Introduction to Graft-versus-Host Disease (GVHD)

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Introduction to Graft-versus-Host Disease (GVHD)

Saturday, April 29, 2023

Presenter: Andrew Harris MD, Memorial Sloan Kettering Cancer Center

Presentation is 38 minutes long with 22 minutes of Q & A

Many thanks to Sanofi, Incyte Corporation, Pharmacyclics, an AbbVie company, and the William G. Pomeroy Foundation, whose support helped make this workshop possible.

Summary: Graft-versus-host-disease (GVHD) is a common challenge for patients who undergo a stem cell transplant using cells from a donor (an allogeneic transplant). It can be mild, moderate or severe. This presentation reviews the types of GVHD, the organs most often affected, common symptoms, and traditional as well as newer therapies for treating GVHD.

Highlights:

• GVHD occurs when transplanted cells from a bone marrow or stem cell donor attack the patient’s body. Acute GVHD typically occurs soon after transplant; chronic GVHD typically occur much later, although both can occur at any time. They can also occur simultaneously which is referred to as overlap syndrome or overlap GVHD.
• Almost half of adults transplanted with stem cells or bone marrow from a donor will experience some form of acute GVHD within a few months of treatment.  Chronic GVHD occurs in 15% to 40% of patients.
• There are many therapies for GVHD that can be used in different combinations to prevent or minimize graft-versus-host disease. The type of transplant a patient is receiving and any comorbidities will also be considered to personalize their medication regimen to treat GVHD.

Key Points:

(00:05:28): One method to prevent GVHD is to modify donor cells by removing cells that are most likely to cause GVHD before transplantation.

(00:07:42): Medications like cyclosporine and tacrolimus are also used to prevent GVHD. These medications must be closely monitored to produce the desired effect and minimize other risks.

(00:17:00): Acute GVHD typically affects the skin and can also affect the digestive tract and/or liver.

(00:20:30): Treatment for acute GVHD includes topical steroid creams or more systemic steroid therapy.

(00:22:26): Steroids can be effective in treating acute GVHD but have many unpleasant side effects, especially with prolonged use. If steroids are not effective in treating GVHD, other treatments like Jakafi® and photopheresis are now available and they can be fairly effective. 

(00:27:16): Chronic graft-versus-host disease can involve almost any part of the body, or any combination of body sites, including the eyes, lungs, skin, mouth, digestive tract, genitals, muscles and joints.

(00:30:47): Localized treatments like creams, mouth washes, artificial tears or antibiotics with anti-inflammatory propertiers are preferable treatments for if chronic GVHD is not affecting many different organs simultaneously.

(00:33:18): Systemic therapies like steroids are also used to treat chronic GVHD. It may also be treated with Imbruvica®, Jakafi®, or Rezurock®.

(00:36:15): Treatment for chronic GVHD can bring physical challenges like muscle weakness, weight gain, and limited mobility.

(00:36:58): Steroid treatment for chronic GVHD can bring many emotional challenges and affect a patient’s quality of life, participation in school or work, and sexual health on top of the direct effects pf GVHD itself.

Transcript of Presentation:

(00:00:00): [Michala O’Brien]:  Introduction. Welcome to the workshop, Introduction to Graft-versus-Host Disease. My name is Michala O’Brien, and I will be your moderator for this workshop.

(00:00:10): I'd like to thank Sanofi, Incyte Corporation, Pharmacyclics, an AbbVie company, and the William G. Pomeroy Foundation, whose support helped make this workshop possible.

(00:00:22): It is now my pleasure to introduce today's speaker, Dr. Andrew Harris. Dr. Harris chose a career in transplantation and cellular therapy after he underwent a transplant for acute leukemia while in college. He has been a pediatric transplant and cellular therapy specialist for 12 years and serves as the medical director for the Memorial Sloan Kettering mSK Kids' pediatric multidisciplinary GVHD clinic. Dr. Harris performs clinical trials for patients with both acute and chronic graft-versus-host disease and serves on several national and international committees in the field of transplantation and cellular therapies, with a focus on cancer and post-transplant complications. Please join me today in welcoming Dr. Harris.

(00:01:18): [Dr. Andrew Harris]:  Overview of Talk. Thanks, Michaela, and welcome everybody to my talk. I'm going to be talking with you all today, introducing graft-versus-host disease. And since that's a mouthful, I'm going to be referring to it as GVHD going forward.

(00:01:32): So, the learning objectives for my talk today are to discuss the differences between acute and chronic GVHD and to discuss the different sites or parts of the body, namely the organs and the tissues that are typically affected by graft-versus-host disease. I’ll talk about the incidence, which means how often it occurs, and the typical onset of acute and chronic graft-versus-host disease. Next, we will talk about some therapies to prevent and to treat both acute and chronic GVHD, as well as some side effects of these therapies. And finally, I will be talking about some physical and emotional challenges associated with GVHD and its treatment.

(00:02:09): Please keep in mind that there are a lot of excellent sessions by colleagues, that go into much more detail about these different unique topics that I'll be addressing today in this introductory talk.

(00:02:23): So, I'd like to first start off by explaining to you how bone marrow transplants or stem cell transplants, in general, cure cancers like leukemia, lymphoma, myelodysplastic syndrome (MDS) and other related diseases. So, on the right you'll see a picture of a person who is the patient, also known as the host. And when this person gets leukemia, lymphoma or one of these other diseases, they have a significant amount of cancer in their body, represented by these black circles.

(00:02:49): Patients diagnosed with blood cancers and related diseases first receive standard chemotherapies and immunotherapies to reduce their cancer burden. If they have high risk disease, transplant may then follow. When they're first diagnosed, we treat them with standard immunotherapies, chemotherapies and radiation to get this cancer burden down to a very low level, and in many instances down to a level that we can't detect with our imaging, bone marrow testing and other tests. And at this point in time, for patients with high-risk disease, they will often go forward with the transplant.

(00:03:10): When we give a transplant, we take the bone marrow or the stem cell graft from a donor. The majority of these grafts consist of blood stem cells. These are the cells that will grow up to become our white blood cells, our red blood cells, our platelets, and our immune system. But often these stem cells are accompanied by immune cells, that are collected at the same time as the stem cells.

(00:03:36): We give patients chemotherapy, immunotherapy, and radiation, in different combinations for different diseases to get their body ready to receive a transplant of donor cells. And when we transplant these cells into the patient, these immune cells will, over time, eradicate any of the residual cancer cells in the patient.

(00:03:55): GVHD occurs when transplanted cells attack the patient’s body. Unfortunately, sometimes these immune cells can also attack the healthy parts of the patient, and when this occurs, this is that graft-versus-host disease, or the donor immune system versus the patient, and that is what GVHD is.

(00:04:11): Acute GVHD occurs soon after transplant; chronic GVHD can occur much later. So, there are two major forms of graft-versus-host disease that we talk about. The first is acute graft-versus-host disease. This form of graft-versus-host disease typically occurs earlier after transplant. It primarily affects the skin, the digestive tract, and the liver, and is considered more of an inflammatory process.

(00:04:33): On the other hand, there is chronic graft-versus-host disease, which typically does not occur until at least two months after transplant, but can occur much, much later as we'll talk about in later slides. It can affect most parts of the body. Chronic graft-versus-host disease more closely resembles autoimmune diseases, whereas acute GVHD does not.

(00:04:54): When both of these types of GVHD occur simultaneously, it's referred to as overlap syndrome or overlap GVHD, which you may hear a doctor talk about, if you or a loved one is experiencing this particular manifestation of GVHD.

(00:05:09 There are a lot of different ways to try to prevent graft-versus-host disease. One of the ways is by manipulating that graft, so those cells that we collect from the donor before we give them to the patient. And I'm going to talk about those different ways that are currently being done and some of the future ones that are being explored.

(00:05:28): One method to prevent GVHD is to modify donor cells by removing cells that are most likely to cause GVHD before transplantation. The first method is through T-cell depletion or CD34 selection. So these T-cells are thought to be the major drivers and effector cells. They're part of the immune system, and they are thought to be the cells that cause graft-versus-host disease. These are also the cells that are thought to help prevent infection and recover the immune system. So, when we get rid of these cells, this can be associated with an increased risk for some infections, and slower recovery of the immune system in general.

(00:05:59): I forgot to mention that CD34 selection is another way to get rid of these T-cells. Instead of just getting rid of the T-cells, we select only the stem cells themselves, and all the other cells are discarded. Both approaches result in a very pure product of stem cells that we transplant into patients.

(00:06:18): This is not being done at most centers as we've become savvier in how we are to manipulate these grafts. One of the more common ways we manipulate grafts is what's called an alpha/beta T-cell and B-cell depleted graft. And in this, we get rid of a large number of T-cells.

(00:06:35): There are two major types of T-cells. There are alpha/beta T-cells and there are gamma-delta T-cells. It's thought that the alpha/beta T-cells are the ones that cause graft-versus-host disease, while the gamma-delta T-cells are important for protecting against infection and fighting the cancer that we're trying to cure with the transplant. This is felt to improve the risk for infections, risk of relapse, and keep the rates of graft-versus-host disease quite low.

(00:07:08): Last, there are some newer strategies that are currently being investigated at some centers. Some centers are doing what is called naive T-cell depletion, where they get rid of any T-cells that have not already been trained to attack specific infections and other proteins and things like that. And this is thought to reduce graft-versus-host disease, while minimizing risk for infection, and helps keep the risk for relapse low. And there's a new product being made by a pharmaceutical company that's called an ORCA-T graft that is being explored in clinical trials right now.

(00:07:42): Medications like cyclosporine and tacrolimus are also used to prevent GVHD. For patients that do not have these graft manipulations done, we use medications to try to prevent graft-versus-host disease. The first two agents that are used are called calcineurin inhibitors. Their names are cyclosporine and tacrolimus. Tacrolimus is also called Prograf® or FK-506. If you hear those names, they're the same drug. And for cyclosporine, its trade name is Neoral®. These are immunosuppressive medications that are also used to prevent rejection for patients that get solid organ transplants, like a heart transplant or a lung transplant, or kidneys or a liver.

(00:08:21): These medications must be closely monitored to produce the desired effect and minimize other risks. Typically, these medications are started before the day of transplant, and continued for two to six months before we start to taper them off. Unfortunately, these drugs can be very finicky, and we have to keep them in a very controlled level in the bloodstream for patients. So we have to monitor drug levels because if they get too low, they don't reduce the risk for graft-versus-host disease because they're not being immunosuppressive enough. But if they get too high, they're associated with a lot of toxic side effects that can affect the nervous system, the kidneys, and things like that.

(00:08:52): Even when these drugs are being used at the appropriate levels, and we're always changing the doses for patients to keep in these levels, they can be harmful to the kidneys. They can cause some higher blood pressures, and they can cause low magnesium levels in the blood that can be dangerous if we don't replace magnesium for patients either by IV or with oral replacements. So many of our patients that are on either cyclosporine or tacrolimus will need some magnesium supplementation.

(00:09:19): And cyclosporine can cause thickening of the gums and cause excess hair growth for patients. This can lead to some body issues for patients, which is a challenge, particularly for adolescents and adults.

(00:09:36): Methotrexate can also prevent GVHD, but it has side effects and may be contraindicated for some patients. The next medication I'd like to talk about is methotrexate. And this is a chemotherapy agent that can be used to treat cancer but is also used at lower doses to treat autoimmune diseases. When we use methotrexate to prevent graft-versus-host disease, we give it at lower doses, comparable to what's being used to treat autoimmune diseases. We often will give methotrexate on days one, three, six and 11, after the transplanted cells go in.

(00:10:02): When we give this methotrexate, it tends to be well tolerated, but it can worsen the mouth sores that patients experience from the chemotherapy and radiation that they receive to get their body ready to receive their transplant. And when we get these sores in the mouth and throughout the digestive tract, we refer to this as mucositis.

(00:10:19): There are a couple of important times that we cannot give methotrexate, even if we had planned to use it. If a patient has a significant liver injury, either from their chemotherapy, or coming into their transplant, we cannot use methotrexate because it doesn't get cleared by the body and leads to much higher exposures and toxicities. And if patients have any fluid collections, these are called effusions or ascites, so collections of fluid around the lungs, in their tummy, or around the heart, we can't give methotrexate because it will pool in those fluids and cause additional toxicities and will slowly get back out into the system and give longer exposures as well.

(00:10:58): Mycophenolate can also be used to prevent GVHD but it also has side effects that must be managed. Another agent that we use is called mycophenolate. This is also known as MMF for short, or CellCept® or Myfortic®. This is typically started around the time of transplant and continued for the first month after transplant.

(00:11:11): Mycophenolate can cause some lower blood counts for patients, and can also cause gastrointestinal symptoms of nausea, vomiting, diarrhea, or sometimes abdominal pain. Unfortunately, these symptoms can overlap with graft-versus-host disease that affects the GI tract, so it can be difficult, sometimes, to differentiate if these symptoms are related to side effects from the medication or related to GVHD. It takes a seasoned and expert pathologist, talking with your transplant doctor, to determine what they feel is the most likely etiology [cause] if these symptoms occur when we're at risk for GVHD, and on this medication.

(00:11:50): Sirolimus can be used in place of tacrolimus or cyclosporine to prevent GVHD. Another agent that is used in some centers is sirolimus, also known as rapamycin (Rapamune®). It is typically used in a place of tacrolimus or cyclosporine. This medicine can also be harmful to the kidneys. And just like cyclosporine and tacrolimus, we do have to monitor levels of this drug to keep it in a narrow target range. This agent can cause high blood triglyceride and cholesterol levels, so we need to monitor patients to make sure they don't have high fat or cholesterol levels in their blood, which can cause additional side effects and injury to the liver and other organs.

(00:12:27): Cytoxan is an older chemotherapy drug that has new uses to reduce GVHD. Another agent that's being used more and more widely for patients is cyclophosphamide (Cytoxan®), given after transplant. This is an agent that we have decades of experience using to treat cancer, and over the past 10 years we've learned how to use it very effectively in the early post-transplant setting to reduce the incidence of graft-versus-host disease. When this agent is used, it's typically given on days three and four after transplant.

(00:12:50): While it's being administered, it can cause some nausea and vomiting. And when it's processed, broken down and cleared by the body, one of the toxic byproducts can be very irritating to the bladder. It can even cause injury and bleeding in the bladder. To minimize this problem, we give patients extra fluids by IV, and an IV medicine called Mesna, that binds up the toxic byproduct of this medicine and minimizes the risk of bladder irritation.

(00:13:14): The newest agent on the block for the prevention of graft-versus-host disease, is a medicine called abatacept. This is an IV medicine that currently is approved to be given in four doses over the first month after transplant. It tends to be very well tolerated but may cause higher blood pressure in patients. It's currently being explored in multiple different settings, but it's most widely used right now for patients for whom we don't have a perfectly matched donor for their transplant. It helps decrease the risk for GVHD to a similar level as patients who are getting a fully matched transplant from an unrelated donor or from a stranger.

(00:13:54): We combine these medicines in different combinations in different patients in different settings to try to prevent graft-versus-host disease. The backbone for most of these strategies is using tacrolimus, cyclosporine, or sirolimus (Rapamune®), combined with either methotrexate for patients that are getting a fully matched transplant from a sibling, or from a fully matched unrelated donor.

(00:14:24): Mycophenolate will be combined, instead of methotrexate, with tacrolimus, cyclosporine or sirolimus in a lot of different settings. One of the more common ones is if we use a cord blood unit as our graft that is transplanted into the patients. We also will use it in patients where we're worried about bad mouth sores, liver dysfunction, or if they have other preexisting conditions and we worry about the safety of giving methotrexate.

(00:14:49): One of the more popular regimens that's widely being used for transplants from a half-matched related donor, so from a sibling, a parent or a child, and is now more widely used with matched unrelated donor transplants, and slightly mismatched unrelated donor transplants, is post-transplant cyclophosphamide, followed by tacrolimus and mycophenolate.

(00:15:16): And the last of the common combination that's being used now is abatacept (Orencia®) given in combination with tacrolimus and methotrexate. This is most widely used following a less than perfectly matched stranger/donor transplant, and it's being investigated in different settings as well.

(00:15:32): The type of transplant a patient is receiving and any comorbidities will be considered to personalize their medication regimen to minimize GVHD. So, when a doctor chooses one of these different regimens, or something else entirely for the patient, it's based on how the patient's getting the transplant, if they're going to be getting a fully ablative or a reduced intensity regimen to prepare them for the transplant. What comorbidities the patient has, meaning what other problems they have in their body because of their treatments and their health. What type of donor we're using and how well they're matched. And so these are all personalized to each individual patient.

(00:16:05): Almost half of transplanted adults will experience some form of acute GVHD. So, moving on now to acute graft-versus-host disease, incidence meaning how often it occurs and how it typically looks when it does show up. Acute GVHD can occur in anywhere from one in four patients, to seven out of 10 patients, depending on how old the patient is, the type of transplant that's being done, which donor's being used, and other additional risk factors. For a majority of adults, 40 to 50% of them will experience graft-versus-host disease that's going to require systemic therapy, meaning therapy by IV or by mouth.

(00:16:43): It most often occurs two weeks to two months of transplant, but it can also occur much later. With some of the newer strategies that we're using for a transplant, we are seeing acute GVHD occurring a little bit later, sometimes beyond even six months after the transplant.

(00:17:00): When acute GVHD occurs, it can involve any combination of skin, digestive tract or liver involvement. The skin is the most commonly involved site affected by acute GVHD. It typically presents as a red rash that can be either splotchy or more widespread. It can come in patches. Sometimes you'll see little raised bumps. Sometimes you'll see flat patches of red skin. When it's most severe, it can cause large blisters on the skin or sloughing of the skin. And although this is rare, it can be life-threatening, and we often have to utilize the expertise of our burn specialist doctors.

(00:17:48): So, since I'm a pediatrician, the pictures you're seeing are going to be of children, but those are similar in appearance to what is seen in adults. On the left you see a foot that has redness over the sole. The soles of the feet and the palms of the hands are often affected and involved with skin GVHD when it's present.

(00:18:08): In the middle picture you see a child's back that has these red bumps and red patches all over, and it involves much more of this patient's skin. The arms and back, most likely also on the front of the torso, and it's probably affecting this child's legs as well.

This patient on the far right has an open wound on the left side of their back where a large blister has opened up. And on the back of the right shoulder, you see a dressing over another area. That was another blister that had opened up, and that is that most severe form of skin GVHD that we rarely see, but it can occur.

(00:18:46): When acute graft-versus-host disease involves the digestive tract, we divide that into the upper digestive tract and the lower digestive tract. When it involves the upper gastrointestinal area, the symptoms that are experienced by the patient are constant and pervasive nausea. Some will have frequent vomiting, and some will have a loss of appetite with associated weight loss. So, we can see any combination of these three in patients that have GVHD affecting their upper digestive tract.

(00:19:16): When patients have GVHD effecting the lower digestive tract - this is the smaller intestine and/or the large intestine also known as the colon - it typically presents with watery diarrhea, three or more episodes a day. There may be crampy pain that occurs with the diarrhea and gets better after stooling. But when it's most severe, lower gastrointestinal acute graft-versus-host disease can lead to persistent severe pain requiring IV pain medicines or having blood in the stool.

(00:19:49): Acute graft-versus-host disease can also affect the liver. The liver is the least commonly involved site of acute graft-versus-host disease. When we see acute graft-versus-host disease of the liver, this presents with increased bilirubin on blood tests. What is seen clinically is jaundice, which is yellowing of the eyes or the skin, and darkening of the urine because of this increased bilirubin in the bloodstream. This is typically painless, although some patients can be itchy with this, but it can get quite severe in some patients. We grade the severity of liver GVHD, based on how high that bilirubin level gets in the blood.

(00:20:30): Treatment for acute GVHD includes topical steroid creams or more systemic steroid therapy. So, moving on to the treatment of acute GVHD. For mild skin involvement, meaning skin involvement where less than half of the body is covered with red involvement of acute GVHD, we can often get by with just using topical steroid creams and ointments.

For GVHD that affects just the upper gastrointestinal tract, sometimes we will try to treat them with non-absorbable steroids that we take by mouth, that are thought to be a topical coating for the upper GI tract. The two different steroids that we use for this are called budesonide and beclomethasone.

(00:21:06): But for all other GVHD, so skin GVHD that involves more than half the body surface, for GVHD that affects the lower GI tract or for GVHD affecting the liver, we need to use systemic therapy, which means oral or IV steroids as the first agent that's used.

(00:21:24): There are a lot of clinical trials that are currently being performed at multiple different centers, that are looking at the use of steroids, because of all the side effects, both short-term and long-term that we associate with steroid use. We will talk about those in another few slides.

(00:21:45): Treatment for acute graft-versus-host disease typically happens over several weeks to a couple of months. So, this is a much shorter period of treatment than what we do for chronic GVHD, which is typically months to sometimes even to years. So, when I talk to patients about treatment of acute GVHD, I tell them that this is the sprint, compared to the marathon of treatment that is for chronic graft-versus-host disease.

(00:22:08): When we start treatment with steroids for a patient with acute graft-versus-host disease, more often than not we use twice daily dosing, and we give this first higher dose for anywhere from five days to longer. And if the GVHD is improving, we will try to decrease the steroids fairly quickly, because steroids have a lot of potential side effects.

(00:22:26): Steroids can be effective in treating GVHD but they bring many risky side effects, especially with prolonged use. These side effects include weight gain all over the body, and the rounding of the cheeks and that moon face that sometimes you'll hear someone talk about. Steroids at higher doses are associated with mood swings and sleep disruption. Patients can get very angry or emotionally labile. Steroids can cause high blood sugar and high blood pressure. Some patients will need to go on insulin or other diabetes medications if their blood sugar stays high. And some patients will also need to be put on blood pressure medications because of their steroid therapy. Thankfully, when we get off of these steroids, the higher blood sugars and higher blood pressures typically will go away, but not always, and the weight gain will go away over time.

(00:23:11): While on these higher doses of steroids, because they are very, very immunosuppressive, our patients are at risk for infections. So, bacteria, fungus, molds and viruses are all risks for patients while on high doses of steroids.

(00:23:24): After steroids are used for a longer period of time, they weaken our bones, which gives us concerns for bone health as a long-term effect. So, patients can have osteoporosis, low bone mineral density, also known as osteopenia, or they can actually have effective killing of bone in the joints, which is called avascular necrosis.

(00:23:49): For patients that don't have a good response to steroids or an incomplete response to steroids, we must talk about using different medicines. When graft versus-host-disease does not respond well to steroids, it's very worrisome to us doctors, because we know we're in for a big fight, and that our patients are at risk for bad outcomes from their transplant.

(00:24:10): If steroids are not effective in treating GVHD, some newer treatments like Jakafi® and photopheresis are now available and they can be fairly effective.  Thankfully, we've had a few different medications that have been studied and approved for treatment of GVHD that does not respond well to steroids. The first one is ruxolitinib, also known as Jakafi®. This is an oral medication that's given twice a day to patients. Its major side effect, that we have to watch for when we start a patient on this medicine, is that it can cause low blood counts. So, when a doctor starts a patient on Jakafi, they typically check blood counts once or twice a week to make sure that the blood counts are staying in safe ranges. When a patient has been on this medication for a period of time, if we don't see the low blood counts, that monitoring can be much less frequent. Ruxolitinib is the only FDA approved second-line therapy for acute graft-versus-host disease.

(00:24:56): But there's another treatment called extracorporeal photopheresis or ECP, because that's a mouthful. This is a treatment where we hook patients up to a machine and run their blood through the machine to collect the white blood cells. We then expose those cells to UV light and infuse them back into the patient.

This is not as immunosuppressive as a lot of the other agents and can be fairly effective in treating GVHD. It's typically given twice a week initially, and each treatment lasts roughly three to four hours. This is a big time commitment, which can hugely impact the quality of life for patients. So, we try to use other agents first typically, but this is a good option for patients that either can't tolerate other agents or don't respond to other agents. After we see them responding to ECP, if they respond to ECP, we can start spacing out the treatments from twice a week to twice every other week, and then further out from there.

(00:25:55): There are a lot of clinical trials that are currently underway for treatment of graft-versus-host disease that does not respond well to steroids. To list just a few, there are mesenchymal stem cells; there are hormones, such as gonadotropin (Pregnyl®); and there's a whole slew of new medicines that are actively being explored. Many centers have at least one clinical trial open for patients that have acute GVHD that is not responding to steroids. They may discuss a study with you and ask you to participate to help us learn if this medicine is effective, so that way we can start using it for more patients, but also because it may be of benefit to you as a patient.

(00:26:37): Chronic GVHD occurs in 15% to 40% of patients and most often appears between four months and two years. Moving on from acute GVHD to chronic GVHD, chronic GVHD occurs in 15% to 40% of patients, depending on the patient's age, the transplant type and other risk factors, like did the patient have significant acute graft-versus-host disease earlier, which does put them at higher risk for chronic graft-versus-host disease later.

(00:26:58): Chronic GVHD most often occurs between four months and two years post-transplant, but it may occur sooner. The earliest cases I've seen are roughly two months out from transplant. In rare cases, it can happen beyond two years out post-transplant, so lifelong follow-up is important for our patients.

(00:27:16): Chronic graft-versus-host disease can involve almost any part of the body, or any combination of body sites, including the eyes, lungs, skin, mouth, digestive tract, genitals, muscles and joints. Here is a list of some of the more common sites targeted by chronic graft-versus-host disease.

(00:27:30): So, for the eyes, the symptoms patients often have are light sensitivity, dry eyes or a gritty sensation in the eyes, like there's something in them. They can have excessive tearing. They can have pain in their eyes or redness.

(00:27:47): For the lungs, this is one of the organs we worry most about because it can be extremely severe and life-threatening. The symptoms can be shortness of breath. or increased intolerance to activity, or a cough. They can have an emphysema-like picture. They can experience frequent lung infections, which can be a red flag that there is chronic GVHD present in the lungs, or they can develop fluid collections around the lungs.

(00:28:12): For the skin, we can see thickening of the skin. We can see scarring or stiffness of the skin, and these are more worrisome when they occur. We can also see dryness, color changes of the skin, nail changes, itchiness, things like that, which can also be manifestations of chronic graft-versus-host disease of the skin.

(00:28:38): Chronic GVHD can affect the mouth and cause redness of the gums and the cheeks and the tongue. It can cause sores or bumps in the oral cavity, or the mouth. It can cause mouth dryness, or it can cause sensitivity, particularly to foods such as minty foods and toothpaste, acidic foods, things like that.

(00:28:59): Chronic GVHD can also affect any part of the digestive tract. If it affects the esophagus, that can lead to food getting stuck or difficulty swallowing. It can lead to choking on food when eating. When it affects the lower GI tract, it can cause constipation or diarrhea.

(00:29:21): Chronic GVHD can also affect the genitals. It can lead to irritation or disfigurement of the penis for males. It can lead to scaring, narrowing, painful sex or extreme dryness for females.

(00:29:34): And last of the common sites for chronic GVHD are the muscles and joints which can lead to limited mobility or loss of flexibility. It can lead to muscle cramping and pain.

(00:29:46): There are also some more recently recognized, less common sites, for chronic graft-versus-host disease. The scalp can have thickening of the skin, often with flaking or sometimes with hair loss that may or may not be associated with scarring.

(00:29:59): Chronic GVHD can also affect the brain, the heart, and the immune itself. It can affect the brain and lead to personality and speech changes, seizures, weakness, confusion or sleepiness. This tends to be uncommon, but something to keep in mind, that this is something that's recognized as a manifestation of chronic graft-versus-host disease.

(00:30:16): It can cause a fluid collection around the heart, called a pericardial effusion. It can affect the kidneys leading to injury to the kidneys, which is shown on blood tests, or it can lead to patients losing a lot of their blood proteins in their urine, which looks like foamy urine to our patients.

(00:30:34): Last but not least, the immune system that affects and causes GVHD can also attack blood counts and lead to life threateningly low blood counts because they're being destroyed.

(00:30:47): There are a lot of different treatments for chronic graft-versus-host disease. Localized treatments like creams, mouth washes, artificial tears or antibiotics are preferable if they work. Whenever we can give treatments locally to different areas that are affected, that's always preferable because we know our systemic therapies have a lot more side effects.

(00:31:01): So, for the skin we have a lot of different options. There are topical steroid creams and ointments that we can use, just like we use for acute GVHD. Dryness is a very common problem post-transplant, especially in patients with chronic GVHD of the skin. We do want patients using hypoallergenic moisturizers for the skin. There are a lot of other prescription creams and ointments that can be used for patients. There are topical formulations of tacrolimus, of ruxolitinib and other agents that can be used, and we can also use UV therapy directly to the skin as well.

(00:31:36): For the mouth, we have steroid mouth washes that patients can swish to decrease inflammation and irritation in the mouth. We also have light therapies, that are under investigation, that are thought to help with treating the symptoms of GVHD in the mouth.

(00:31:51):  For the eyes, many patients will be given artificial tears, but there are also prescription drops that are either steroids or other immunosuppressants that can be used as well. Beyond these, there are surgical approaches and specialized contact lenses that can be used for the eyes.

(00:32:06): One thing you'll note is that we have a steroid form that we can use topically for patients because steroids continue to be our best and most reliable agent for treating graft-versus-host disease.

(00:32:20): There are some specialized treatments for the lungs, if the lungs are involved. This is something that is frequently used in patients when there's concern for lung GVHD. We refer to this as FAM therapy, and what that consists of are three different agents. The first is an inhaled steroid, similar to the inhaled steroids that are used for patients with moderate to severe asthma.

(00:32:41): The second is a medicine called azithromycin that many patients will be placed on. This is an antibiotic that can help prevent or minimize the risk for lung infections, but also has anti-inflammatory properties. And when it's given to help treat lung GVHD, it's typically one pill three times a week. So many patients will take it on a Monday, Wednesday, Friday schedule.

(00:33:00): And then there's a third medicine called montelukast, its trade name is Singular®. This is also used for asthma. This is a daily pill. Many patients will be put on this, in addition to their other therapies, if they have lung graft-versus-host disease.

(00:33:18): Systemic therapies like steroids can also be used for chronic GVHD. Moving on to systemic therapies for chronic graft-versus-host disease. I want to mention that there are local and topical therapies. We always try to use those, even when we're using systemic therapy, so we can get off those medicines that have more global effects on the body and the immune system.

(00:33:35): Just like with acute GVHD, steroids are typically our first-line treatment. We do use a lower starting dose for chronic GVHD typically than we use for acute GVHD, but we use it over a much longer period of time, typically over several months.

(00:33:50): The side effects and the toxicities that we worry about with the steroids are the same as those that we worry about with acute GVHD. that we talked about in an earlier slide.

(00:33:58): Chronic GVHD may be treated with Imbruvica, Jakafi, of Rezurock. So, beyond steroids, there are three approved medications for the treatment of chronic GVHD. The first is ibrutinib (Imbruvica®). This is approved for patients one year old and older. It's a once daily pill or a liquid, but it does have a lot of side effects. There's a risk of bruising, bleeding and tiredness. A lot of patients will have nausea and diarrhea. This can also cause muscle spasms and does increase our risk for infections. So, while this was the first approved agent, it's often not the first agent that we'll go to for treating patients that need another agent on top of or beyond steroids.

(00:34:35): Ruxolitinib (Jakafi®), which is the same medicine that is used for steroid refractory acute GVHD, is also approved for chronic GVHD in patients 12 years old and older. This is, again, a twice daily pill, and we must watch blood counts. Like I mentioned before, there is a risk for infections with this.

(00:34:50): The last of the three agents is belumosudil (Rezurock®), and this is a medication that's approved for patients that failed steroids plus one other agent. It's approved for children and adults at least 12 years of age. It can be given either once or twice daily, depending on what other medicines you're on. Its most common side effects are nausea, diarrhea, fatigue, liver irritation or inflammation, and a risk for infections. In my experience, this tends to be very well tolerated and the side effects are less frequent and less problematic.

(00:35:24): We can also use extracorporeal photopheresis (ECP), that I talked about earlier, which involves using a machine to collect immune cells from a patient, treating them with UV light and giving them back. This is the same treatment that we use for acute GVHD.

(00:35:41): There are a lot of upcoming and experimental therapies. I want to specifically mention an agent called Axatilimab, that has completed a clinical trial with promising results, and is being reviewed for possible FDA approval. This is given IV every two weeks, but there are a lot of other experimental therapies that are under investigation. A lot of things that are being used off label for patients as well.

(00:36:01): I'd like to quickly go over some brief physical challenges and emotional challenges in my few minutes that I have left with you. These will be gone through in much greater detail in other talks as well. So I do encourage you to attend those talks.

(00:36:15): Treatment for chronic GVHD can bring physical challenges like muscle weakness, weight gain, and limited mobility. So, when we talk about physical challenges from GVHD, we have to talk about medication side effects and problems from GVHD itself. Because chronic GVHD tends to be the more long-standing issue that patients deal with, I'm going to focus on chronic GVHD.

(00:36:29): For patients that are on steroids, this can cause muscle weakness. It can cause weight gain. And these are things that lead to patients to not feeling well, not being happy with their body appearance, and can hinder their ability to participate in their normal activities.

(00:36:46): Chronic GVHD, itself, can lead to limited mobility because of tightness of the joints or the skin. It can lead to fatigue, and it can lead to limitations in activity, particularly if there's lung involvement.

(00:36:58): Steroid treatment for chronic GVHD can bring many emotional challenges and affect a patient’s quality of life, participation in school or work, and sexual health.  For emotional challenges, steroids are one of the major ones that we worry about. They can lead to sleep disruption, mood swings, a labile [unstable] mood, anger, anxiety, things like that. And body image issues can lead to emotional challenges. There are concerns about hair loss that that's associated with GVHD. The physical appearance of rashes and scarring of the skin, and with the steroids, these can cause acne and weight gain that can also be distressing to patients and not make them happy with their appearance as well. There are a lot of treatments that can be used for these things, so talk to your doctors.

(00:37:34): The inability to fully participate in work or school also leads to some emotional challenges for families and patients. And then for chronic GVHD, just the long-term treatment and the need to take medicines for a long period of time, in of itself does pose emotional challenges for patients as well.

(00:37:51): And finally, not just because of the potential for chronic graft-versus-host disease to involve sex organs, but also because of body image issues and the stresses of transplant, all of that that can impact sexual health, which can significantly impair a patient’s quality of life.

(00:38:08): So, with that, I thank you for your attention, and I welcome your questions.

(00:38:27): [Michala O’Brien]:  Q & A. Thank you, Dr. Harris for an excellent presentation. We will now begin the question and answer session. The first question is: Have you seen any benefit from Rezurock® as it relates to the chronic lung GVHD or is there any benefit primarily from for other types of GVHD?

(00:39:01): [Dr. Andrew Harris]:  So, one of the challenges with chronic GVHD is that it's caused by a lot of different types of immune cells, and it involves a lot of different biologic pathways in the body. We're still trying to learn how to decide which agents to use for each individual patient to maximize our chance for successful therapy. I have seen successful treatment of chronic GVHD of most organ systems by using ruxolitinib or from belumosudil, and from steroids and things like that as well.

(00:39:35): Just this past week I was in Europe for the European Bone Marrow Transplant Scientific Conference, and there was talk about using Abatacept, that we talked earlier as being used to prevent GVHD, as a potential treatment for lung GVHD as well. So, the short answer is, yes. I have seen ruxolitinib successfully treat GVHD of many different organ systems, including the lungs.

(00:40:01): We know from the clinical trials that some patients do have responses in the lungs that has beem demonstrated beyond my experience. But every patient's experience is going to be different and not every agent is going to work for every patient. So thankfully we're having more and more different options that we can use to treat patients.

(00:40:20): [Michala O’Brien]:  Can sunburn, swimming in a chlorine pool or another outside exposure to chemicals trigger your skin GVHD?

(00:40:29): [Dr. Andrew Harris]:  So that is a great question, and the answer is, yes. Whenever we have irritation of the skin, that can be from a sunburn, from chemical irritation, that it can even be from a reaction to a new detergent or a soap or something like that. Whenever there's inflammation or irritation, the immune system goes and looks at where that inflammation or irritation is very, very closely. And after a transplant, that immune system, when it's looking very closely in those areas, it may find proteins in those different organ systems or those tissues, that it doesn't like, that aren't supposed to be there. It's just that they're from a different person. So those things can trigger graft versus host disease.

(00:41:10): So it's very important to wear sunscreen and sun protective clothing after transplant to help minimize that risk. But our patients are also at increased risk for skin cancers, as a late effect from their other treatments and from GVHD itself. So, it's important to wear sunscreen and sun protective clothing lifelong to help minimize risk for skin cancers as well.

(00:41:27): [Michala O’Brien]:  Can you discuss the pros and cons of using bone marrow versus peripheral stem cells for transplantation?

(00:41:37): [Dr. Andrew Harris]:  That's a very good question. There was a large, randomized trial comparing bone marrow and peripheral blood stem cells from fully HLA matched unrelated, or stranger, donors to try to get to the pros and cons of the two different graft sources. The findings from that study have not been reproduced with sibling transplants or half match transplant or any of the other settings, but we do try to extrapolate somewhat to those other settings as well.

(00:42:09): I'm also going to limit my comments to situations where we're giving a peripheral blood stem cell transplant or a bone marrow transplant and have not manipulated the graft e.g., taken out any cells or selected any cells in that graft.

(00:42:20): What we know is that if we use bone marrow instead of peripheral blood stem cells, it does decrease the risk for chronic graft-versus-host disease. And what was a surprise for us clinicians was that there was not an increased risk for acute GVHD or a decrease in relapse using bone marrow, because we know that there are more of those lymphocytes that are part of the peripheral blood stem cell graft when we give it.

(00:42:42): So, the "pro" of the bone marrow transplant over a peripheral blood stem cell transplant is a decreased incidence of chronic graft-versus-host disease. The benefit of a peripheral blood stem cell transplant is that we saw more reliable engraftment meaning that the graft took.

(00:42:59): Now the numbers of primary graft failures with bone marrow and peripheral blood stem cells were both low, but there was significantly less when using peripheral blood stem cells when compared to bone marrow. So, I can speak to pediatrics where we tend to not have a lot of graft failure because we are using larger donors for smaller patients, particularly when using a parent or a stranger. Strangers must be at least 18 years of age and therefore they're adult size for our pediatric patients to get very good doses of cells.

(00:43:32): For adult patients, particularly those that are obese, sometimes getting a good cell dose can be challenging with bone marrow and therefore they'll use peripheral blood stem cells, knowing that there is some of this increased risk of GVHD. Some of this risk is being changed with more and more use of that post-transplant cyclophosphamide, and there are a lot of studies going on, looking at how much that improves our risk for graft versus host's disease after peripheral blood stem cell transplants. So that's speaking specifically to a T-replete or a non-manipulated, perfectly matched stranger transplant as opposed to these other scenarios for a transplant, which we've not formally studied.

(00:44:14): [Michala O’Brien]:  Is there a way to know if I have GVHD versus an autoimmune syndrome, like Sjogren's?

(00:44:24): [Dr. Andrew Harris]:  So that's a very challenging question to answer because autoimmune conditions can occur after bone marrow transplant. But the fact that you've had a transplant, and the immune system that's causing these autoimmune conditions is originally from somebody other than yourself, it's hard to say that it's autoimmune, meaning caused by the self, or alloimmune, meaning coming from the other or from the donor. So, these autoimmune conditions that are diagnosed, I personally think are still an alloimmune reaction and are one of the many different manifestations of chronic graft-versus host-disease.

(00:45:08): But this is a very controversial topic in GVHD. So, when we see manifestations of an autoimmune disease that is not the typical manifestation that we think of in chronic GVHD, we'll often work closely with our rheumatologist and immunologist specialists and colleagues to help with management. So that's a very controversial topic that I don't think we have a clear, straightforward answer for, and there are many strong opinions about.

(00:45:38): [Michala O’Brien]:  How effective is photopheresis in your opinion?

(00:45:44): [Dr. Andrew Harris]:  So, I think that it can be very effective in a lot of different settings. It's been looked at in a few studies, but it's more  just kind of been given to patients, and then people have reported their experience in giving it. There's a lot more literature in adults than in children, but the response rates reported in adults are anywhere from 40 to 50% of patients. And this is typically used in patients that have not responded to steroids.

(00:46:10): In pediatrics, those numbers have been anywhere from 45 to 70%. So, this is an important treatment option that we do have for our patients. It is much more disruptive to their life than taking a pill or an intermittent IV infusion or an injection. But it's something that should be considered for patients that aren't able to tolerate those, or that are not responding to some of those. So, in my experience, it can be effective, but the responses tend to be a little bit slower than some of these other medicines, so it's a big investment of time.

(00:46:43): [Michala O’Brien]:  My donor was a 100 percent match for my sister. Does this increase or decrease my risk for chronic GVHD?

(00:46:51): [Dr. Andrew Harris]:  So, she is saying that her sister was her donor and was 100% match?

(00:46:57): [Michala O’Brien]:  Her sister, yes, with the donor and 100% match. Does that increase or decrease chronic GVHD?

(00:47:04): [Dr. Andrew Harris]:  So that's a little bit of a mix in the answer to that. So, we know that a sibling who has a full match is always a preferred donor, because it does decrease the risk for graft-versus-host disease compared to using a stranger or a half-matched donor, or a less than fully matched donor. So that is why we prefer to use them. We see less of these later complications and immune mediated complications of transplant.

(00:47:30): When we look at our donors, if we have the option of a male versus a female donor for patients, particularly for male patients, we do prefer a male donor over a female donor because the Y chromosome does make proteins that the immune system can recognize and attack. So, when we use a female donor for a male recipient, there is a slightly higher risk of GVHD than if we use a male donor for a male recipient.

(00:47:54): But having a fully matched sibling is a better match than an unmatched stranger, and most people would prefer using a female fully matched sibling over an unrelated male donor because when we use a sibling, a lot of the proteins that we don't test for, that can be recognized by the immune system, are more likely to match up between the sibling donor and the patient.

(00:48:19): [Michala O’Brien]:  How do you differentiate acute from chronic GVHD, if the timeline of occurrence could be overlapping? By pathology?

(00:48:28): [Dr. Andrew Harris]:  So yes, these are very different disease processes and there can be some overlap and difficulty in distinguishing between the two. So historically, any GVHD issue that occurred before day 100 was considered acute, and anything that occurred beyond day 100 was chronic. But as we change how we do transplants, as we learn more about the biology of these diseases, we learned that acute and chronic GVHD are two different processes.

(00:48:48): So when we look at biopsies under the microscope, there are differences that we can see between the two. The hallmark of acute GVHD, particularly in the gut, is something called apoptosis or programmed cell death that's caused by the immune cells, and the way that they interact with the healthy tissue cells. For chronic GVHD, we tend to see more fibrosis, which is a fancier name that, for all intents and purposes, is scarring. So, we see more fibrosis in chronic GVHD.

(00:49:18): And then how the symptoms of the disease present themselves also helps us distinguish between the two. One thing we're learning as we are doing more of these different types of transplants is that we can see more and more acute GVHD that occurs much later after transplant than we had historically seen. So, we have to go by the constellation of symptoms and signs that we're seeing, and if we do biopsies, what we're seeing under the microscope, to help distinguish between the two.

(00:49:48): [Michala O’Brien]:  If you're having trouble staying off tacrolimus two years post-transplant, what other options would you have?

(00:49:57): [Dr. Andrew Harris]:  So, it's very difficult to try to answer this question without knowing a lot more details of this case. I can tell you that calcineurin inhibitors are used very long-term at some centers and not at others. And this is a better discussion to have with your physician, especially if you're having challenges or complications or difficulty with taking it. It's good to explore what other options you may have with your transplant physician, and if you're not satisfied with that answer, you're always entitled to ask to see somebody else in consultation for a second opinion.

(00:50:36): [Michala O’Brien]:  I have chronic GVHD of the skin. If ECP is given as a treatment, will it make it so the GVHD will go away indefinitely? Can you also discuss some of the long-term effects of ECP?

(00:51:20): [Dr. Andrew Harris]:  Sorry, I lost you guys for a second. So, the question was about ECP and can it make GVHD go away. The hope with any of our GVHD therapies is that they will make the GVHD go away, and we can get off of the therapy. And I've seen that with many of the different treatments that we use for GVHD.

(00:51:36): ECP is a little bit unique in how it works, compared to some of our other agents, in that we don't fully understand its full mechanism. But one of the things that we know that it does do is expand some of our immune cells that lead to regulation and tolerance in the body. So the hope, with ECP, along with a lot of these other therapies, is that these cells that promote this tolerance will expand, grow, and ultimately lead to a point where we'll be able to be off other therapies, although that doesn't always happen for patients, unfortunately.

(00:52:04): [Michala O’Brien]:  Do you find teeth sensitivity a GVHD symptom?

(00:52:11): [Dr. Andrew Harris]:  So, teeth sensitivity in and of itself, I typically don't see as a symptom of GVHD. I worry more about gum and cheek and mouth sensitivity as a whole. I do worry about dental health in our patients, with all the treatments that they've had, especially in patients that have had radiation, that may lead to teeth sensitivity.

(00:52:31): Having said that, it may be possible, because GVHD can affect pretty much any part of the body. So if we are able to rule out some of these other things, like small cavities or microscopic cavities from some of the treatments patients have been on, things like that, and we still have dental sensitivity, that may, in fact, be a diagnosis of exclusion that we could make.

(00:52:56): [Michala O’Brien]:  Is blurry vision as symptom of GVHD of the eye?

(00:53:01): [Dr. Andrew Harris]:  It certainly can be a symptom of GVHD of the eye, but there are a lot of other things that can cause vision blurriness as well. So, for all my patients that I see and treat for chronic GVHD, I have them do regular follow up with an ophthalmologist who is familiar with chronic GVHD, along with the other eye concerns that we have. For example, patients that have had radiation therapy are at risk for cataracts, and those can certainly cause blurry vision as well. So having good eye doctor follow up is an important part of ongoing care for patients with chronic graft-versus-host disease.

(00:53:33): [Michala O’Brien]:  Is there any treatment for GVHD related hair loss? I'm 10 years post-transplant and still experiencing significant hair loss.

(00:53:45): [Dr. Andrew Harris]:  So, there are some therapies that can be considered for hair loss post-transplant, whether it's related to GVHD or to other causes. Oftentimes this is something that could be discussed with the dermatologist. I know the dermatologist I work with will prescribe things like minoxidil and finasteride, which are medicines that are used for other hair loss in patients, and it has seen some good responses, but I typically defer that management to her because that's much more her area of expertise than mine.

(00:54:17): [Michala O’Brien]:  Does chronic GVHD burnout after a period of time and treatment?

(00:54:24): [Dr. Andrew Harris]:  So, there are varying opinions on that. I personally think that, yes, it can burn out. Now one of the challenges with chronic GVHD is, even if it's quiet, is that if it's caused significant fibrosis or scarring, some of that scarring may be irreversible. So even if there's not an active attack and destruction, or active progression of chronic GVHD, there may still be lingering symptoms and issues because it was there. So, I do think that GVHD, over time can burn out, but it doesn't mean that all of the symptoms will go away, especially if there's significant scarring or fibrosis.

(00:55:01): [Michala O’Brien]:  Does treatment for GVHD with immune modulators like Imbruvica cause cancer relapse in long-term use, if you use it more than a year?

(00:55:14): [Dr. Andrew Harris]:  I think I'm hearing two different concerns here. One is if we must go on further immunosuppression, does it increase our risk for relapse of our cancer that we had our transplant for? And is there an increased risk for other cancers afterwards? Unfortunately, the answer for both of those is, yes. If we have to go on higher doses of immunosuppression, it does increase our risk for both of those because our immune system is important, first for treating our cancer, which is part of why we do a transplant, but also, screening for cancer and pre-cancerous cells in our body and killing them before they progress into a clinically meaningful cancer that we have to treat more traditionally. So unfortunately, those are risks.

(00:55:55): I can tell you that the development of GVHD also is associated with less relapse of the underlying cancer for which you had a transplant, but it doesn't take that risk to zero, unfortunately. So, these are concerns that we talk about both short-term and long-term. It's why we do try to get off these medications, because there are long-term risks with long-term use, and it's something that we're always mindful of.

(00:56:18): [Michala O’Brien]:  Is there a connection between the increased infection rate and Rezurock® because of immunosuppression? Do you have any recommendations to diminish the infection rate?

(00:56:52): [Dr. Andrew Harris]:  So, for Rezurock®, it's typically been used in combination with other agents or in patients whose immune system is already fairly weak from having a lot of steroid exposure and things like that. In the clinical trial of Rezurock®, which is probably the largest pooled experience that's been reported, they did see some slightly increased risk for infections of the lungs that can be both viral and bacterial. How immunosuppressive it is on its own is something that I don't think any of us truly know just yet. So, if people are onbelumosudil or Rezurock® just by itself, it's unclear what their infectious risk is, because we just don't know.

(00:57:30): Having said that, we all worry because we know that in patients with chronic GVHD, their immune systems are not working properly to begin with, which is why most patients when they have chronic GVHD, are on some form of infection prophylaxis. And so I think the most important thing is to have a close monitoring discussion with your doctor, talking about what the prophylaxis plan is, and if you do see that you're having recurrent infections, talking with your doctor about ways of trying to prevent those specific infections that you're experiencing, whether it's changing antibiotics, whether it's an antiviral, whether it's because you have low antibodies, you need IVIG replacement or some of the other strategy altogether. So, it depends on the infections that you're seeing. But belumosudil or Rezurock itself is something that, if given in isolation, I don't think we have a clear understanding of just how immunosuppressive it is. Certainly, there is concern that it is affecting the immune system because we're using it to treat GVHD.

(00:58:23): [Michala O’Brien]:  Okay, It looks like we can ask one more question.

(00:58:28): [Dr. Andrew Harris]:  Okay.

(00:58:29): [Michala O’Brien]:  All right. We hear that a little GVHD is a good thing to help prevent relapse. Is this true?

(00:58:36): [Dr. Andrew Harris]:  So, yes and no. We know that a little bit of GVHD, in several different diseases for which we do transplants, has been associated with a decreased risk for relapse. So, a little GVHD, if it responds well to treatment goes away and it doesn't come back, it's something that's okay.

(00:58:56): Having said that, GVHD, in and of itself, can be life-threatening. So, a lot of GVHD is something that we worry about. So, the other thing, when we talk about GVHD, is that we also must talk about GVL, which is something I didn't go into, and that's the graft versus leukemia or graft versus cancer effect that we want from the transplant. We've not been able to separate GVHD from the graft versus cancer effect. And that's kind of the holy grail of GVHD treatment research, learning how to completely quiet and silence graft versus hosts disease without impairing that immune system's ability to fight off the cancer and other infections and things like that. So yes, that's an observation that is made, but I always worry that a little GVHD can turn into a lot of GVHD. So, when GVHD occurs, we need to treat it.

 (00:59:51): [Michala O’Brien]:  Closing. Thank you, Dr. Harris, for this excellent presentation.

(00:59:56): [Dr. Andrew Harris]:  It's my pleasure. And I thank everybody for their attention and the wonderful questions and discussion we were able to have at the end.