Introduction to Graft-versus-Host Disease (GVHD)

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Introduction to Graft-versus-Host Disease (GVHD)

Saturday, April 30, 2022

Presenter: Amin Alousi, MD, Director of the GVHD Clinic and Research Program and the Inpatient Medical Director of the Department of Stem Cell Transplantation at MD Anderson Cancer Center.

Presentation is 47 minutes long with 10 minutes of Q & A

Thanks to Equillium, Kadmon, a Sanofi company; Pharmacyclics, an AbbVie company and Janssen Biotech; Syndax; and the William G. Pomeroy Foundation, whose support, in part, made this workshop and recording possible.

Summary:  Graft-versus-Host-Disease (GVHD) occurs when transplanted donor cells attack the patient’s body. It can affect virtually every organ in the body and may require prolonged treatment. This presentation reviews the different types of GVHD, symptoms you should watch for and report to your doctor, and the available treatment options.

Highlights:

• Initial symptoms of GVHD may be subtle. Patients should closely examine their mouth, skin, joints and genitals for signs of GVHD weekly.  This is especially important after day 100 when clinic visits may be less common.
• It is crucial that patients take all prescribed medications for GVHD as directed. Stopping them without notifying your doctor can worsen problems and even lead to death.
• Steroids have been the standard therapy for GVHD. There are now three FDA-approved therapies for chronic GVHD patients who do not respond to steroids:  ibrutinib (Imbruvica®), belumosudil (Rezurock™) and ruxolitinib (Jakafi®).

Key Points:

(04:30): Graft-versus-Host disease (GVHD) is actually two diseases – acute GVHD and chronic GVHD. Acute GVHD most commonly affects the skin, the GI tract and, less frequently, the liver. Chronic GVHD most often affects the eyes, mouth, skin, joints and fascia, gastrointestinal tract, liver, lungs, and the genitals.

(08:52): Chronic GVHD can develop at any time, but 90% of patients who develop chronic GVHD do so within the first year of transplant.

(11:31): Skin is the most common organ affected by GVHD and the most common site for secondary cancers. Symptoms include a rash, scarring, swelling, changes in skin color and/or a tight-feeling skin.

(21:01): Symptoms of GVHD in the mouth include a dry mouth, sensitivity to foods, swelling, redness, pain or bleeding of the gums.

(23:19): Symptoms of GVHD in the eyes include dryness, an inability to produce tears, burning, itching or a gritty sensation.

(24:06): GVHD of the GI tract can cause weight loss, nausea, vomiting, abdominal pain, bloating, cramping and diarrhea.

(25:08): GVHD of the joints, fascia and muscles causes joint stiffness, reduced range of motion, tightness in the muscles and tendons, cramps, spasms, and/or occasionally, swelling.

(29:46): Symptoms of lung GVHD may be a dry cough, wheezing, a cold that extends beyond two weeks or shortness of breath. Some patients have no early symptoms at all which is why periodic pulmonary function tests are important. 

(33:38): Women should routinely examine their vulva and vagina, and men the tip of their penis and foreskin, for symptoms of genital GVHD.

(39:39): Supportive care therapies such as physical therapy, occupational therapy, pelvic floor therapy, topical treatments and special lenses for ocular GVHD are equally important as systemic treatment.

Transcript of Presentation:

(00:00): [Sue Stewart]:     Introduction. Hello, and welcome to the workshop, Introduction to Chronic graft-versus-host disease. My name is Sue Stewart and I will be your moderator today. I'd first like to thank organizations that have sponsored this workshop, Equillium; Kadmon, a Sanofi company; Pharmacyclics, an AbbVie company and Janssen Biotech;  Syndax; and the William G. Pomeroy Foundation, whose support made this workshop possible. It's now my pleasure to introduce to you today's speaker, Dr. Amin Alousi.

Dr. Alousi is a professor of medicine and the inpatient medical director of the Department of Stem Cell Transplantation at the University of Texas MD Anderson Cancer Center. He's also the director of the GVHD Clinic and Research Program. Dr. Alousi specializes in the treatment of graft-versus-host disease and has pioneered an innovative multidisciplinary program at MD Anderson to provide excellent care for patients living with graft-versus-host disease. Please join me in welcoming Dr. Alousi.

(01:15): [Amin Alousi]:     Overview of Talk. Thank you all for joining in today and thank you Sue, for the kind introduction, and more importantly, for organizing this wonderful symposium. You and BMT InfoNet have compiled a wonderful list of topics and great speakers, and I'm thrilled to take part in this year's symposium. As you mentioned, I have the distinct honor to lead a large team of physicians, advanced care providers, nurses, pharmacists, and therapists, who all specialize in the care of patients with graft-versus-host disease. What I hope to accomplish in today's talk is to drive you the knowledge needed to be an informed and active participant in your care.

 (01:57): What is graft-versus-host disease (GVHD)? Undoubtedly, at this point in your journey, you have heard of this complication of allogeneic transplantation referred to as graft-versus-host disease. GVHD in its simplest term, is a multisystem disorder - by multisystem, meaning it can involve various organs - that occurs when immune cells transplanted from a non-identical donor recognize a recipient as foreign. The result is an immunologic process resulting in tissue injury and impaired organ function, which can result in an impaired quality of life and in severe forms can limit survival.

(02:38): So what do you need to know about graft-versus-host disease? Well, in our GVHD clinic at MD Anderson, we teach three simple rules to live by. Number one, we want you to know thy self. Number two, know thy foe, and by foe, I mean graft-versus-host disease. And number three, make sure that thy self is never thy foe. So let's get started.

(03:04): Patients should examine their own body for signs of GVHD, including mouth, skin, joints, and genitalia weekly. Number one, what do we mean by know thy self? Well, very early after discharge from transplant, we teach our patients to examine their body thoroughly. Certainly, as they approach day 100 after the transplant and are getting ready to transition back to normal life or back to their home community, we tell them that, "Weekly, we want you to examine your body. We want you to examine your mouth. Look thoroughly within it. Do a total skin examination, and examine your joints and your genitalia. We want you to pay attention to any new symptoms."

(03:43): Symptoms of GVHD can often present as subtle changes and if you know your body, you're going to be the first to recognize these subtle changes long before a clinician ever does. GVHD, like any disease is best to catch early when interventions can be most successful and to get the best results and outcomes. Don't be afraid to ask if something is normal. Don't assume a change or a symptom that you are experiencing is, quote-unquote "normal" following chemotherapy and transplantation. When in doubt, it's better to ask and be told it's nothing than to assume incorrectly that that is the case.

(04:30): Graft-versus-Host disease (GVHD) is actually two diseases – acute GVHD and chronic GVHD. So rule number two, know thy foe. Know graft-versus-host disease. So to start with, graft-versus-host disease is actually two diseases, not one, it's two diseases. There's acute graft-versus-host disease and chronic graft-versus-host disease.

(04:49): Acute GVHD most commonly affects the skin, the GI tract and, less frequently, the liver. Acute GVHD is recognized as affecting three main organs. The skin is the most common organ involved by acute GVHD, and it has a very distinctive rash. That rash is described as morbilliform, which means measles-like, or you may also hear it described as a macular-papular rash. In upcoming slides, I'll show you a picture of what that rash can look like.

 (05:15): The GI tract, the gastrointestinal tract, can be involved by acute GVHD and has two distinct manifestations. There could be upper GI symptoms, where patients have persistence of nausea and vomiting or poor appetite, not wanting to eat, what we call failure to thrive. And these are symptoms that extend beyond the chemotherapy that's initially given with the transplant. And when these symptoms persist, this can be a manifestation of graft-versus-host disease.

(05:46): Separately, patients can have lower GI involvement with the hallmark being what's called a secretory diarrhea. What's meant by secretory? Well, this is a diarrhea that persists. You can eat or not eat, you're still going to have loose, watery bowel movements. As the disease gets more severe, it can present with abdominal pain and cramping, and then it's most severe form present with frank blood in the stools.

(06:14): And then less commonly, acute GVHD can involve the liver. And we're going to recognize this by changes in blood chemistry, specifically abnormal liver labs, specifically total bilirubin, alkaline phosphatase, and sometimes ALT and AST.

(06:33): Chronic GVHD most often affects the eyes, mouth, skin, joints and fascia, gastrointestinal tract, liver, lungs, and the genitals.  So, chronic GVHD on the other hand can involve many different organs. In fact, the average patient with chronic GVHD can have four different organ manifestations. Virtually, every organ in the body has at least been reported as having a manifestation of chronic GVHD but the most common organs involved include the eyes, mouth, skin, joints and fascia, gastrointestinal tract, liver, lungs, and the genitals.

(07:09):   So historically, graft-versus-host disease acute and chronic, was defined as acute GVHD being that which occurred within the first 100 days of transplant and chronic GVHD which occurred after day 100. We now know that was a simplified view of these diseases and in fact these diseases have distinct pathophysiology and distinct manifestations, which I will review.

(07:39):  Acute GVHD can occur any time and is not limited to the first 100 days after transplant. So acute GVHD is not limited to the first 100 days of transplant. It is true that the most common first signs of acute GVHD do occur early on, typically a week or two after engraftment of the white blood cells, but acute GVHD certainly can and commonly does occur after day 100. So this could be a patient who has initial manifestations of acute GVHD, and the symptoms persist beyond day 100. Separately, this could be a patient who early on had acute GVHD, received treatment, the GVHD went away, later to come back after day 100. And then separately, acute GVHD can occur after day 100 in a patient who had no prior history of acute GVHD and this is commonly seen when the immune suppressive agents are being tapered. For instance, if you're on tacrolimus or cyclosporin or sirolimus, and your provider is beginning to reduce those medications in an effort to stop the prophylaxis and take the brakes off the immune cells of the donor, acute GVHD can appear for the first time.

(08:52): Chronic GVHD can develop at any time, but 90% of patients who develop chronic GVHD do so within the first year of transplant. Now, chronic GVHD has a median onset of five to six months after transplant for its first manifestations. However, certainly chronic GVHD can occur before day 100. The earliest I have ever seen a patient show manifestations of chronic GVHD was as little as day 35 after transplant but typically, again, it has a median onset of five to six months after the transplant. Importantly, 90% of patients have chronic GVHD manifestations within the first year of transplant. 90% of patients who develop chronic GVHD will begin to show signs of it within the first year. And it's very rare for chronic GVHD to occur beyond two years as a new onset.

(09:46): Day 100 after transplant is when patients must monitor closely for GVHD symptoms because they are seen less often by their medical team. Many patients early on view day 100 as a finish line. So they've been admitted to the hospital, they've received their conditioning chemotherapy, they've engrafted, they've been discharged. They're at that interval where they're being seen frequently in the clinics, maybe on a daily basis or multiple times a week. And as they get to day 100, they are like, "Finally, I'm there." But actually, the day 100 is not the finish line, it's in fact the starting line. And importantly, this is the period where we put patients on high alert. This is the period where we want them to really monitor most closely for the signs and symptoms of graft-versus-host disease and we educate them, as I'm going to do in today's talk, on what those symptoms and signs are, because we want them to be able to recognize them and report back.

(10:36): Why is day 100 to 360 such a high alert period? Well number one, commonly patients have left the transplant center and have gone back to their home communities. They may be being seen less frequently and oftentimes by people who may be less experienced in the manifestations of GVHD. Number two, it's during that period as I mentioned, that commonly the immune suppression is being tapered and GVHD symptoms can first appear. And then finally, as I mentioned, chronic GVHD has a median onset of five to six months post-transplant. And so this is when the disease, if it's going to occur, is likely to occur again. 90% of patients who develop chronic GVHD show signs of it within the first year of transplant. So day 100 to 360, you got to know what to look for and be on high alert.

(11:31): Skin is the most common organ affected by GVHD and the most common site for secondary cancers. So what are those organ manifestations of chronic GVHD? Skin, just like in acute GVHD, is the most common organ involved by chronic GVHD followed by mouth manifestations, liver, eyes, GI tract, joints and fascia, lungs, and genitalia.

(11:50): So we want patients to know thy skin. Examine your skin. Your skin is, again, the most common organ involved by chronic GVHD as well as acute GVHD. In addition, your skin is also the most common site for secondary cancers after transplant. So skin cancers are more common in patients that are immune compromised, such as receiving an allogeneic transplant and being on immune suppressants, and so we really want you to examine your skin. Do a total skin exam weekly and have a total skin exam performed by a transplant professional and/or dermatologist at least once yearly.

(12:30): So in medical school, we learned the proverb that the eyes cannot see what the brain does not know. What this means is, unless you know what you're looking for, your eyes simply won't see it. In a GVHD clinic, we've taken that a step further and we say that the eyes cannot see what the eyes cannot see. So when we examine patients, we get them out of their clothes, we put them in a robe, and we do a total skin examination, a total body examination. We look in every nook and cranny for evidence of GVHD, and we disrobe the patient.

(13:07): GVHD of the skin can have many signs beyond just rashes, including changes in color, pigmentation, or texture. So when looking at the skin, what are you looking for? Most patients assume they're looking for rashes and in fact, rashes are a manifestation of GVHD. By rash, we mean red, raised skin lesions or redness, but oftentimes and in fact more times than not, chronic GVHD doesn't appear with a rash but a change in skin texture. There's scarring of the skin or what we call cellulite-like changes, which I'll show in the upcoming pictures. Rarely, chronic GVHD can present simply as swelling, swelling in the hands or the wrist, swelling in the lower extremities. Sometimes without even any changes, patients will say, "My skin just feels tight. I'm noticing limited mobility. It's harder for me to open jars. It's harder for me to bend my wrist. It may be hard to walk upstairs or get off the floor."

(14:05): We tell patients to look for pigment changes and that's darkening of the skin, what we call hyperpigmentation, or lightening of the skin, hypopigmentation. We tell them to look at their hair for changes, to examine their nails. And then, as I mentioned, because skin cancers are common to this population, we tell them, "Pay attention to your moles. Look for new moles or changes in any pre-existing moles."

(14:32): Rashes from GVHD can take many forms. Here, we see some skin rashes of GVHD. The top panel to the left, the red rash that's described as macular-papular, that is the acute GVHD manifestation. Other manifestations of chronic GVHD include the pictures shown here. An entity called poikiloderma, hallmarked by atrophy or thinning of the skin, pigment changes, and small blood vessels that appear on the skin. Keratosis pilaris, which look like goosebumps that persist. Snake skin, ichthyosis can be a manifestation of chronic GVHD when it appears new in patients who don't have that to begin with. Lichen-planus, which are purple or scaly, silvery, polygonal skin lesions can be another manifestation of chronic GVHD. These are all rashes of GVHD and there's many more that have been described and reported.

(15:33): GVHD can cause changes in the skin’s texture. Now, when we talk about changes in skin texture and scarring, that's what's shown on this picture here. So if you look at the top panel that says fixed sclerosis, not only do you see a difference in the color of the skin and the pigment of the skin, but if you were to feel the skin within that circle area, it would feel different. It would feel more leathery or thickened than the skin outside that area, which would have a normal feel to it. So changes in the way the skin feels.

(16:06): Sometimes GVHD causes cellulite-like changes in the skin. The cellulite-like changes that are referred to, this woman in this picture here that's not cellulite, that is actual GVHD. And what's happening is these are deposits of scar tissue in the skin or the skin is being affixed or attached to the structures below the skin, such as the fascia that line our muscles or the tendons and the skin is being puckered or pulled inwards and affixed to those structures. You can have a groove sign shown in the circled picture in the middle on this gentleman's leg, or on the arm in the circled picture on both sides up here. You can see dimpling commonly in the flank areas. For whatever reason, these manifestations often appear in areas where there may be a little bit more fat tissue like in the abdomen or belt line, under the bra, underneath the arms. And so we look closely for these changes, which initially could be quite subtle and patients can assume they're just normal.

(17:11): GVHD can cause scarring or fibrosis of the skin.  Here's another manifestation of scarring or fibrosis or fibrotic manifestation referred to as morphea, shown in the panels to the left. Pigment change, again darkening or lightening of the skin shown in the panels to the right. That can be manifestations of chronic GVHD.

(17:30): Hair loss after transplant can be caused by problems other than GVHD, as well as GVHD. With respect to the hair, there's many reasons why the hair can thin after the transplant. There's a lot of non-GVHD medical reasons why this could happen, and we of course want you to report those changes. You shouldn't assume it's normal. You can also have hair loss specifically from GVHD and scarring of the scalp and often, this is irreversible. The scalp is scarred and there's some hair loss shown in the patients in the panels to the right.

(18:03): Nails can also be a site of GVHD. With respect to the nails, what are we looking for? Well, early on, you may see what is called longitudinal ridging shown in the pictures to the left. You can have fragility to the nails. They can split, have nail splitting at the edges. They can get caught on things very easily. Those are early manifestations of GVHD that involves the nails. In later stages of that, you get scarring at the nail bed. And then ultimately, complete loss of the nails which are permanent, shown in the pictures to the right.

(18:41): Moles can signal skin cancer; regular skin checks are essential. As I mentioned, we pay attention to moles because skin cancers are so frequent following allogeneic transplants. Immune suppressed patients are at higher risk for these skin cancers, so we want patients to pay attention to moles, moles that are new, moles that are changing. We teach patients the importance of using sun protectants, whether it be protective hats with a wide brim or protective clothing, using sunscreens with SPF greater than 30. And then just frankly, avoiding laying out in the sun or peak sun hours because not only are you at higher risk of skin cancers but sun exposure has been linked with flares in GVHD, and no one, let alone the transplant patient, should lay in the sun.

(19:36): As I mentioned, it's important to see a dermatologist ideally once a year. If you have a prior history of skin cancer, more like twice a year would be the standard recommendation. For more information about GVHD of the skin, there's a number of resources. I want to point out that May 3rd at 2:45, my distinguished colleague Sharon Hymes, who's a dermatologist whom I've worked with in the past 20 years at MD Anderson, she's been caring for patients with GVHD for 40 plus years and she's a tremendous resource and knowledgeable source of information about skin conditions following allogeneic transplant.

(20:18): Several resources are available for screening GVHD of the skin. Other resources include Be The Match where they have a screening information sheet for screening for chronic GVHD of the skin, as well as Fast Facts. This is a sheet that provides a quick, lowdown information on what you need to know when screening for chronic GVHD of the skin. Importantly, at the end of today's talk, I have compiled a list of resources for all the various organs that can be involved, as well as general information about GVHD, where you can get more information. And I'm not going to take the time to review those after each organ but I'll have you come back later if you would like those and you can download that information.

(21:01): Oral GVHD can appear as dry mouth, sensitivity to foods, swelling, redness, pain or bleeding of the gums. So chronic GVHD of the mouth, what should you look for? Dry mouth is a symptom of chronic GVHD. Now, there's many reasons why patients can have dry mouth following allogeneic transplant. Medications can cause the mouth to be dry, but one manifestation or symptom of GVHD of the mouth can be dry mouth. Sometimes patients report early on a rough sensation to their mouth. It kind of feels like that sensation you get when you eat something too hot, scalded mouth sensation I call it. Commonly, patients with chronic GVHD report painless, small, fluid-filled lesions that come and go throughout the day, depending on what they eat. These are called mucoceles. I'll show you a picture of that in the upcoming slide.

(21:50): A common symptom of patients who have oral GVHD is new sensitivity to foods. These are spicy foods or acidic foods, toothpaste, carbonated beverages. When the patients eat or are exposed to these items, the mouth and the mucosa of the mouth becomes very sensitive and they don't tolerate it.

(21:11): Patients can have swelling, redness, pain, or bleeding of the gums. And they can ultimately develop ulcers in their mouth and, of course, pain that can result in weight loss from not wanting to eat because of the pain.

(22:25): Here, we see pictures of oral GVHD. The circle panel to the left shows the buccal surface, the inner cheek surface, showing what is called lichen planus-like lesions. These are the lacy white striations shown along the inner part of this patient's mouth. Under the tongue, you can see these white striations in the upper panel in the middle. You can see these white striations on the roof of the mouth in the middle panel at the bottom. If you look closely, you can see tiny, little, small, fluid-filled blisters. Again, these are the mucoceles that come and go throughout the day and are commonly seen in patients who have chronic GVHD of the mouth. As I mentioned, redness and ulceration are some of the severe manifestations of chronic GVHD of the mouth and associated pain with these lesions.

(23:19): GVHD of the eyes can involve decreased tearing, dryness, burning, itching or gritty sensations. Chronic GVHD of the eyes, what are you looking for? Well, early on patients actually can report excessive tearing. But with time, chronic GVHD of the eyes presents with decreased tearing. The eyes feel dry. They're burning. They are gritty. It feels like they have sand in the eye or a foreign object sensation in the eye. They may itch. The eyelids may itch. And in the morning, they may have discharge with the eyes being crusted over in the morning. Commonly, it's sensitivity to light and/or wind. And then diminished visual acuity and blurred vision because the tears are actually important in how we see, and when there's diminished tear production from chronic GVHD of the eyes, visual acuity can be impaired.

(24:06): GVHD of the GI tract can cause weight loss, nausea, vomiting, abdominal pain, bloating, cramping and diarrhea. Chronic GVHD of the GI tract, what are you looking for? Well, anorexia, no desire to eat, nausea, vomiting, abdominal pain, bloating, cramping, diarrhea. Sometimes a diarrhea is greasy stools with undigested food material, maybe a symptom of chronic GVHD of the GI tract. Painful swallowing can be a symptom. One of the hallmarks of chronic GVHD of the GI tract is narrowing of the food pipe, of the esophagus, what we call strictures which result in difficulty swallowing dry foods and pills and as it progresses, difficulty swallowing even liquids. Ultimately, the various manifestations of GVHD can result in weight loss. We ask our patients to weigh themselves closely and we ourselves monitor the weights over time because while many [inaudible 00:25:00] weight loss, GVHD is a common cause during the late post-transplant period.

(25:08): GVHD of the joints, fascia and muscles causes joint stiffness, reduced range of motion, tightness in the muscles and tendons, cramps, spasms, and/or swelling. What about GVHD that involves the joints, fascia and muscles? You're looking for joint stiffness, reduced range of motion, tightness in the muscles and tendons. One of the more common complaints from patients who have chronic GVHD is that they experience severe muscle cramps, that charley horse sensation. Sometimes they have spasms where their fingers or toes are in a locked position for a couple of minutes and it just subsides on its own and can be quite painful. In severe forms of chronic GVHD involving the joints and fascia, the joints are in a contracted, flexed position with the inability to straighten them as I'll show in the upcoming pictures. Rarely, swelling alone can be a manifestation of chronic GVHD and even rarer, you can sometimes have fluid within the joints, and pain associated with that, as a presentation of chronic GVHD of the joints.

(26:07): Joint flexibility can be measured with PROM scores. Here, we see a tool that we use in characterizing and monitoring over time patients' joint mobility. This is called the PROM scores. This is a tool that we do at each visit when we're screening and examining patients for chronic GVHD. So number seven in the top three rows is a normal range of motion. And for the ankle, a number of four is normal. And so if we go to the top row and look at the shoulders, a person should be able to do what's called the touchdown sign, touchdown where they raise their arms straight above their shoulders. Obviously, people can have shoulder injuries or arthritis or rotator cuff that causes impairment, but when you have chronic GVHD that involves the skin underneath the armpit or in the arm, under the arm, or along the chest wall, the skin is tightened and there's a tightness that results in impaired ability to raise the arms above the shoulders. And as that skin gets tighter, it becomes more impaired and becomes the lower numbers, the complete inability to raise their arms above their head.

(27:20): When we look at the elbow as the structures, the skin, the joints, the fascia become involved proximal to the elbow. There can be a progressive flexion of the arm, inability to straighten the arm due to that scar tissue formation.

(27:38): Wrist flexibility can be tested with the prayer sign or other simple actions. We teach all the patients at day 90 or so that when they go home to their home community, every week we want them to do what's called a prayer sign. And the prayer sign is shown in this third row here. The prayer sign is for the wrist. Normally, one should be able to bend the wrist and hand to a 90-degree angle and make that prayer-like motion but an early sign of chronic GVHD can be tightness and inability, where you're unable to get to that 90 degrees. And as it progresses and gets more scarred and the more it leads to contractures, you can see in the panels one and two for the wrist and hands. This patient has an inability to straighten their fingers. They can't make the clapped hand motion. They can't put their hands flat together because their fingers are contracted in a flexed position. Similarly, they can't bend the wrist. The wrist in panels one and two, are completely inability to bend the wrist. It's contracted. Ankles, similarly shown in the bottom, inability to raise the foot off the floor.

(28:50): Here, we see [pictures of] patients with chronic GVHD involving the joints and fascia. The panel to the left, this is a patient of mine, this was his first manifestation of chronic GVHD, impaired prayer sign. This is new for him. He used to be able to do this to a seven but he's now having impairment and would have a PROM score of a five. Here's a patient in the middle with more severe involvement with a PROM score of four. And then this is one of my patients who has severe chronic GVHD, and you can see he has a complete inability to straighten his fingers. He cannot even make his hands flat against each other and the wrists are scarred to the point where he can't bend at the wrist. Here is another patient, inability to straighten his arm or raise his arms above his head because of skin and joint and fascia tightness, respectively.

(29:46): Symptoms of lung GVHD may be a dry cough, wheezing, a cold that extends beyond two weeks, shortness of breath, and some patients with lung GVHD have no early symptoms at all.  What about chronic GVHD of the lungs? What are you looking for? Well, a symptom can be a dry cough. It can be wheezing. Sometimes, chronic GVHD develops after having a cold, after exposure to certain viruses. And so normally, a cold should last one or two weeks but oftentimes, a hallmark of chronic GVHD is that cold that just never gets better. Just continued cough that extends beyond one or two weeks, and it's now going on three, four, six weeks. That may be a sign of chronic GVHD of the lungs. As the disease process progresses, patients are going to have shortness of breath. Commonly patients early on will say that they feel like they can't take a deep breath. They can't expand their lungs, can't get air into their lungs. But most commonly, patients are asymptomatic. They have no symptoms. And this is why screening is so important. This is why we screen for GVHD of the lungs.

(30:46): So, what are we measuring when we do pulmonary function tests? We're measuring the flow of air into our lungs with inhalation and out of our lungs with exhalation. And the hallmark of GVHD of the lungs is the inability or impaired ability to get the air out of our lungs. And because our lungs are filled with air and we have air trapping, when we take a deep breath in, it feels tight. It feels like we can't get all that air in because there's already air trapped in the lungs. This could be one of the most serious forms of chronic GVHD and can result in limited survival. And this is why we believe that it's so important to catch this early. Sometimes, we can't improve the pulmonary function test but if we can catch it early and stabilize things with treatment and prevent it from getting worse, this is important for outcomes.

(31:41): Who's at highest risk for chronic GVHD of the lungs? Well, patients who are at highest risk are those who have chronic GVHD that involve other organs, the skin, the eyes, the joints, etcetera. They're at highest risk for developing subsequent lung GVHD. As I mentioned earlier, GVHD can be triggered by certain community respiratory viruses, specifically RSV, respiratory syncytial virus, which is a common cold-like virus. Parainfluenza and other common cold-like virus can also trigger GVHD of the lungs. So being careful during exposures in your community to these common community respiratory viruses are so important.

(32:27): Screening with pulmonary function tests can detect GVHD early and stop progression. So how do we screen? Again, we screen by pulmonary function tests and we screen because we want to catch this early and stop progression. And so patients are screened with routine pulmonary function tests that should be done certainly within the first two years of transplant, serially within the first two years, maybe three years of transplant. And if you have chronic GVHD involving other organs, active chronic GVHD, we often screen with PFTs beyond three years. Importantly.

(32:56): At MD Anderson and other cancer centers, we're studying these new devices where patients can monitor at home. So this is a handheld device that does a simplified form of pulmonary function test and the data is transmitted remotely back to the transplant center. And an alarm goes off and alerts the providers back at the transplant center that there are new changes, new impairment that may be consistent with a patient manifesting chronic GVHD of the lungs. Patients will do this on a daily or weekly basis and that information is transmitted back. And if changes are seen, the patient's brought back for more formal testing.

(33:38): Women should routinely examine their vulva and vagina for symptoms of genital GVHD. What about genitals? For females - and I'm going to warn the audience that the upcoming slides do show pictures of male and female genitalia - so for females, the external and internal genitalia can be involved. The vulva can be involved. We tell patients to look for areas of redness, focal areas of white plaques or thinning. We tell patients to examine the internal vaginal mucosa using a hand mirror. We want them to look to see if the tissue is uniform in color, no areas of redness, white striations, scar tissue, adhesions, loss of elasticity, and ultimately narrowing of the vaginal canal.

(34:21): Symptoms can include itching, burning, dryness, painful intercourse, pain with urination, and bleeding. Now, many things can present with those symptoms, not just GVHD, but if you have those symptoms, report them. Don't assume it's normal. Sometimes clinicians forget to ask about these symptoms and unless you report it, we won't know. And importantly, we should refer you to either a pelvic floor therapist or a gynecologist experienced in what to look for to see if this is indeed from GVHD or not.

(34:53): Here, we see a picture on the next slide of... It's hard to see somewhat. On the picture to the left, you're seeing white, lacy striations on the labia minora. With more severe manifestations, the labia minora becomes affixed and you have adhesions. In the most severe manifestations of chronic GVHD involving the genitalia, there's complete scarring and closing of the vaginal canal and this can be quite debilitating. And of course, we want to catch this early.

(35:26): Men should examine the head of their penis and how smoothly their foreskin retracts to check for symptoms of genital GVHD. For men, men can also experience GVHD of the genitalia. They tell the patient to examine the head of the penis or the glans of the penis. Is it uniform in color, no areas of redness or white striations, burning, or paining? We tell them to retract the foreskin. It should retract easily and without pain. Note areas of scar tissue and adhesions. Pain and burning at the head of the penis is a symptom. Very rarely, GVHD of the genitalia can result in scarring where the urine comes out, the meatus, and impaired urinary flow. And then patients who have scarred-like tissue, like sclerodermal GVHD, they can actually develop a bend to the penis when it's erect and this is a rare manifestation of GVHD of the genitalia.

(36:16): Here, we see a picture of GVHD affecting the glans of the penis, the white area of striations and redness. This patient was told by a home provider that this was a yeast infection,when, indeed, this is a manifestation of GVHD.

(36:32): I forgot to mention earlier but for females, one of the closest associations for development of GVHD of the vaginal mucosa are those who have oral GVHD. And so if you have oral GVHD, clinicians and patients should be at heightened alert to look for vaginal involvement as well.

(36:54): Lab test can also be helpful in monitoring chronic GVHD. What about labs? Well labs are important monitoring for chronic GVHD, particularly important when we're tapering immune suppression. Routinely, we get labs at least monthly between days 100 to 365 to look for lab manifestations of GVHD. We pay attention to the liver function tests, including the ALT or AST, the alkaline phosphatase and total bilirubin. Sometimes, there can be other clues for chronic GVHD. One finding that can be seen in patients with chronic GVHD is an elevation of a certain type of white blood cell called an eosinophil. So absolute increase in numbers of these white blood cells can be seen in patients with chronic GVHD. Rarely, but can happen, is an immune-mediated fall in the neutrophils or platelet count, that happens in patients with GVHD and so we monitor for that as well.

(37:51): Patients must take all prescribed medications as scheduled. So I said rule number three was, don't let thy self become thy foe. And what do I mean by that? Well, take your medications. They are vitally important for preventing and treating GVHD. I can tell you a number of patients over the 20 years I've been caring for, patients in the transplant setting who have stopped, prematurely without consulting their physician, their medications and developed horrific GVHD and ultimately died from GVHD. So never stop your medications. Take them consistently as prescribed. Monitor and report as I've mentioned. Don't assume anything is normal. Report something you're experiencing. It's better to report and be told its nothing to worry about than to catch something late.

(38:39): When feasible, travel to see a transplant provider and subspecialist who best know and can treat GVHD. I understand this can be costly and difficult and I know it may not be feasible for everyone but, really, seeing providers who know GVHD and know what to look for is so vitally important. Don't resist taking therapy or doing therapy that's required to treat your GVHD such as steroids. Often patients come to my GVHD clinic, they're at that point where their clinician has begun to stop some of their medications and they come to see me and they have GVHD. And I tell them, "Oh, we got to start steroids and resume these other medicines." And they're frustrated. They don't want to do it. They're at that point where they are hoping to stop medications, not start new ones, but these medicines are important to stop the GVHD restore normal organ function and ultimately to improve survival.

(39:39): Supportive care therapies are as important as systemic treatment for GVHD. Other therapies are just equally important to our systemic treatment, what we call supportive care. So each organ that has GVHD, there's a whole list of supportive care that's done to improve symptoms and quality of life in patients who have that organ manifestation. For instance, if you have severe dryness of the eyes from ocular GVHD, we may give topical agents to help. We'll tell you to use artificial tears. Ophthalmologists may cauterize or put plugs in the ducts that drain the tears so they can pool in your eyes and help treat those symptoms of dryness. In severe patients, we give them specialized lenses that trap moisture into the eyes and help treat the symptoms. But each organ has supportive care measures that are done to help improve organ functionality and improve quality of life, and they're equally important.

(40:32): Oftentimes, especially in our patients who have skin and sclerotic manifestations of GVHD, joint and fascial involvement, we refer them to occupational therapy and physical therapy. If they have genital involvement, pelvic floor therapy, and these therapists are highly trained and can do wonders to improve and restore function. Nutritional support is so important as well.

(40:57): Steroids have been the standard treatment for GVHD. What about systemic treatment? Well, the hallmark of treatment, the standard treatment is steroids either in the form of prednisone or methylprednisolone. This is a first line treatment for both acute and chronic GVHD.

(41:11): Patients though, sometimes don't get better with the steroids and are refractory, or they get better and the disease comes back as we taper the steroids and we call that steroid dependence. Maybe as much as half the patients with chronic GVHD will have steroid dependent or refractory GVHD. What do we do in those cases?

(41:31): Ruxolitinib (Jakafi) is available for steroid-refractory acute GVHD. Well, for acute GVHD to start with, there is currently one FDA-approved therapy for patients who have steroid-refractory acute GVHD and that's ruxolitinib. It also goes by the name Jakafi or Jakavi. This is the only FDA-approved therapy for patients with steroid-refractory acute. There are new therapies being studied and it's so important that patients get involved in clinical trials because they can benefit from these new therapies, just like Jakafi benefited patients.

(42:02): There are three FDA-approved therapies for chronic GVHD:  ibrutinib (Imbruvica®), belumosudil (Rezurock™), and ruxolitinib (Jakafi®). For chronic GVHD, there are three FDA-approved therapies. As little as six or seven years ago, there was no FDA-approved therapies but through clinical trial, we now have three drugs available for patients with steroid-refractory chronic GVHD. That's ibrutinib or Imbruvica, belumosudil, ruxolitinib again called Jakafi. Belumosudil goes by the name Rezurock. And there are a number of other agents that aren't FDA-approved but are commonly used to help patients with chronic GVHD shown here. Again, a number of new, exciting drugs that are being studied, and so it's important to participate in clinical trials if you have the ability.

(42:41): Ibrutinib is the first FDA-approved therapy for patients with steroid-refractory chronic. It works by inhibiting the immune cells that drive chronic GVHD. It was studied in patients 18 years and older, who failed to respond to steroids and had either a red rash or oral GVHD. And in these patients, 67% of the patients had a GVHD response and roughly 25% of them had a meaningful improvement in symptoms and quality of life,, using validated measuring tools for that.

(43:15): Ibrutinib can have side effects. Side effects of ibrutinib include hospitalization for infections. So a third of the patients who participated in the trial developed an infection requiring hospitalization. Fatigue can be seen in patients with GVHD but fatigue can also be a side effect of ibrutinib. Diarrhea, a third of the patients on the trial reported diarrhea. Sometimes a lower dose of ibrutinib is used to avoid these side effects.

(43:43): Rezurock is a unique new drug for patients failing more than two lines of prior GVHD therapy.  Belumosudil or Rezurock, this was just approved last year for patients failing more than two lines of prior therapies. It's a first of its kind drug. It works by targeting a unique pathway called ROCK. ROCK 2 protein, it inhibits. Inhibition of this pathway is believed to take the immune milieu of the patient from this inflammatory milieu to one of a tolerogenic or tolerising milieu. In addition, this pathway is felt to be important in causing fibrosis and when we inhibit it, we may stop or improve fibrosis. It was studied in patients 12 years and older with very advanced and severe forms of chronic GVHD. These patients had failed many lines of prior therapy and in this study, 74% of the patients had a measurable GVHD response, and roughly 60% reported improvement in quality of life using validated tools to measure symptoms.

(44:44): Side effects, 10%, had a pneumonia that required hospitalization. 20%, elevated liver enzymes. Fatigue was reported again in half the patients. Again, this could be for GVHD or perhaps from the medications. Nausea or diarrhea reported in about a third of the patients.

(45:03): Ruxolitinib is FDA-approved for patients failing one or more prior therapies.  Finally ruxolitinib was FDA-approved recently, just this past year, in patients failing one or more prior therapies. As I mentioned, it's previously approved for patients with steroid-refractory acute GVHD, and then became FDA-approved for chronic GVHD, again, that failed one or more lines. This was the only one of these three agents that was studied in what we call a randomized trial. So half the patients on the trial received ruxolitinib or Jakafi as it's called, the other half received a handful of other options.

(45:35): These drugs show measurable improvement with limited side effects. Head-to-head comparison was done in these patients 12 years and older with moderate and severe chronic GVHD, and 50% of the patients who got the Jakafi or the ruxolitinib had a measurable response improvement in their GVHD, versus 25% who received the other best available therapies. 25% of the patients who got ruxolitinib or Jakafi had a meaningful improvement in symptoms and quality of life versus 11% of the control arm.

(46:03): Side effects of Jakafi may include infections. Pneumonia requiring hospitalization was seen in 8.5% of the patients on that trial. Jakafi or ruxolitinib is known to cause some count suppression, including anemia, lowering of platelets or lowering of the neutrophils. And so monitoring of blood counts when patients receive this drug is vitally important.

(46:27): Conclusion. With that, I'm going to go ahead and stop and take any questions. I'd like to thank the team that I have at MD Anderson who sees patients with me in the GVHD clinic. I'm so proud of them. Many of them will be speaking at this symposium and they are so dedicated to helping patients and I've learned so much from them. Here you see some of them shown in the picture here. And again, I just want to remind everybody that at the end of this talk, I've included a list of information and resources you can turn to for more information about GVHD as well as the various organ manifestations. And with that, I'll stop and turn the flow over to Sue, who can direct me to any questions.

(47:09): [Sue Stewart]:     Q & A. Thank you very much, Dr. Alousi for that very thorough talk. We do have a lot of questions. We'll try to get to as many of them as we can.

(47:19) We'll start with the first one from a woman who said she's an eight-year survivor of an allogeneic stem cell transplant, and she's still dealing with sensitive tongue and occasionally decreased saliva. She's wondering whether the sensitivity to textures, spices, acidic foods will ever go away because she longs to eat a crunchy cracker without having to deal with the aftermath. Can you respond to that please?

(47:45): [Amin Alousi]:     Yes. So we call that the crunchy cracker test to detect GVHD. If you give a patient a cracker and they can't swallow it, then that could be a sign of GVHD. So it can be symptoms that can last for some time. There are therapies that can improve it. There's a number of therapies that my oral specialists will be presenting in his talk. Dr. Vigneswaran is giving that a talk, but there are therapies that can help improve saliva production. These are drugs that promote saliva production and are generally pretty well tolerated.

(48:23): Maybe about 40% of the patients report improvement. There are over-the-counter agents that can also promote saliva production. If your mouth gets very sensitive to those food exposures, this can flare and so using topical steroids during an acute flare or following a night of indulging in those foods with the little topical steroids can help quell those symptoms. And so please speak to your providers about things that can benefit you. I can take the next question.

(48:57): [Sue Stewart]:    Sure. Can you discuss muscle cramping a bit more? Why does that occur? What is helpful treatment? For example, muscle cramping in the hands.

(49:08): [Amin Alousi]: Yes. A very common complaint for patients with GVHD and one we know very little about. Not a lot has been studied about it. There are stretches that help prevent the cramping, especially at nighttime. There are exercises and avoidances. Things to avoid, like having the sheets on you in a certain way to prevent those spasms. Sometimes low doses of Norvasc, a blood pressure medicine, can be used. Sometimes medicines that are used for muscle spasms, like Flexeril can be used, but it can be very challenging and really frustrating for both the patient and the provider to treat. I'm sorry you're experiencing that.

(49:53): [Sue Stewart]:     All right. Thank you. The next person wants to know whether there's any particular area of the body, area of the skin where you most commonly see GVHD?

(50:05): [Amin Alousi]:    Yeah, great question. So for whatever reason, GVHD often can develop in areas where there's a little bit more fatty tissue or areas of constriction. So underneath the bra line, the waistband area, underneath the arms. That's why it's so important to disrobe when you see your provider so we can look in those areas. Those are common skin areas to develop the fibrotic or scar-like tissue of GVHD. Otherwise, it can involve any area of the body, any area of the skin.

(50:37): [Sue Stewart]: All right, the next person says that she has a red and swollen tip of the tongue, wants to know if this might be a symptom of GVHD.

(50:51): [Amin Alousi]:     It can be, but it also might not be. And so there are conditions that result in trauma to the tip of the tongue and the entity - I think Dr. Vigneswaran shows in his talk - and I encourage her to tune into his talk that's upcoming in this series. But if there's trauma, you can develop this entity that's called TUGSE. It's an acronym for a condition. So I really would encourage her to see somebody, an oral health specialist who can examine that area and see if it's from GVHD. If it's from GVHD sometimes an injection of steroids to that area can promote healing and get resolution of that, but you would first want to make sure that's GVHD.

(51:34): [Sue Stewart]:   All right. The next person wants to know whether you've seen Restasis help ocular GVHD.

(51:42): [Amin Alousi]:     There are reports that it does help. My personal belief is if patients haven't reported improvement after a few months of taking it, I don't continue it indefinitely. It can sometimes sting and burn as they're putting it in. And unless there is some measurable improvement with its use, I don't use it indefinitely. It is commonly prescribed by the ophthalmology community, Restasis and other drugs in that class, but it's kind of hit or miss whether it works. And if it doesn't, I don't believe in continuing it indefinitely.

(52:19): [Sue Stewart]:   All right. This gentleman wants to know if there's any special physiotherapy that can help him recover the range of motion and strengthen his limbs.

(52:29): [Amin Alousi]:    Oh, I'm so happy you asked that question. So occupational therapy, skilled occupational therapists have tremendous tools which can result in improvement. At MD Anderson, I have a wonderful occupational therapist who's going to be giving a talk during this symposium, and she actually makes devices. These are casts that you can put on and off to help improve range of motion. You would wear them initially maybe at nighttime for a couple of hours and then we make new casts to get further improvement. And so yes, seeing an occupational therapist. If your local occupational therapist is not familiar with that, I've had my occupational therapist reach out to community occupational therapists and teach them some of the things that can be done in patients such as yourself.

(53:23): [Sue Stewart]:     Great, and she will do be doing a presentation on Friday if people want to see that. The next question is, this individual has a lot of dizziness after a stem cell transplant that was six months ago. Wants to know whether that might be a symptom of GVHD or medicine that they're taking.

 (53:41): [Amin Alousi]:   Yeah, not commonly a symptom of GVHD of itself. There're many things that can result in dizziness or feeling of lightheadedness, when you go from sitting to standing. Yes, medications can do that but no, that would not be a classic symptom or presentation of GVHD.

(53:58): [Sue Stewart]:   All right. This individual had cryptogenic organizing pneumonia, COP and went on a vent. She got better and then it happened again 10 days later, and she went back on the vent and in a RotoProne bed. What's the probability that this is going to happen again.

(54:17): [Amin Alousi}: So cryptogenic organizing pneumonia is not the hallmark of lung GVHD. It can be seen in patients who have graft-versus-host disease but in and itself, it's not a disease-defining manifestation. It can be seen in people outside of transplant and patients who receive chemotherapy and never had a transplant. But yes, cryogenic organizing pneumonia can have flares and recur and immune suppressant drugs like steroids are used, and it can come back. And so, most pulmonologists are familiar with this entity and can review with you, options to try to prevent recurrences and monitoring for improvement.

(55:00): [Sue Stewart]: All right. This person says, as a person of African and Caribbean descent, how might you suggest I address dermatological issues in GVHD with my medical professionals? I feel as those things are being missed.

(55:15): [Amin Alousi]:    Yeah, I'm sorry you feel that way but the approach is the same. We need to do a total skin examination. The changes that are seen in patients with GVHD can be easily recognized in people with pigment, as well as fair skinned people. In fact, sometimes it's easier to recognize those changes in people with pigment because some of the immune inflammatory responses cause either increased pigmentation or decreased. And so, there's nothing that should inherently be different on how they approach you than they approach anyone and the key is doing a thorough, dedicated skin examination. And if possible, seeing a dermatologist or a transplant specialist familiar with graft-versus-host disease.

(56:07): [Sue Stewart]:    All right. And I think this will need to be our last question. Have you seen any improvement in chronic GVHD in the wrists with manual therapy, for example, myofascial release massage?

(56:21): [Amin Alousi]:   Absolutely. That and other therapies which occupational therapists employ. Again, I would highly encourage you. Carly Cappozzo, who's giving the talk later this week is an occupational therapist and I've learned so much from her. You can't believe how specialized she is and informative she is. And yes, there are therapies including what you state, the myofascial release that can help that manifestation.

(56:52): [Sue Stewart]:    Well, thank you. I wish we could finish with all of the questions but our time has run out. I want to thank BMT InfoNet and our partners and thank you, Dr. Alousi, and you the audience for some excellent questions and an excellent presentation.