Introduction to Graft-versus-Host Disease

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Introduction to Graft-versus-Host Disease

Saturday, April 17, 2021

Presenter: Marcello Rotta, MD, Colorado Blood Cancer Institute (CBCI) at Presybterian St. Luke's Medical Center

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

Summary: Graft-versus-Host Disease (GVHD) is a common condition after a bone marrow or stem cell transplant that uses cells from a donor (an allogeneic transplant). The donor cells are called the “graft” and the patient is called the “host”. When the donor’s immune cells (the graft) are transplanted in the patient’s body (the host) they often unleash an immune system attack against the patient’s organs and tissues which can be mild, moderate or severe.

Highlights:

• There are two types of GVHD: acute GVHD and chronic GVHD. Each type differs in the time of onset, organs it affects and how long it persists.
• GVHD can be mild, moderate or severe and may affect one or many different organs at a time.
• Promising new treatments are now available for patients whose GVHD does not respond to traditional therapies.

Key Points:

(02:33) To reduce the risk of developing graft-versus-host disease, the donor and recipient should have similar genetic markers on their cells called human leukocyte antigens or HLA.

(03:32) In a bone marrow, stem cell or cord blood transplant, the donor’s cells replace the patient’s blood cells and create a new immune system that can attack the patient’s cancer. This is called the graft-versus-leukemia effect.

(06:52) Sometimes, the donor’s cells don’t recognize the patient’s organs and tissues as something that belong inside the patient’s body and unleash an immune system attack. This is called graft-versus-host disease.

(08:59)  Immunosuppressive drugs are given to the patient prior to transplant to reduce the risk of developing a severe case of graft-versus-host disease.

(10:22) You can eliminate graft-versus-host disease by eliminating specific immune cells from the graft, but that reduces the graft-versus-leukemia effect.

(17:41) Acute GVHD occurs early after transplant in about 70% of patients. It is severe in 10-15% of patients. Risk factors for developing acute GVHD include a mismatch between a donor and the recipient, older donor and/or older recipient, and the use of peripheral blood stem cells from the donor, instead of bone marrow or cord blood.

(20:16) Acute GVHD typically attacks the skin, GI tract, and liver.

(21:13) Chronic GVHD appears later after transplant and affects 30-70% of patients. The most frequent targets of chronic GVHD are the skin, eyes and mouth, but it can affect many other organs as well.

(30:26) Treatment for chronic GVHD should start early. It may involve topical treatments for a single organ, or systemic treatment with steroids if the disease is affecting many organs or if the topical treatment, alone, does not work.

(33:53): Effective treatment of chronic GVHD require a team approach involving healthcare providers with sub-specialize in different areas of medicine, as well as diverse supportive staff of nutritionists, physical and occupational therapists, and psychosocial support.

Transcript of Presentation:

(00:00) [Sachit Patel] Introduction. Hello, everyone. Thanks for joining. My name is Dr. Sachit Patel. I'm a Pediatric Bone Marrow Transplants and Cellular Therapy physician and the Director of the Program at Nebraska Medicine and Children's Hospital in Omaha. I have a wonderful speaker today with a presentation entitled "Introduction to Chronic Graft-versus-Host Disease". And without further ado, it's my pleasure to introduce today's speaker, Dr. Marcello Rotta.

(00:32) Dr. Rotta is the Director of the Leukemia Service and Co-Director of the Long-Term Follow Up Service at the Colorado Blood Cancer Institute at Presbyterian St. Luke's Medical Center in Denver, Colorado. He has worked in the field of stem cell transplant for nearly 20 years, and extensive experience in complications following stem cell transplant and other cellular therapies. His research focuses on late effects of transplant, including graft-versus-host disease and multiple myeloma. He's got a wonderful presentation put together today, so please welcome Dr. Rotta.

(01:11) [Marcello Rotta] Overview of Talk. Thank you very much, Dr. Patel, for your kind introduction. And so, without further ado, I am going to move forward with my slides.

I was asked to put together a presentation to introduce graft-versus-host disease. I will focus my presentation on all the aspects of graft-versus-host disease, and I am thinking about my personal experience in discussing graft-versus-disease with patients, in particular when patients go through the consent conference, when they make the final decision to move forward to a transplant.

 (01:54) So today, I'm going to discuss these complications, these relevant complications post-transplant, and I want to start just creating a context for graft-versus-host disease, that it's something that is expected in a donor cell transplant or allogeneic transplant.

Then, we will discuss the mechanism that causes graft-versus-host disease.

We'll discuss incidence and risk factors.

Eventually, we'll move toward what GVHD looks like and also, how we try to prevent GVHD when we design transplants, as well as how we treat graft-versus-host disease.

(02:33) A successful transplant requires the that the  genetic markers (HLA or human leukocyte antigens)  on the donor’s cells match those on the recipients cells as closely as possible. So, in a donor cell transplant, of course, there is a donation between a donor and a recipient in need. We would consider the graft to be what is collected from the donor, and host would be the recipient. And of course, the donor and the recipient have a certain degree of matching, that we call HLA matching, before we pick a specific donor for that specific recipient. So, these are the players of my talk today: the graft and the host.

(03:03) Stem cells can be from the donor’s bone marrow, bloodstream or from an umbilical cord. Now of course, the source of cells for an allogeneic stem cell transplant can be collected from the donor in many ways. The most common is the peripheral blood, then the bone marrow harvest and then the cord blood unit. And ultimately, the donor can be a donor within the family of the recipient or a volunteer. Usually, a volunteer [is the source] for the collection of cord blood.

(03:32) In a stem cell transplant, the donor’s cells replace the patient’s blood cells and create a new immune system that can attack the patient’s cancer. This is called the graft-versus-leukemia effect. Now, what is the donor really donating? In my mind, I always say that the donation is a donation of two things that are collected in the same bag. On one side, there is the donation of the stem cells, so the blood forming cells, the ones that will replace the host's stem cells. And ultimately, we give to the recipient new white blood cells, red cells, and platelets.

(03:58) But most of all, we have to consider that the donation, the graft, from a donor is really a donation of a new immune system. So, what we collect in the bag are a number of immune cells, and we are asking these immune cells to destroy the cancer cells in the recipient to provide what we call graft-versus-leukemia effect, which is ultimately what cures the leukemia or the cancer that the patient has.

(04:30) Stem cell transplants are a form of immunotherapy. In this regard, the transplant is really a unique way to treat cancer. It is an immunotherapy because it is really a donation of an immune system coming from a healthy donor. And that acquired new immune system that is going to reside in the recipient will fight, life-long, the leukemia in the recipient and will not allow it to come back

 (04:56)  Of course, it's unique because, unlike other form of treatments such as simple chemotherapy, it requires [the patient] to have a donor, and it requires an extended amount of support for the patient.

 (05:11) As I mentioned, it is an immunotherapy, and the goal of transplant that we always have to keep in mind is to cure of the leukemia or the malignancy, the type of cancer that the patient has. And it's certainly a life-changing treatment. From day zero, when the transplant is infused, the life of the recipient changes from that time onward, by virtue of these donations.

(05:40) Transplanted cells may be rejected by the recipient. So here, you see the little bag, the graft and the host. And, of course, if the host’s immune system, because of disease, pushes away the graft, we call this a rejection. So, it's like, you transplant me with an organ. I reject it because my immune system would reject it.

(06:12)  Engraftment means the donated cells are accepted by the host and they fight the leukemia and provide immunity.  But we have to remember that the graft is an immune system on its own. So, what we would see in successful transplant is the graft prevailing and entering the host without being rejected. And what we would see, then, is what we call engraftment, so really, the graft setting up shop inside the recipient. And ultimately, with the engraftment, what we are asking the graft to do is to fight the leukemia, to form new blood in the recipient, and to form the donor immunity against the leukemia.

(06:52): Graft-versus-host disease is when the graft launches an immune reaction against the host. Consequences of this, though, are what we call graft-versus-host disease. And we'll discuss exactly what we mean by that, but it's substantially an immune reaction of the graft against the host, against the recipient.

 (07:09) A successful transplant requires engraftment, cure of the disease, and no or minimal GVHD. When we discuss a transplant, we need to define success. When I talk to a patient and I tell them, "How would we say that your transplant went well?" Of course, the first thing is that the graft has to take, the transplant has to work. Just like when you plant a seed, you want to see the flower coming up, right? So first of all, you need to see engraftment, you need to see people growing back their blood counts, you need to see their platelets.

(07:40) Second, of course, you want to cure the leukemia. You want to cure the cancer that the patient has. That's why you do the transplant.

(07:48) Third, you want to make sure that the transplant is not harming the recipient, that there's no graft-versus-host disease or that the graft-versus-host disease is tolerable.

(07:58) And ultimately, what you're going to ask is for the recipient to live a normal life in the environment, a life where they can definitely fight infection. So, the graft will provide life-long immunity.

(08:14) The key concept of a successful transplant is tolerance. So, the state in which the graft and the host, they become friends. They don't fight each other. In particular, the graft doesn't fight the recipient.

(08:30) Conditioning prepares the host for transplant. So, the way in which, historically, we have been doing transplant, has always had some treatment before the transplant, which is indicated here as Day Zero. HSCT means hematopoietic stem cell transplant, so our donor's transplanted [cells]. There is a part before transplant – conditioning - which is really to prevent the host from rejecting the graft.

(08:59) And then, of course, post-transplant immune suppression is provided . And if you see, there is this yellow box going down. it's provided, hopefully, not life-long, but it's higher at the beginning, and it has to taper down over time. And it's supposed to be a mechanism to reduce the attack coming from the graft [donor] against the recipient [patient]. So, transplants are designed to facilitate the tolerance that I told you about, facilitate engraftment, and reduce the chance of graft-versus-host disease.

(09:38) Graft-versus-host disease (GVHD) is an expected outcome after a stem cell transplant using donor cells (allogeneic transplant). So, what is graft-versus-host disease, or GVHD? It is a substantial biological consequence of doing the transplant. If you think about it, it is a disease that comes from transplant. It is not something that is clearly naturally occurring. It is an artificial disease because, really, it comes from doing the transplant, from giving an individual a new immune system.

It is an obvious consequence of the transplant. Therefore, it is always necessary to give some immunosuppressive medication to prevent the graft-versus-host disease because we expect it to happen in all cases.

(10:22) You can eliminate graft-versus-host disease by eliminating specific immune cells from the graft, but that reduces the graft-versus-leukemia effect. You can eliminate the graft-versus-host disease if you remove specific immune cells from the bag of cells given to the recipient. So, there are ways in which we can manipulate the bag of cells and remove the T-cells, and that would wipe away the graft-versus-host disease.

 But you need to know that with graft-versus-host disease, there is an association that we've known now for many decades, called the graft-versus-leukemia effect. When you remove the immune cells from the bag of cells that you're infusing into the patient, it's true that you take away the graft-versus-host disease, but you also remove the anti-leukemia effect of the transplant. So, the price to pay to completely remove the graft-versus-host disease can be an increased risk for the leukemia to come back.

(11:17) Graft-versus-host disease begins with inflammation caused by the chemotherapy given before transplant.

So, how does it happen? So, there are many mechanisms. The first, what we see and believe can induce the start of graft-versus-host disease, is when you give them a bunch of chemo beforehand. That chemo, of course, causes a bunch of inflammation to the GI tract, for example. And that causes the release of a bunch of substances in the body, that's somewhat like setting off an alarm inside the body, and these substances induce a lot of inflammatory reaction.

(12:03) Donor cells then attack this inflammation and, because they don’t recognize the patient’s organs and tissues as something belonging in the body, they attack the patient’s organs and tissues as well. With all that happening, the immune cells from the graft start discover host tissue. By definition, the graft comes from another individual. This other individual, even if he's well matched, has an immune system that is designed to recognize the non-self.

So. what happens is that there is this tissue damage. There is this alarm going off. Then, all of a sudden, you have a bunch of these cells from the donor that discover that they are in a foreign body. So, the cells start recognizing the fact that they are not in the right place, that there is a lot of inflammation going on and they start doing what they are designed for. The immune cells are designed to fight the non-self, so they start to fight in many directions and with many strategies.

Ultimately, what becomes a problem is that they start over-fighting. And also, they start losing their own normal control and they lose some degree of education that should make them tolerate the situation. And what happens is that the more they fight, the more the tissue damage gets perpetuated. So, this is a general description of how graft-versus-host disease happen.

(13:34) Acute GVHD is a form of GVHD that is typically seen early after transplant. Now, we will discuss about acute and chronic graft-versus-host disease. I know that generally speaking, chronic graft-versus-host disease is generally what we see long-term and we'll discuss that a little more.

But acute graft-versus-host disease is the form of graft-versus-host disease that we see sooner, earlier. And what we normally describe as the mechanism for the acute graft-versus-host disease is first, the inflammation, as I mentioned before; second, the phase during which the donor immune cells recognize that they are not in their own body, they're not in their own environment; and next, there is the effector phase - the [donor] cells start fighting and they cause an attack to the tissue that looks like inflammation. Okay? So, there is an inflammation from the donor cells that attack the recipient.

 But eventually, things get more complicated. I always use the example of the immune cells from the donor being just like an army, a big army. Imagine the Army of the United States. There are so many different professions, there are people with many different jobs. And like the army, the immune cells do a lot of different things. Some are direct warriors. Some are in the background: they organize strategies or they make antibodies.

(15:07) Chronic GVHD typically occurs later after transplant and can last for a long time. So, chronic graft-versus-host disease has the same phases as acute GVHD: there is a damage, there is recognition of an enemy, and there is an attack. So, you see here in red a few key words: inflammation that come from the tissue damage and the cells that escape regulation. So, you have this army that doesn't follow commands, that starts going rogue and allows the inflammation to persist. And then, as we know well, if an inflammation perpetuates, the result is fibrosis. Fibrosis means basically, formation of scars, formation of changes that damage tissues. And also, there is a production of antibodies that can attack the body of the recipient.

(15:59) So, as I mentioned, there is this acute graft-versus-host disease, that really means an acute inflammation, so, a rapid redness. , A rapid change happens that wasn't there one day, and the next day, is present.

(16:15) Chronic graft-versus-host disease is something that happens more life-long and is progressive., So where the inflammation is more chronic, more slow-going, and it ends with the formation of scar tissue.

(16:31) Acute GVHD usually peaks within 100 days after transplant. When we look at the timing of transplant, so you see here, Day Zero moving in the future, we see that acute graft-versus-host disease, generally speaking, peaks by Day 100. Indeed, this acute inflammation can occur later on, but definitely we see the frequency of this acute kind of GVHD closing in one year. So it goes up, and [down] in one year.

As you know, post-transplant, there is the first 100 days, which are typically the days that one stays close to the bone marrow transplant center. That's when one would expect to see some acute graft-versus-host disease.

 (17:14) Chronic GVHD appears later and more gradually. The chronic graft-versus-host disease, being more of a complex phenomenon, takes a little bit longer. So, one may start to have something creeping up by Day 100, and eventually, it gets more and more of a problem when you move away from the day of transplant. And of course, there can be some degree of overlap between these two: acute and chronic graft-versus-host disease.

(17:41) Acute GVHD occurs in about 70% of patients and is severe in 10-15% of patients. Now, let's just analyze them separately. So, the acute graft-versus-host disease, I always mention to people, we have many percentages. So, the percentages I'm going to give you are general to give you a general idea.

So, I always say that about 70% of people get it. What I'm saying is that the number of people that don't get any GVHD, any acute GVHD at all, is really the minority. So, it's a common phenomenon. It happens, generally speaking, between two and six weeks after transplant. So, by the time the cells start coming up, it's fair game to start seeing some acute graft-versus-host disease.

Even though the majority of the patients get it, only 10 to 15% of the patients get the really severe, life-threatening form of acute graft-versus-host disease.

(18:40): Acute GVHD requires treatment quickly,  which may not work in 30-40% of cases. Acute GVHD that does not respond to treatment can result in early death after transplant. It's important to know that when we see somebody with acute graft-versus-host disease, we start treating it, even if the patient is already on immunosuppression. We add some more medication. And a certain proportion of people you treat won't respond to the treatment. So, the first treatment may not work in 30 to 40% of cases. And, indeed, acute graft-versus-host disease can be a leading cause of early mortality post-transplant.

(19:13) The risk of developing acute GVHD depends on characteristics of the donor cells as well as transplant treatment plan for a particular patient. Now, what are the risk factors? Of course, donor factors: the more there is a mismatch between a donor and the recipient, so there is more of a disparity between the two, the more the graft may attack the host, right?

(19:32) Another thing to know is that the older the donor, also the older the recipient, you can see more commonly the acute graft-versus-host disease.

(19:43) We have also certain factors that depend on the transplant itself. So, we know for example that peripheral blood, as the stem cell source, has a tendency to give more acute graft-versus-host disease compared to other stem cell sources [like bone marrow or cord blood]. But also, different ways in which the transplant is designed may really affect the chance of getting acute graft-versus-host disease. So, the risk factors can be connected to the donor or can be connected to the transplant design.

(20:16) Acute GVHD typically attacks the skin, the GI tract and the liver. Acute graft-versus-host disease typically attacks three organs: the skin, in the form of a quick skin rash that looks like the picture. It can also be just a little bit of redness, that we call erythema, all the way to blisters.

(20:36) The next organ commonly affected by the graft-versus-host disease when it's acute is the GI tract. Typically, historically, we always have measured the diarrhea. So, an inflammation of the lower GI, of the colon, that can cause diarrhea that is typically watery. But also, the acute graft-versus-host disease can affect the upper GI system causing nausea and vomiting. And another form that can be very severe affects the liver and shows up in the lab work.

(21:13) Chronic GVHD appears later and affects 30-70% of patients. Now, let's move to the chronic graft-versus-host disease. Chronic graft-versus-host disease, as I told you, may start creeping in around three months post-transplant and continue into the future. It is, indeed, the most serious, it's really the big deal post-transplant. It can occur in between 30% and 70% of people. So what I'm trying to say is, it is something that we really have to watch for because it's common.

(21:52) Chronic GVHD typically starts four-six months after transplant and affects three or more organs in 50% of patients who get it. Generally speaking, we see it coming four-to-six months post-transplant . In at least 50% of people that get chronic graft-versus-host disease, it affects three or more organs at the same time. Okay. So, it is a multi-system disease by definition, and the treatment can be long, can require at least two to three years of treatment. Other treatment may be prolonged, even life-long.

(22:22) The biggest risk factor for chronic GVHD is prior acute GVHD. Here, I want to point out that the number one risk factor to get chronic graft-versus-host disease is a previous history of severe acute graft-versus-host disease. In many ways, I always see the first hundred days, when I watch the patient very closely, as so critical because if we do our job well, and we are aggressive and careful in recognizing and treating the acute [GHVD], that has an impact life-long on the chronic graft-versus-host disease. The risk of chronic GVHD risk always remain, due to the disparity between the donor and recipient and also the certain transplant factors that might increase the chance of chronic graft-versus-host disease.

(23:16)  Chronic GVHD most often affects the skin, mouth, eyes and GI tract, but can affect other organs as well. The organs that are most typically involved are the skin, the mouth, the eyes and the GI tract. And then you see here, moving forward, the liver, joints, muscles, genital tract, esophagus, and so forth. So, it's really a multi-organ disorder.

(23:36) Chronic GVHD can cause changes in the skin, hair loss, an inability to sweat, changes in nail, and stiffness in the joints. Now, what you feel with chronic GVHD. So, we start with the skin. You can feel tightness of the skin, hardening of the skin, or the skin just looking different, scar-like, or sometimes seeing some spots on the skin.

(23:56) Changes to the sweat glands, like inability to sweat, loss of hair just like loss of changes to the nails.

(24:05) Next, stiffness in the joint or pain, for example, in the wrist and fingers and also other joints such as shoulders.

(24:14) Chronic GVHD can cause dry eyes and a sensitivity to light and wind.  The eyes. The chronic GVHD of the eye is really a progressive dryness, sensitivity to the environment, need for lubricant.

(24:24) Chronic GVHD can cause a  dry mouth, changes in taste, and sensitivity to acidic foods.The mouth very typically is involved, and just like the eyes, there is dryness. And also, taste alteration, sensitivity, pain with acidic stuff, when you eat some tomato, when you have something too salty or even the mint from the toothpaste can be a problem. Trouble sometimes swallowing.

(24:45) Chronic GVHD can cause breathing difficulties, and can also affect the genitals.  Lung involvement exists and is a problem. So trouble breathing, shortness of breath and chronic cough.

(24:55) Dryness of genitals, vaginal dryness, also tightening of the skin of the penis.

(25:02) And, also, unexplained weight loss.

(25:06) Chronic GVHD is a progressive fibrosis or inflammation. As you see, I'm mentioning on these last two slides, a bunch of different symptoms. They all deal with basically some degree of wasting of the individual that is not quite an inflammation; it is really a chronic, progressive fibrosis, a chronic, progressive inflammation. Nothing really acute, per se, but progressive and really life-altering.

(25:29) Description of pictures showing how chronic GVHD affects the various layers of the skin, the eyes and the mouth. So now, a few pictures. Chronic GVHD, when you think about it, I always think that there's a process that starts from the surface of the skin all the way through the layers of the skin and involving the layers around the muscles. So you see here some superficial changes on the top of the skin, right? And even in this picture, something a little more shiny, but going down in the next slide here, you see that not only the skin can be affected, but also the structures that are around, the membrane around the muscles themselves really tightening and reducing the range of motion.

(26:13) Eyes and mouth as I mentioned can be critically affected. And when the organ, the eyes, are affected it is not really the organ of sight that's affected, it's really all the structure that keep the eye lubricated. They are vital for the eyes, so you see red eye, a lot of dryness, a lot of weird loss of the eyelashes and a lot of vein in the conjunctiva. Here a few picture of the mouth and a picture of the nails that can be progressively damaged.

(26:52) When we think about graft-versus-host disease, once again, this is a multi-organ disease. In acute graft-versus-host disease, there is a triangle: GI symptoms, skin, and liver issues. These are really the trio, the three organs that are affected by the acute inflammation.

(27:14) Chronic GVHD is more complex than acute GVHD and can affect virtually all organs. Chronic graft-versus-host disease is more complex. The number of organs affected are almost innumerable. It can involve virtually all organs. There are certain organs that we are less certain, but that said, one can have many organs affected at the same time. So, as we say, there are many different ways and you may find out that there are no two individuals that have the same kind of chronic graft-versus-host disease. That makes it tough.

(27:47) Chronic GVHD can cause mild, moderate, or severe disability. The way we look at the chronic graft-versus-host disease and say it is bad or less bad, is really based on how much it causes disability, how much it makes people change their lifestyle. So, mild, moderate, severe disability is how we count them. And then of course, we have to make a judgment by assessing how many organs are involved at the same time. So, we discussed about graft-versus-host disease in the acute and the chronic form.

(28:23) Several transplant strategies seek to minimize GVHD. The way in which we design transplant continues to evolve, meaning that we are trying to use different forms of transplant and different transplant recipes, as I like to say, including treatment before infusing the cells and also treatment after you infuse the cells to avoid the graft-versus-host disease, doing what we call the graft-versus-host disease prophylaxis.

(28:53) So, we plan an immunosuppression. The schema that you see in this slide is the most common using two drugs: tacrolimus or cyclosporine plus methotrexate. This is somewhat of the classic backbone to reduce the graft-versus-host disease. But many changes. For example, using a serum, anti-T cells, anti-immune cells that we give to the recipient before giving the transplant because these antibodies stick around in the body of the recipient and they reduce the activity of the immune cells of the donor that can cause the graft-versus-host disease. So when we use these, we see there is less graft-versus-host disease.

(29:39) Next, there is another change that was really a genius introduction from the group at Johns Hopkins in Baltimore, which is using a dose of chemotherapy right after transplant that allow us to really control the proportion of the immune cells coming from the donor that will ultimately cause the graft-versus-host disease. So, the way that we think about it would be basically to take away these bad cells that can attack the recipient and allow less graft-versus-host disease. So, this has been a modification that's somewhat recent in the design of the transplant.

(30:26) Treatment for chronic GVHD should start early and may involve topical treatments for a single organ, or systemic treatment with steroids. Now, treatment: some of the principles. When I see graft-versus-host disease, the first thing that we have to think about is that we always have to consider that it is common, and we have to start treatment early and we should start it locally. So when graft-versus-host disease affects one organ, you should start thinking treating that organ first.

(30:52) For example, in case of skin, using some ointment or some creams or some gels and also get the specialist involved. Get dermatology right away. GI tract, get gastroenterology right away.

(31:08) Next, you need to know that the steroids, so the Prednisone, Solumedrol, they remain the mainstays still That's mainstay of systemic treatment. Systemic treatment means pills, means IV. So basically, when we see graft-versus-host disease, that's how we start treating it. Again, the response is not 100%. Sometimes, the response may be more on the order of the 50/50. But the response, when there is a response to steroid, has to occur fast. Okay?

(31:45) Now for chronic graft-versus-host disease, the course of steroid treatment may be longer, but again, we haven't proven that adding things to the steroid is necessarily better.

(31:57) The next thing that you need to know is that if the steroid doesn't work, it is always an issue. It makes our job more difficult and the life of the transplant recipient more difficult if the steroid doesn't work because we can add other treatments, but we will anticipate the course of the disease being longer and more difficult.

(32:28) So when I mentioned that you start early, you start local, it is because we have a ton of things that can be given to the single organ to mitigate, to take away, the inflammation. For example, topical steroid for the skin, treatment with lights, topical immunosuppressive drugs. Also, same thing for the eyes. For the lungs we can use a medication that one can inhale. Treatments that defend the liver from inflammation, the steroid that don't get absorbed but they just work through the gas. Same thing for the genital, urinary area. So, the idea is to use these resources, those topical treatment.

(33:15) The goal of GVHD treatment is to relieve the symptoms and avoid progression of the disease to sclerosis. Managing graft-versus-host disease has to have, as a goal, to relieve the symptoms and to avoid the progression to sclerosis. For example, if there is tightening when you have movement, we need to stop and reverse it, to get life back. This is what we need to do as transplanters: avoid chronic graft-versus-host disease, but when we see it, we have to relieve it and avoid progression. Again, the treatment of chronic GVHD is a long one and a number of patients need treatment long-term.

(33:53): Effective treatment often involves many professionals and support staff. The treatment of graft-versus-host disease requires many different professionals. You need subspecialists to treat the different organs. You need, for example, a gynecologist that knows about the involvement of GVHD in the vagina; or the dermatologist that knows how to treat [skin] GVHD; the ophthalmologist who is aware of the eye problem; and, of course, the dentist that knows how to GVHD can affect the mouth.

(34:25) You also need a lot of supportive staff. Key roles are physical therapy, occupational therapy and nutrition. These can never be underestimated. And also, certainly, psychosocial support for the patient and the caregiver. The transplant, when it's complicated by chronic graft-versus-host disease, is really a lot. And we need to acknowledge the amount of support that is necessary for the patient, but also for the caregiver.

(34:54) And we have to always focus on keeping people active. The more you keep people active, keep them busy, get them back to work, that's going to ultimately achieve our treatment goal for chronic graft-versus-host disease.

(35:13) Treatments for patients may differ for many reasons. For chronic graft-versus-host disease, again as I mentioned, when the steroids fail, there are a lot of different treatments. But again, there is no one [treatment] that is the treatment of choice. And so, you'll see that when you talk to other people and they have chronic graft-versus-host disease, it's possible that people are being treated in different ways. And sometimes, the type of treatment that the physician chooses may be based on the logistics, the cost, the availability of an agent for a clinical trial or how easy it is to get a medication from insurance or whatnot, because there is not really one treatment that is, per se, the optimal choice.

(35:58) Sorry this slide is complicated, but I want to just introduce this concept, the fact that for us, when we manage graft-versus-host disease, we really go back to the biology of the disease and we think about, "What is the mechanism that we can stop to make the disease go away?" And this is how, over time, we have been trying different medications to fight the graft-versus-host disease and in particular, in the chronic form.

(36:26) New medications for GVHD have recently become available. So here, I show you a few medications here, there are three medications that are newly introduced. And this is a very exciting time to fight graft-versus-host disease because, for the first time, we have medications that are approved by the FDA to treat these diseases. Believe it or not, for both acute and chronic graft-versus-host disease, up until 2017, there was not one FDA-approved medication. So, we were all using medication based on kind of a grandfathered treatment. But there was never really an FDA directive on to what to use.

(37:07) Now, these are a few medications – ibrutinib [Imbruvica], Jakafi - those are medications that may be known to people, but here, the idea is that they have been introduced and are now [FDA] approved because they can really give good success, a good chance to treat patients that don't respond to steroids. And the success is being compared in certain studies to best available treatment. So, we know that these medications work. And at least in the first two lines, Ibrutinib and Jakafi are approved for the treatment of chronic or acute graft-versus-host disease that fails steroid treatment.

(37:49) Most recently, there was a very exciting trial of Jakafi [ruxolitinib] in patients that had very bad chronic graft-versus-host disease and it was compared to best available therapy. And the response to ruxolitinib [Jakafi] was twice as good as the best available treatment.

(38:08) Ultimately, I just want to mention a medication - we participated in this trial - called belumosudil, that is really an exciting medication in this field because it has an anti-inflammatory, immunomodulatory capacity but also has an anti-fibrosis effect. And there is discussion at this point on whether this will become available to the larger population and be available to prescribe.

(38:39) Treating GVHD poses several challenges and can have a life-long impact on quality of life. So, the challenges of graft-versus-host disease: the graft-versus-host disease can be acute, can be chronic. It is a multi-organ disease. Sometimes, it is difficult to diagnose because it may not look like anything but eventually, it becomes... it shows itself. And if you want to treat it early, you really have to look for clues.

(39:03) The next thing is that it is different from one person to another person, and the treatment cannot be the same for all patients.

(39:12) We require many kinds of different specialists to help. When you start treating somebody, you do not know who will respond to steroids or not. There is a lot of activity on checking lab work. We call biomarkers. So, lab tests that you can get from the lab to have the idea who's going to respond, who's not. At this point, we don't know. So sometimes, we treat everybody with steroids first, but we will not know who's going to respond or not.

(39:44) Again, the first line treatments are inefficient because for a treatment that is efficient, you would expect an almost uniform response. This is not what we see in graft-versus-host disease. So, this is a challenging type of disease.

(40:00) The treatment is, per se, toxic. As you guys know, giving steroids long term is bad because it causes diabetes. It's bad for the bones. And it's bad for the immune system.

(40:14) People needing treatment for GVHD are more likely to get infections, and the treatment might be life-long. And indeed, the big challenge of GVHD is that it can be a disease post-transplant that can have a life-long impact on the quality of life, return to family life, altering and changing relationships, and changing the capacity to provide for the family, to work.

(40:43) There are positive prospects for and medications for treating GVHD more effectively in the near future. That said, I don't want to end on a bad note. I want to be positive because we have a lot of things that are happening. We are understanding this disease, the complexity of this disease better and better. We are improving the recipe for transplant to reduce the chance of graft-versus-host disease and we really see that change, a progressive, slow improvement.

(41:14) As I mentioned before, we have some work on biomarkers that is going to help us in the future treat this disease correctly and early. And we finally have new medications. For many decades we were without any new drugs. Now finally, we are seeing new agents and more active agents coming on the horizon. There are more and more clinical trials in this space. And ultimately, we are improving the culture of how we treat GVHD. We are understanding that we need long-term follow up teams, that we need to have to have a good group of subspecialists helping, including a nutritionist and an expert in supporting our patients.

(41:59) So ultimately, this was my last slide. I thank you very much for your attention and again, I just want to... I'm really thankful for the BMT InfoNet for allowing me to speak to you today. With this, if you have any questions for me?

Question and Answer Session

(42:18) [Sachit Patel] Q & A. Thank you so much. This is Dr. Patel again. And that was a wonderful, comprehensive talk on GVHD, really well put together. And on two fronts: I think it was great in the sense that it was comprehensive, understandable to the patient, but also as we know, our patients are very, very intelligent and they understand many aspects of GVHD and I really commend you, Dr. Rotta, for diving into some of the detail as well in this.

(42:51)  So we have a number of questions, which is a testament to the topic. First off, there are over 180 participants, 187 participants logged in at the moment. So, there are a lot of questions and I'll try to get to as many as I can. I think some of them have been answered quite well such as the symptoms of GVHD.

(43:16): One question is, "On average, how long after transplant does GVHD last?" And I think you sort of touched on that, but...

(43:26) [Marcello Rotta] Yes. So as I mentioned, chronic GVHD can be a coming and going issue. So, it can be a life-long issue. What we know is that the treatment is reported as lasting two years as a median time, but there is a proportion of patient, about 15% of patient that need treatment for GVHD past seven years. So, we're talking about long-term treatment.

(43:54) [Sachit Patel] Wonderful. One of the questions is, you touched on this as well a little bit, but non-medical treatment such as diet, exercise of course you mentioned, but stress reduction or lifestyle changes? Can you speak a little bit to the importance of non-medical interventions?

(44:16) [Marcello Rotta] Yeah. The non-medical interventions have a huge impact on the management of this chronic disease. So, with activity and nutrition are key. I see those as a necessary support. Without those, you wouldn't really... the value that we put on the medication would be nothing in proportion.

(44:48) Nutrition, for example, is key. And maintaining an active life would definitely help would maintain the range of movement and help achieve a better quality of life. We are talking about a disease that patients may suffer from, potentially, the rest of their life. So, all those non-medical methods are absolutely necessary and should be promoted.

(45:36) [Sachit Patel] Excellent. I think there are several questions about maybe some of the more common side effects seen with those newer agents like Jakafi or excuse me, ruxolitinib and ibrutinib, maybe some of the common things that people can experience?

(46:05) [Marcello Rotta] So I would say, generally speaking, ibrutinib, for instance, has some known side effects including tendency of bleeding, some bruising as well as a tendency to get atrial fibrillation, so heart arrhythmia. There is something about Ibrutinib in chronic graft-versus-host disease where there are a few side effects that have been considered problematic like, for example, a low rate of pneumonitis that can occur with the ibrutinib. So it is a medication that is effective, but one has to closely watch for the adverse event, the side effects.

(46:47) As far as Jakafi or ruxolitinib, the most typical side effect is lowering [blood] counts, causing some degree of anemia, causing some degree of low platelets. And so, at that point, one may just kind of make it work by reducing the dose. But generally speaking, ruxolitinib with the experience that we have, is considered to be a very safe drug.

(47:16) [Sachit Patel] Wonderful. Wonderful. I know I'm jumping around on topics a little bit, but I'm trying to ask questions that have been asked multiple times to sort of get the most response here. So this is a two part and answers a handful of questions. It's in relation to donor selection. And one question is, "Why are all siblings not matches to each other?" So, if you have a brother, why is he not a match all the time?

(47:50)  And the other is sort of a commentary on, "How does GVHD relate to sex matching?" So, female to female, male to male. I imagine the question relates to perhaps female donors is the main question there. So, why are not all siblings the same? And, why are some male and female donors preferred over others?

(48:20) [Marcello Rotta] So, the genes to make the match basically come from mom and dad. So, the distribution that we call haplotype is differentiating among different siblings, among different brothers and sisters.

So, what happen is that, at any given time, when you have a brother or sister, the chance to be a match to your brother or sister is about 25%, 25 to 30%. So, if you think about it, the chance is not very high. So, for each sibling that you try to match, you kind of roll the dice. You have a 30%, 25, 30% chance of matching. And that's just because of this gene distribution.

(49:06) On the other hand, as far as the sex mismatch, so donor female for a recipient who's a male, et cetera, we still anticipate that there is a certain degree of mismatching. For, for example, if the donor is a female, the female immune system will recognize these antigens that comes from a male environment. And so, to some degree, that can have some effect on graft-versus-host disease.

But most of all, what we think about when the donor is a female, is whether the woman who's donating had many children. Because a donor who had many pregnancies over time had other people in her belly, so she mounted an immune system against tissues of another individual. So, a female that has had many children, for example, can have more of a tendency to cause graft-versus-host disease in the recipient. So, we are always looking at that mismatch and if the donor who is a female, we try to figure out whether they had pregnancies.

(50:17) [Sachit Patel] Wonderful. Another question that's in there is, "How is GVHD affected by other autoimmune diseases that I may have?" I imagine this is related if I have thyroid disease or diabetes or other rheumatologic diseases, can that exacerbate GVHD or what is the relationship there?

(50:42) [Marcello Rotta] So, there isn't a direct relationship that I can mention. I don't know if you, Dr. Patel, have any other experience per se. We would anticipate that sometimes, in the context of the transplant, we see certain autoimmune conditions, autoimmune diseases, that get better. And sometimes, they get better because the transplant, itself, provides a blanket of immunosuppression that takes away the immune conditions. And sometimes, those immune conditions reappear later on when the immunosuppression goes away. But I do not believe, I'm not aware that the presence of an autoimmune, for example, a thyroid problem, would make a recipient more likely to get graft-versus-host disease.

(51:35) [Sachit Patel] Yes, absolutely. I would agree. When your graft is returning, or your immune system is trying to return, there are certain things that can be triggered and certain things that can happen such as, we have this entity called, autoimmune cytopenias.

(51:54) And it's, as your immune system is learning to recognize the recipient or learning to recognize the right things from the wrong things, it makes the wrong judgment. So, as your immune system is reconstituting or coming back, it can do things in the wrong way. And those things can manifest as and look very similar to more common diseases. And that's kind of the concept of, when you have a thyroid disease potentially, or a drop in counts or joint problems, it's an inappropriate immune reaction. And so, it's very similar. It's a really good question to ask and a really similar mechanism.

(52:45) So, the one thing that you may know or not, Marcello, is, when you do think belumosudil will become available? This may be something you can't answer in this venue, but I'll at least see. When do you think these new drugs will become available to patients?

(53:08) [Marcello Rotta] I can tell you that I was involved in the trial and I am still in the dark. We had hopes for this medication to be available in the year 2021, but I don't know yet. It's a medication that we have seen working in trials, so we are really looking forward to see what's going to happen to it. Yeah. I don't know yet.

(53:39) [Sachit Patel] Yeah. I figured. And that's an interesting question. And that's the crux of the question that we get from patients all the time.

(53:47) And as a physician and provider, we are not always privy to that information and it's frustrating on our end too because we're dangled these fruits of promise and we never quite know when we can get that to the people on the ground.

(54:05) We have limited time left here, I think about four minutes remaining in the session. So, I'm going to try to tackle... I think you already mentioned, "Is there relief from chronic GVHD after 30 or more years?" And there's another question that says, "How long can GVHD last? Can it last a lifetime?"

(54:28) [Marcello Rotta] Yeah. The comment is that, generally speaking, we all have direct experience of individuals, many decades after transplant, living a normal life and basically not being affected by GVHD at all. We also have some experience of patients 10, 15 years post-transplant, they're still on immunosuppression and they are still affected and they have to come to the clinic fairly often. So, there are situations where GVHD can last almost a lifetime or can have an effect on duration of life. When see patients that are off immunosuppression for many decades, we are realizing there a tolerance where the GVHD is really subclinical. So if there is anything, it's not really something that bother people.

(55:21) Sometimes though, GVHD though can be provoked and there can be some flaring of GVHD. So, people that were just fine can have some recurrence of GVHD. Sometimes, the trigger is a viral infection or something not really clear. Prolonged sun exposures can sometime trigger some GVHD in somebody off immunosuppression. So, it is always something to watch after transplant, even life- long.

(55:58) [Sachit Patel] Great. Great. I think we have maybe time for one more question and I'm sorry. I'm going to try to stay on and answer some of the questions in the chat. But, let's see. Perhaps talking a little bit about things that can be done for corneal involvement or eye involvement. What sort of specific experience do you have with treatment for this problem?

(56:28) [Marcello Rotta] Yeah. Our specific experience is to have, along with a long-term follow up group, a specialist, an eye doctor who is a specialist for cornea disorders who is very well-versed in examining the eyelashes and structures such as the tear ducts. There are many combinations including using a topical steroid, an anti-inflammatory of course, lubricant and topical immunosuppression. But also, the consideration, sooner rather than later, of using things such as scleral lenses, because ultimately, the name of the game is to protect the cornea from getting too dry or too damaged. So, I would say the main thing about that is to have available to the center an ophthalmologist who is well-versed in those issues. Yeah.

(57:35) [Sachit Patel] Well, thank you. I'm really sorry I have to cut things short. There are so many good questions and I'm going to try to answer those and see if I can answer those after they're completed here. But again, thank you so much, Dr. Marcello Rotta, for joining us this afternoon, and all of the recipients, a true testament to the topic, having over 180 people tuned in around the country is quite remarkable. So, thank you.

(58:01) Marcello Rotta] Thank you so much. Thank you for your attention. Once again, thank you for the organizer.

(58:13) [Sachit Patel] Okay. I think that will conclude the session. Thank you.