk.

(12:32) Differing morphologies of skin GVHD. Historically, the morphologies of chronic skin GVHD were described as either scleroderma or lichen planus. As we've learned more, we recognize that in fact, there are many more morphologies of chronic graft-versus-host disease that can occur in the skin. We'll review these that are listed here. These include sclerotic, and morphea-like, lichen planus and lichen sclerosis-like. We'll discuss pigmentary changes and we'll discuss eczema and papulosquamous-like graft-versus-host disease.

(13:15) GVHD in the deepest layers of skin are the most serious and may involve fascial damage. So going back to that diagram, I'm going to essentially start at the bottom of the skin and reverse order and go up from that. And the reason for that is the inflammation and the damage that may occur from graft-versus-host in the deeper parts of the skin tends to lead to a more severe graft-versus-host disease.

(13:40) So this is an example of a patient who has maybe fascial damage which is resulting in this dimpling-like appearance or pseudo cellulite-like changes, and even what we call a dry river bed that's developing in the forearm. And the reason that's occurring is because the fascia is essentially inflamed and scarred down, and it's retracting the skin above it and causing it to be tethered down. There's a tendon that runs right there in the middle of your forearm and the fascia near that is pulling down. And that's why you're seeing those spaces.

(14:29) Here's an example of... Well, just to return, another feature that we look for as clinicians is the pinchability of the skin. Most normal skin will allow you to pinch your skin and grab skin between it. The patients with sclerotic skin changes have a reduced pinchability, and it is sign of deeper skin scarring. When this type of scarring occurs around a joint, such as the shoulders, elbows or wrists, patients will notice a reduction in the range of motion around that joint. And that can be very debilitating.

(15:05) Skin thickening or sclerosis may respond to stretching and exercise. Here's another example of skin thickening or sclerosis, or also called scleroderma. As mentioned previously, when developed around the chest or trunk area, a major concern is that patient's ability to expand their chest to take deep breaths becomes limited. We send these patients for pulmonary function testing to objectively evaluate for this concern so we can pick up on it early.

(15:36) If sclerotic symptoms are noted, what can you do? Well, your transplant doctor will discuss various systemic therapy options with you, which I will list later, to try and slow down the progression and hopefully reverse some of these symptoms. In addition, I really emphasize non-medication interventions such as regular stretching, physical therapy, yoga, and exercise as able. Anecdotally, many of my patients have expressed that these physical efforts have allowed them to adapt to their new limitations and slowly improve the range of motion and functionality. I have several patients who are remarkable and inspiring in the activities that they are able to continue to do. One patient of mine comes to mind, continues his passion of painting despite having significant scarring and reduction in mobility in his wrist. And he has really made an effort to continue in these passions of his.

(16:42) This is a localized form of sclerosis called morphea. Morphea refers to an autoimmune disease that occurs in the non-transplant setting. And it presents as sclerotic areas of the skin that are very localized. Again, we don't know why some people develop sclerosis in a more widespread manner while others can develop it in a very localized fashion.

(17:12) Sclerosis can also occur from non-transplant trauma. There are some reports that external forces or trauma can trigger sclerosis. For example, it is often noted that the waistline will develop morphea-like skin thickening related to the pressure from the elastic band and belt around the waist. In addition, another example of localized sclerosis is that we often see it in areas of prior skin damage. One type of specific skin damage that's commonly reported about is areas of the skin that have previously had shingles. So a patient has had shingles, they've gone on later to have a transplant, or they have shingles after the transplant, but at that time did not have any chronic GVHD. And down the road, they develop chronic GVHD or sclerosis just in the area of the prior shingles infection. And so clearly, trauma or skin damage seems to trigger development of skin sclerosis , or at least is one trigger.

(18:23) Lichen sclerosis may lead to atrophy of the skin. Going back to this anatomic diagram, moving more superficially in the skin, another morphologic subtype of chronic GVHD that we observe it's called lichen sclerosis. And this occurs when there's chronic inflammation in the superficial area of the skin that ultimately leads to thinning out of the skin. Something that we refer to as atrophy. And this atrophic skin is very prone to tearing and ulcerating.

(18:53) Here's another example of thinning and fibrosis of the superficial skin. And when I zoom in on what the skin looks like, it often has this cigarette paper-like wrinkled appearance that's very typical of atrophic skin. The skin is prone to tearing or easily breaking down.

(19:18) Lichen planus-like GVHD involves an overgrowth of the top skin layer. Also, another case of superficial inflammation is something that's referred to as lichen planus-like graft-versus-host disease. As opposed to the atrophy seen in the previous case, this tends to lead to overgrowth of the top layer of the skin. So this is an example of a patient with lichen planus-like chronic graft-versus-host disease developing and presenting as itchy bumps in her hands.

(19:54) And here's another example of it being a little more widespread and here's a zoomed in photo of what an individual skin lesion looks like. They're often referred to as purple papules or bumps, and they have this classic thin white scaling on top of the lesion. Patients with this rash tend to also develop scaling and symptoms in their mouth, as well as potentially on the genitals. This lichen planus-like skin chronic graft-versus-host disease is more likely to respond to skin directed therapies that we'll go over here soon.

(20:42) Papulosquamous disorders cause itching, scaling and cracks in the skin. Finally, another superficial skin chronic graft-versus-host disease, and other morphology, I should say, is something that we refer to as papulosquamous. The superficial inflammation here leads to overgrowth of the top layer, and it causes rashes, and may mimic, psoriasis or eczema. These patients may experience itching, and because of the excessive scaling, they may have discomfort from their skin because it may crack. So the skin essentially becomes what we call hyperkeratotic or heaps up. It doesn't fall off and that skin, when it dries out, can fissure and crack, and that can be very painful to whoever's experiencing it. Moisturizing and using topical medications are really helpful for this type of chronic graft-versus-host disease.

(21:39) Pigmentary changes may be the most common skin finding after transplant. Perhaps the most common skin finding that I see in patients who have undergone a bone marrow transplant is pigmentary changes. I often say to my patients that this is 'the mask of transplant' that shows the evidence that you've had a prior transplant. Focusing on the two photos on the left which are of the same individual. This is a very typical pattern of pigmentary change that we see. This patient experienced inflammation that was triggered by his graft-versus-host disease and it essentially led to a disruption of the normal distribution of pigment that's already been laid down throughout the skin.

(22:27) So prior to the graft-versus-host disease, there's already a pattern of pigment that's very important for determining what your skin looks like. When you have an inflammatory process, like graft-versus-host disease, that distribution pattern gets messed up. And you get this scattered dislocation, or some areas of low pigmentation and some areas of higher pigmentation develops. It's one of the most common types of skin changes that we see in patients after their transplant. And it can be of varying degrees of severity.

(23:08) Now, if you focus on the right photo, you see a very distinct pattern of pigment loss. That's consistent with a condition called vitiligo-like graft-versus-host disease. In this case, the immune system is attacking the specific cells that are responsible for producing and storing the pigment in the skin. And those cells are called melanocytes. This case was a very interesting case because his son was his donor and his son actually has autoimmune vitiligo, he's never had a transplant, never had leukemia, but he does have autoimmune disease in which immune cells are attacking his melanocytes. And when his stem cells were used as a donor stem cells and given to the father, the exact same skin condition developed, and in some way is a proof of principle that it is the immune system that plays an important part in development of these chronic graft-versus-host disease symptoms.

(24:22) Reversing pigmentary changes is challenging. Now, before moving on, I want to make a few comments about post-transplant pigmentary changes. One, reversing pigmentary changes is very challenging, particularly when it's on a widespread scale. Most pigmentary changes that occur after transplant do improve with time, but they may not fully resolve. I tell patients that folks who are interacting with you after several years may notice improvement, and they may get to a place where they're not even seeing the pigmentary changes, but you'll always be aware of it.

(25:05) And the reason I'm mentioning this is because traditional treatments for graft-versus-host disease that are immunosuppressive, so traditional systemic treatments, are not aimed at reversing the pigmentary change. And that statement is important because pigmentary change should not be really used as a measure of disease improvement. Most disease improvement measures have more to do with the body surface area of inflammatory rashes or sclerosis. And so I think it's important to have that perspective as a patient.

(25:46) In some patients, the pigmentary changes are very significant and cause very understandable emotional distress. And in those local settings, I tend to be as supportive as I can. And I try to remind patients about the fact that the pigmentary changes will improve with time. And I may offer a low potency topical retinoid to help with improving the balance of the color. I've had some patients who have been very happy with the improvement in their skin pigmentation after the use of topical retinoid. However, you have to be very careful in ensuring that the expectations are not that the skin color will go back to totally normal. And I have to be careful, as the dermatologist, to monitor for any skin irritation because these topical retinoids can have side effects.

(26:54) Nail changes are common in chronic GVHD and also hard to reverse. Finally, the nails are a part of the skin, or I should say they are an extension of the skin. And so nail changes are also common in chronic graft-versus-host disease. And unfortunately, these, too, are very challenging to reverse. Most patients are not affected by it significantly or bothered by it, but some patients do express significant concern over these changes. And in that scenario, I might consider injecting steroid into the stem cell of the nail. Okay. So, that's the proximal portion of the nail where it inserts into the skin. That's typically where the GVHD inflammation is occurring. And the steroid is hopefully going to reduce the inflammation in the stem cells of the nail. However, I always remind patients that it is not 100% effective. And so we really have to measure our expectations about the improvement on the nail changes. And in addition, it sometimes can be a very painful procedure to sit through. And so I would only really recommend it if a patient is expressing significant concern over the nail.

(28:25) Treatments may be skin directed or systemic. So focusing a little bit more on the treatment specific concerns, there are two categories of treatment for chronic skin graft-versus-host disease. From a dermatologist perspective, there's skin directed therapy, which are primarily going to be organized and managed by a dermatologist with the assistance of a dermatologist, and there are systemic therapies. And your transplant doctor typically is the quarterback in managing your systemic therapies.

(29:06) Skin directed therapies are administered by dermatologists and treat upper layers or superficial subtypes of GVHD. Skin directed therapies include topical anti-inflammatory medications including topical steroids and topical non steroids, which are primarily calcineurin inhibitors. Topical steroids are the mainstay of management tools for a dermatologist. And they are used very often. So you might have come across some of these.

(29:34) And then there's also phototherapy which may or may not be available at your clinical providers office. This is a skin directed therapy that harnesses the immune modulatory effects of targeted wavelengths of ultraviolet radiation or light. And there's three main types. There's ultraviolet A phototherapy, there's ultraviolet A in combination with psoralen which is a medication that I'll talk about. And there's ultraviolet B phototherapy.

(30:14) Now, just as a 40,000 foot view about these skin directed therapies, we tend to see a higher efficacy for superficial subtypes of chronic graft-versus-host disease like the ones I mentioned, lichen planus, lichenoid, psoriasiform, or eczematous. And this should make sense. The medications that are skin-directed are going to only be able to penetrate so deeply, and so are more likely to have an impact on the superficial areas that they interact with. Sclerotic subtypes are less likely to improve with skin directed therapy, although, there are some reports.

(31:03) Topical steroids can offer effective treatment. Turning to topical steroids, this photograph demonstrates how many different topical steroids there are. And as a dermatologist, I'm really thinking about three main issues when I'm deciding which one to use. I'm thinking of the potency of the topical steroid. Potencies range from very mild potency topical steroids, which essentially you can get over the counter, so everyone's probably heard of cortisone 10. That's about the mildest topical steroids you can find. And it ranges from super, super potent topical steroids such as clobetasol all and betamethasone.

(31:48) What also is important is how the medication is delivered. Is it delivered in an ointment which is greasy? Or is it delivered in a solution which is very watery and liquidy? There's a whole range of different vehicles that the medication can be delivered in and that's relevant because the vehicle determines in some ways how effective it is at delivering the medication. So ointments are more effective at delivering a steroid than is a watery vehicle like a solution.

(32:31) And finally, we'll consider site-specific issues. So the skin on the eyelid is very thin about a millimeter thick, and it's going to be able to handle topical steroids less well compared to the skin on the back, which is about two centimeters thick. But an important point is that overusing topical steroids can be damaging to the skin. So it is very important to avoid overuse and really use them as directed.

(33:11) Calcineurin inhibitors are medications that you may have heard of, for example, tacrolimus. These are a safe, alternative to topical steroids. However, the downside is they can be expensive.

(33:20) Moisturizing is crucial to help dry skin. I cannot emphasize enough how important a dry skincare is and moisturizing is to patients with graft-versus-host disease. It is especially helpful for patients who are prone to dryness and experience itching. And it's also helpful for patients who have areas of excessive scaling such as these two examples that have had skin cancer ruled out. These types of excessive scaling areas tend to crack and fissure and that can be very painful, especially when it's on the feet or on the hand. I have these two photographs on the right here of aquaphor and eucerine, so that people are aware that these are just widely available, very effective moisturizers. I'm not endorsing these specific brands. I'm just listing them here because they're widely available, affordable, and they come in large volumes, but really the key is to get what you like and use it.

(34:27) Phototherapy can help with superficial subtypes of GVHD. Very quick slide on phototherapy. So phototherapy is used because the effects of ultraviolet A and ultraviolet B have been shown to modulate the immune system. I will be brief on this slide and just mention that UVA phototherapy is losing its place in dermatologic care, in part, because the machines are not as widely available. And UVB phototherapy machines are still used. Generally, these interventions are better at treating superficial subtypes and graft-versus-host disease than they are the deeper subtypes like sclerosis.

(35:21) And finally, a common question that comes up about phototherapy is what are the skin cancer risks associated with phototherapy? My brief answer is that we don't know for sure what the long-term effects are because the studies haven't really been done. However, these therapies have been around for a long time, and in the case of UVB phototherapy, dermatologists generally do not feel that there's a significant added skin cancer risk because it's such a narrow spectrum of sunlight, of light.

(35:56) Systemic therapies are managed by transplant doctors. This is a long list of systemic therapies that are primarily going to be managed by your transplant doctor. Typically, we start with corticosteroids at the onset of symptom development. And in the last few years, there's been a number of new medications that have been tested in clinical trials to treat chronic graft-versus-host disease. And so certainly, I think the next five to 10 years we're going to see an explosion of novel treatment approaches to chronic GVHD. And so, definitely, keep your eyes open for these.

(36:44) Skin cancers occur at higher rates for transplant patients (and especially those with chronic GVHD), so self-monitoring and annual screenings are advised.  I want to finish out by talking about skin cancer. Non-melanoma and melanoma skin cancers occur at a higher rate in patients who undergo bone marrow transplantation. That's been shown in several different studies and so just having undergone a bone marrow transplantation and the immunosuppression associated with that seems to be associated with a higher risk of developing skin cancers.

(37:14) In addition, we suspect that having chronic graft-versus-host disease also is associated with increased skin cancer. So very important to self monitor and watch out for skin cancer. Dermatologists tend to recommend self-monitoring every one to two months at home, to find a partner to watch your back and evaluate your skin for signs and symptoms of skin cancer.

(37:41) In addition, it's recommended to have an annual screening with the dermatologist after you've undergone a bone marrow transplant and importantly, practice sun safety. Ultraviolet light exposure is really the only modifiable risk factor. And please no tanning booth use. In my opinion, this is the cigarettes of skin cancer. We know that cigarettes lead to lung cancer in the same way we know the tanning booth use leads to the development of skin cancer in the future.

(38:17) Three different types of skin cancer with increasing severity. So these are what skin cancers look like. These are what dermatologists are looking for when they're evaluating you. They can look like a lot of different other things in all, but these are the most common looking lesions. From the left, you have a basal cell carcinoma, which shows up as a pink shiny bump, it may bleed, it may open up and develop a sore that heals, and then does the same thing. They typically occur on sun exposed areas like the face and the top of the ears. And they're diagnosed most typically in a dermatology exams. So seeing a dermatologist and having skin screening.

(38:58) Same is true about squamous cell carcinoma. And this is a different form of skin cancer, but it's also an important one and it develops as these pink, scaly plaques. Sometimes they can be tender, sometimes they can just heap up, they can bleed. Again, they are often discovered by your dermatologist or a patient coming in saying, "Doc, I developed this spot. What is it?"

(39:29) And we also are always on the lookout for melanoma, which in some ways is the most ominous type of skin cancer. I think the most patients are often most aware of it. We described the A, B, C, D Es of melanoma to screen for melanoma. So A standing for asymmetry, B standing for irregular borders, C standing for abnormal different colors, D standing for an enlarging or enlarged diameter greater than six millimeters. And finally E for evolution. This is by far the most important feature to look for and that refers to spots that are changing. A spot that is changing is very, very important. And that's why we say looking at your skin every one to two months is the best way to pick up on evolving skin lesions.

(40:30) Prevention strategies for skin cancer. Finally, this is a handout from the American Cancer Society skin cancer prevention efforts. Really the only modifiable risk factor is sun protection. So it shows getting clothing or accessories to reduce your sun exposure to your skin, and importantly, wearing sunscreen in areas of skin that are not covered by clothing.

(40:59) And one issue that I'll bring up, or one point that I want to make is that the common sunscreen mistakes are forgetting to reapply. So patients will put on their sunscreen before they're going to beach and they'll get to the beach an hour or so later. And it'll be by that time, they'll need to reapply the sunscreen. They forget to reapply every one to two hours. I recommend a broad spectrum sunscreen that's water resistant and anything that's greater than an SPF 30.

(41:32) Early detection and appropriate treatment can improve quality of life for those with skin GVHD. Finally, in summary, we've reviewed a lot here. We've broadly reviewed that chronic GVHD is a common condition after transplant and a major barrier to health. The skin is the most commonly involved organ and symptoms can manifest with one of several morphologies. The treatment for chronic skin GVHD can either be skin directed or systemic therapies or a combination. And finally, chronic GVHD is a chronic syndrome and has a huge impact on quality of life. But I think with early detection and appropriate treatment and intervention, quality of life can be improved. Thank you. I'm happy to take any questions.

Question and Answer Session

(42:28) [Michelle Kosik]      Q & A.  Thank you, Dr. Modi, for this excellent presentation, incredibly informative. We have got a lot of folks asking some great questions. As a reminder, if you have a question, please type it into the chat box on the lower left hand corner of your screen.

(42:47) We're going to start this question and answer period with this one. I have mild GVH on the face and neck for three years, it's controlled by steroid cream. Is this going to be a lifelong or will it eventually dissipate? Also, does this increase other concerns like melanoma?

(43:12) [Badri Modi]      That's an excellent question. Thank you for asking that. If I were to see you in clinic, I would first in my mind, try to evaluate the specific morphology of chronic graft-versus-host disease. Is it one of the superficial inflammatory chronic graft-versus-host disease subtypes that is going to be likely to improve with topical steroids or perhaps topical tacrolimus or pimecrolimus? If it's one of the deeper or the dyspigmentation type of graft-versus-host disease, in particular, pigmentary change, I would really try to counsel about the fact that there will be slow improvement over time with the pigmentary change. And if the pigmentary change is still an important concern, as it very likely maybe because of the development on the face, I might consider using some topical treatments such as topical retinoids which are good at balancing out skin color.

(44:31) Now, I don't expect there to be a perfect response, these interventions are done with a grain of salt and knowing that it may not achieve perfect results, but I have had patients express satisfaction with improvement in their pigmentary changes with the use of some of these topical medications. But thank you for that question.

(44:54) Oh, in regards to your skin cancer question, absolutely. I think anybody who's had a bone marrow transplant really needs to be vigilant about all the things that we mentioned with regards to skin cancer prevention. So things like self-monitoring every one to two months, annual screenings with your dermatologist and practicing sun safety. Michelle, next question.

(45:23) [Michelle Kosik]      Absolutely, that's great advice for all of us, for sure. The next question is, can chronic skin GVH manifest itself at any time after an allogeneic transplant? And if so, what are the common triggers?

(45:41) [Badri Modi]      Thank you for that question. That is also an excellent question. And it's one that's a little hard to be entirely specific on, but I think the broad answer is yes. It can occur anytime after a transplant. I think it's more likely to occur within three years after your transplant. And it's therefore, less likely to occur three to five years after your transplant. In terms of triggers, traditionally, we think of triggers being things that rev up your immune system.

(46:22) So in some scenarios experiencing a viral illness where your immune system is now needing to adapt and be revved up to respond to the virus, it may also inadvertently rev up and be more inclined to attack your own body or your own skin and lead to GVHD symptoms.

(46:51) Similarly, some patients have to undergo things like donor lymphocyte infusion after their transplant. And in that scenario, you're basically getting new immune cells that may inadvertently target your skin or other organs.

(47:12) Another trigger that we think about is tapering of the immune immunosuppression after you undergo your transplant. So let's say you've received your bone marrow transplant, and three to six months later, everything's going smoothly, you're in remission. Your counts are holding up. Your transplant doctor may begin to taper off whatever your post-transplant GVHD prophylactic medications were. We do sometimes see graft-versus-host disease come out in that setting. And that makes a lot of sense because the medicines you were taking were doing a really good job of suppressing the GVHD. And once the medications are being tapered, GVHD may start to develop. And in that scenario, the transplant doctors often slow down their taper, or they may go back up to the previous dose, but it's really case specific.

(48:18) [Michelle Kosik]      Thank you. The next question is, is photodynamic therapy safe for pre-cancer on the face, or people that have chronic GVHD? And then there seems to be some question about what should that exposure be if they do receive that treatment in terms of timeframe?

(48:41) [Badri Modi]     So photodynamic therapy is a specific treatment for pre-skin cancers. And it's a treatment that's aimed at targeting something called an actinic keratosis which has a small percentage of developing into a squamous cell carcinoma. It's a tool that dermatologists used to treat an entire area of the body rather than treating individual lesions with something like cryotherapy. I don't tend to push for something like photodynamic therapy until, or unless I feel the patient's chronic graft versus host disease is stable.

(49:37) So what I mean by stable, I mean that the patient's their graft-versus-host disease has either resolved or that the graft-versus-host disease has been very stable, and there's been no new medications added, and even the transplant doctor is able to reduce the medications. And if that specific patient has a lot of actinic keratosis, I might pursue photodynamic therapy to treat the actinic keratosis. I would probably start with something like liquid nitrogen treatment of individual actinic keratosis rather than jumping to something like photodynamic therapy. But I do think eventually it is a safe thing to try.

(50:23) [Michelle Kosik]       Excellent. There are several questions that our audience have asked on whether or not the pseudo cellulite appearance or any other changes in their skin after transplant are permanent or not? Can you answer that question?

(50:44) [Badri Modi]      That is a really good question. And I don't like to say permanent because I have seen some cases improve. That being said, I think that the deeper sclerosis that occurs in GVHD is very, very hard to reverse. Okay. It's like having a scar and not being able to reverse the scar. So I tend to work together with our patients on our expectations and really try to focus on the areas that are functionally impacting the patient's quality of life. The cellulite change can be cosmetically disturbing, it's maybe a reminder to the patient, so it can be distressing that they have chronic graft-versus-host disease. But the short answer, I'd say, is that it's difficult to fully reverse it, but I've had patients who've had improvement. And part of that is because sometimes the cellulite is also associated with some swelling. And so if we can get the swelling down with things like compression stockings and other strategies, the distension of the skin also and some of that dimpling improves. And it's certainly a common thing that can occur in graft-versus-host disease.

(52:23) [Michelle Kosik]      Great answer and explanation and tactics to reduce. The next question is if someone has sensitive skin, and they have severe graft-versus-host disease, what are some best tips on how to exfoliate the skin safely?

(52:45) [Badri Modi]       Yeah. So this really goes to the part of the presentation where I was saying that it's very common for some patients to develop very excessive scaling. For example, this gentleman, here, you can see has a lot of scaling. And so what are some of the best tips with that exfoliation or scaling? Well A, I would say moisturizing very regularly is just a must. And I tend to prefer greasy or moisturizers like aquaphor or just plain Vaseline.

 (53:26) And depending on how much scaling, I might even prescribe medicines that are directly aimed at dissolving some of the dead skin. So we call those keratolytics and those medicines are really good at softening up heaped up or hyperkeratotic skin. A commonly used one is urea 40% cream. And so that's a prescription. And so you'll need to get that from your doctor or your dermatologist, it's really helpful at helping to reduce some of the scaling.

(54:10) I think dermatologists are really good at helping to manage that symptom because we deal with the condition called psoriasis which is effectively hyperkeratosis or a lot of scaling. We have a lot of strategies to try and decrease that scaling. And I would encourage you to talk to your dermatologist or a dermatologist about strategies aimed at that.

(54:35) [Michelle Kosik]      Excellent. We are running out of time, so this will be our last question. And I know you spoke about this in your presentation, but one of our audience members asked, has there been any progress on patients who have lost their fingernails or toenails? They want to know if there's any new targeted agents or any new advances.

(55:09) [Badri Modi]      I have treated some patients with intralesional injections of steroid into the nail unit. And it's a hard thing to manage because when you look at your skin and you see those scarred nails, you may think that I actively have inflammation in my nail unit. That may not necessarily be the case. You may have had an episode where you had the inflammation and it created irreversible scar in the nail bed. And if that's the case, that nail stem cell may not be able to produce a normal nail again. But I do offer, for the very motivated patients, an opportunity at least injecting the nail unit one or two times or three times in monthly intervals to see if there's an improvement.

(56:14) There have been some studies that show that systemic immunosuppressive therapies are helpful for nail disease. There hasn't been any that are specifically looking at nail GVHD, but in correlate of non-transplant diseases such as lichen planus, nail lichen planus, there is some evidence that systemic therapies are helpful. So it really depends on how motivated I think the patients are in seeking out the improvement in the mail and how much it affects their quality of life. We can try all of these creative options, but they all come with their own side effects and their own potential for harm. And so I really try to balance out the impact of the skin condition on their quality of life before moving on to trying these novel strategies. While on one hand, they offer a lot of hope to patients who may not have great options, but on the other hand, they do come with their own set of issues. And so we always have to think about that risk benefit when talking through these therapies,

(57:39) [Michelle Kosik]    Closing. Dr. Modi, such an exceptional presentation this afternoon. On behalf of BMT InfoNet and our partners, I'd really like to thank you, Dr. Modi, for your very helpful remarks and thank you to the audience for your excellent questions.

(57:57) [Badri Modi]      Thank you again for the invitation. I truly mean it when I say it's an honor to be invited to present and really an honor to take care of this population of patients. It's really the main reason that I wanted to work at City of Hope. And I am very hopeful for the future of chronic GVHD and the therapies that will be developed over the next decade. Thank you.

(58:26) [Michelle Kosik]     Thank you.