Advances in GVHD Treatments and Clinical Trials

Edited by:
Katrina Villareal

Graft-versus-host disease is a potentially life-threatening condition affecting an estimated 50% of blood cancer patients who receive stem cell transplants from a donor. Transplant experts explain GVHD risks, how to watch for symptoms, the current treatments available, and new clinical trials aimed at prevention and treatment.

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Advances in GVHD Treatments and Clinical Trials

Hosted by The Patient Story

Graft-versus-host disease is a potentially life-threatening condition affecting an estimated 50% of blood cancer patients who receive stem cell transplants from a donor.

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Patient advocate and GVHD Alliance co-founder Meredith Cowden shares her experiences with GVHD. Experts from UChicago Medicine, Roswell Park Comprehensive Cancer Center, and The Leukemia & Lymphoma Society who are on the front lines of GVHD research and treatment discuss the role clinical trials play in advancing the treatment landscape and what it could mean for you. Discover how to take steps to learn more about clinical trials from a clinical trial nurse navigator.

This program is brought to you by The Patient Story in partnership with The Leukemia & Lymphoma Society.

Introduction

Stephanie Chuang, The Patient Story

Stephanie Chuang: I’m a blood cancer survivor myself and started The Patient Story out of my own experience. I felt so alone. I wanted to know what it meant after diagnosis and how we could get through it. As we know, a diagnosis is just the beginning of figuring things out. Our goal at The Patient Story is to help patients and care partners navigate life after a cancer diagnosis, primarily through in-depth conversations with patients, care partners, and top cancer specialists.

We are so proud to partner with The Leukemia & Lymphoma Society, the largest nonprofit dedicated to creating a world without blood cancers. For decades, they have invested almost $2 billion in groundbreaking research and pioneering so many approaches. On top of that, they also support patients and families with programs like the Clinical Trial Support Center, which provides free one-on-one support with nurse navigators.

This program is not meant to be a substitute for medical advice, although we hope that you walk away feeling like you have more to ask your own medical team.

Satyajit Kosuri, MD

Stephanie: Dr. Satyajit Kosuri is a hematologist-oncologist with the University of Chicago Medicine. He is an expert in stem cell transplantation and leads the Graft-Versus-Host-Disease Clinic and the research in trying to improve patient access to transplants. Dr. Kosuri, what drew you to this field of medicine and specifically GVHD?

Dr. Satyajit Kosuri: When I started my oncology fellowship, I was going to be a genitourinary oncologist and I was very much set. When I did my transplant rotation, what drew me was that it spanned all fields of medicine, so you had to continue to have a pretty good breadth of knowledge. The immunology was very, very intriguing. We’re dealing with very complex diseases as well as the transplant itself, which is basically an immune system transplant.

When I tell patients, family members, fellows, and trainees about the field of transplant, I tell them, number one, I’m an immunologist, number two, I become an infectious disease doctor, and then, number three, oncology comes in as part of the triad. That’s what drew me to the field and what I find very interesting. Graft-versus-host disease is part of the entire picture that we’re trying to improve upon within the context of transplant.

Shernan Holtan, MD

Stephanie: Dr. Shernan Holtan is a hematologist-oncologist with Roswell Park Comprehensive Cancer Center in Buffalo, New York. She is the chief of the Blood and Marrow Transplantation and has led so many clinical trials in GVHD. Her research has led to the discovery of the amphiregulin (AREG) biomarker for monitoring graft-versus-host-disease. Dr. Holtan, what drew you to medicine and specifically focus on graft-versus-host disease?

Dr. Shernan Holtan: My story is a lot like Dr. Kosuri’s. In medical school, I was most interested in rheumatology, infectious disease, cancer medicine, critical care medicine, dermatology, and plastic surgery. I thought, How am I ever going to pick between these different specialties? I loved cancer reconstruction and the connection with patients going through cancer and giving them hope after a devastating diagnosis.

On a whim, I took a rotation on the BMT service, in part because it sounded cool. The other part of it is you didn’t have to work weekends and as a very tired fourth year med student, I was excited about that. I was stunned. It was every great aspect of medicine rolled in one specialty, so I was sold and never looked back.

Meredith Cowden, Patient Advocate

Stephanie: Meredith Cowden is a chronic GVHD patient advocate and co-founder of the GVHD Alliance. Why did you decide to dedicate your life to advocating for so many other people with GVHD?

Meredith Cowden: I had acute myelogenous leukemia (AML) at 19. Chemotherapy wouldn’t completely work, so I needed a bone marrow transplant. Shortly after, I developed acute graft-versus-host disease and then I developed chronic graft-versus-host disease, which I’ve had since April 2002.

Graft-versus-host disease is rare and we’re spread out all over the place, so it’s isolating and hard to find resources, information, and even the appropriate treatment team.

I originally wasn’t into the patient advocacy world. I didn’t want to deal with it anymore, but I didn’t want anyone else to have to deal with it. I got angry and frustrated, and frustration is one of the greatest motivators for me. When I would talk to other patients, there was a sense of relief and comfort they felt in talking with somebody who could understand their experience. From that point, I thought that this is where I need to be.

Ashley Giacobbi, Clinical Trial Nurse Navigator

Stephanie: Ashley Giacobbi is a clinical trial nurse navigator with The Leukemia & Lymphoma Society. Can you describe the work that you do with the Clinical Trial Support Center?

Ashley Giacobbi: I am a nurse navigator with The Leukemia & Lymphoma Society’s Clinical Trial Support Center. We provide individualized clinical trial searches and clinical trial resources to patients with blood cancers or patients who have had blood cancer in the past but may be managing long-term effects of their disease or treatment.

We provide one-on-one connection with patients, caregivers, and their healthcare providers. We take the time to learn about a patient’s diagnosis, past treatment, and other medical conditions that could play a role in their eligibility for clinical trials. Most importantly, we take the time to learn about patient and caregiver preferences and any unique obstacles that may hinder or support their participation in a clinical trial, so that we can target the support that we’re able to offer and give personalized resources.

When immune systems grow suspicious, they’re programmed to do one thing and that is to attack. This new immune system can attack the recipient from the inside.

Dr. Satyajit Kosuri

Understanding Graft-Versus-Host Disease (GVHD)

Stephanie: Dr. Kosuri, what is GVHD?

Dr. Kosuri: When we’re doing a stem cell transplant or bone marrow transplant, we’re doing an immune system transplant. When we’re healthy, the immune system protects us, whether it’s getting rid of bad cells or protecting us from various infections. It considers the body that it’s growing up in as its neighborhood, so it has an inherent desire to protect its neighborhood and recognizes the body that it’s in as being part of itself. When there are things that are not supposed to be there, it recognizes them and gets rid of them.

We’re taking the stem cells from a person with a healthy immune system and putting them into the transplant recipient, so this immune system is growing inside of a new neighborhood. For the most part — and this is where matching comes into play — it recognizes its new neighborhood as its own and leaves it alone. It takes up the mantle of, “I’m going to protect this body and eradicate any leukemia cells,” and that’s the graft-versus-leukemia effect.

But sometimes, there are parts of the new neighborhood that are not what it’s used to, so it starts to grow a little bit suspicious. When immune systems grow suspicious, they’re programmed to do one thing and that is to attack. This new immune system can attack the recipient from the inside, which can lead to some inflammatory physical damage to the patient or the recipient of the stem cell transplant.

Types of GVHD

Stephanie: Dr. Holtan, what are the main types of GVHD? How do they differ and what are some of the common symptoms?

Dr. Holtan: We mainly think of graft-versus-host disease in two phase although there can be some overlap between the two.

Acute graft-versus-host disease happens within weeks to the first few months post-transplant and that has a particular pattern. Most of the time, it’s a red skin rash, but sometimes it can also lead to nausea, vomiting, diarrhea, and liver abnormalities that we might see on blood tests. There’s a very clear time during which this develops and a pretty clear clinical presentation, so it’s pretty easy to determine what it is.

Chronic graft-versus-host disease typically happens later in the months to years after transplant. It can be more subtle and difficult to diagnose. As Dr. Kosuri was saying, this is primarily an inflammatory reaction at the beginning, which ultimately will gradually lead to scar tissue.

Think of a wound that is having some difficulty healing. There’s a lot of inflammation and the body tries to stop that inflammation by putting a scar on top of it. This can happen in almost any organ in the body. Usually, the skin is involved, but it can also cause dry eyes, dry mouth, mouth sores, difficulty breathing, difficulty swallowing, changes with the muscle tissue fascia, and making people feel stiff and have muscle cramps. Any organ can be involved with chronic graft-versus-host disease.

Even though we think about chronic manifestations as a later problem after transplant, we can see some of those changes even within the first few weeks.

Dr. Shernan Holtan

Stephanie: Dr. Holtan, when does it technically turn from acute to chronic? Is there an official time where now we know it’s chronic? Is there a general time frame?

Dr. Holtan: There isn’t an official rule. When Dr. Kosuri and I were in training, we were taught that acute graft-versus-host disease happens before Day 100 and chronic GVHD happens after Day 100, but that’s not really true. The biologic processes can happen at any time post-transplant. Acute GVHD usually happens in the first few weeks to months, but we have even seen acute manifestations of GVHD happen much later.

Even though we think about chronic manifestations as a later problem after transplant, we can see some of those changes even within the first few weeks. The lines are blurred now, so we describe graft-versus-host disease based on its symptoms and appearance rather than time frame post-transplant.

It took a while before my doctors said I had GVHD because they were thinking it was something else. Over the years, I’ve had a variety of different manifestations of chronic GVHD.

Meredith Cowden

Meredith’s GVHD Story

Stephanie: Meredith, what was it for you in terms of those first symptoms? At what point did you realize that this was not going away?

Meredith: In the beginning, I noticed that I had a couple of different things going on at the same time. My stomach started to bother me a lot and I got very nauseous. It was hard to find food that I could tolerate and that was appetizing. I had some gastrointestinal issues going on. I also developed a rash. I’m naturally a pasty pink person, but my skin got red and burned, so it was hard to wear clothing.

When I received treatment, the issues started to get resolved, but then it started to transition. The GI issues didn’t necessarily go away but they changed and my skin got a little bit different.

I had musculoskeletal involvement. I developed polymyositis, so there was a lot of pain. I was very weak and couldn’t move around a lot. I lost muscle mass. It took a while before my doctors said I had GVHD because they were thinking it was something else. Over the years, I’ve had a variety of different manifestations of chronic GVHD.

Dr. Kosuri: Chronic graft-versus-host disease can affect multiple sites in a way that may be difficult to initially pick up. I’ve gotten feedback from patients that what they’ve found helpful is when I describe chronic GVHD prior to the transplant.

I ask them to imagine taking all the autoimmune conditions and rolling them into one and putting them inside a human body. Those are ways that chronic GVHD can manifest, whether it’s dry eyes, a scleroderma type presentation, or pulmonary fibrosis. It’s a great mimicker.

Stephanie: It sounds like it might be hard to identify quickly if people aren’t speaking up too and share the different things that you’re experiencing and communicating openly with your doctor.

There are many different types of complications, but infection comes to the forefront.

Dr. Satyajit Kosuri

Severe Complications in GVHD

Stephanie: I don’t know if there’s difficulty in noticing what the severe complications are, but, Dr. Kosuri, are there any that you’d like to highlight?

Dr. Kosuri: There are complications of the entity itself and then there are complications that will arise from the treatment or the way we try to treat the disease. GVHD in and of itself is an immune dysregulation. The immune system that’s supposed to behave in a certain way is misbehaving or it might be turned on and can’t really control itself. What happens in this state?

There are many different types of complications, but infection comes to the forefront. We prioritize monitoring patients who have graft-versus-host disease not only from the GVHD itself but also from the medications that we use to try to quell the inflammation and calm things down. Both can lead down the pathway of bringing down the level of protection that the human body has as it’s starting or trying to recover from the stem cell transplant.

One of the things that we emphasize for patients is if they’re feeling unwell in any way, shape, or form, they have to let their transplant providers know very quickly. That way, whatever suspicion we may have, we can diagnose and take care of it very quickly. If it’s a small infection, we can treat it and it doesn’t become a big infection.

Be very proactive and very compliant with the medications. Patients take 20 different medications after a transplant and sometimes it’s hard to take all of them, especially when the pills are big. We hear that as one of the main complaints. We make sure that patients are on antiviral medications, antifungal medications, and a medication to protect them from PJP (pneumocystis jiroveci) pneumonia. These help protect and almost substitute in a way because the immune system is not online early on and when you have graft-versus-host disease, it’s not behaving the way that it’s supposed to.

Dr. Holtan: We certainly know that graft-versus-host disease can affect different organs and tissues, and that the treatment can have just as many toxicities as GVHD itself. Some of the most challenging issues we run into are malnutrition, straight-up difficulty eating, all the way to impaired organ function.

What Dr. Kosuri mentioned is key about notifying for changes in symptoms with chronic graft-versus-host disease. You want to intervene before there’s permanent damage. The longer the inflammation and scar tissue goes, the more difficult it is or it might even become impossible to reverse. Early intervention is necessary to try to avoid permanent damage.

If there’s anything that seems even a little bit wacky, ask. There’s no harm in asking. It’s one of the best ways to take care of yourself.

Meredith Cowden

Stephanie: From your own patient experience, did you know that you could bring these up to your doctor? Do you feel that patients you talk to know that they can do that? What do we need to do to make sure that this is happening?

Meredith: I was diagnosed at 19. I was young and there were things I learned over the years. This might sound naive and silly, but there were things that I thought were completely normal but were actually symptoms of GVHD.

Over time, I’ve developed strong relationships with each member of my care team, so I’m very comfortable saying, “This feels weird. I don’t know about this. Can you look at that? Check me out please.” To have that kind of conversation, you have to build that relationship so that everyone is comfortable and can have a discussion with one another even when they have differing opinions. You can get more out of that conversation than if a typical patient-doctor exchange. Oftentimes, things get missed that way.

For patients, treat your doctors like people. Be friends with them. You’re going to be with them for a long time. They want to help you. If there’s anything that seems even a little bit wacky, ask. There’s no harm in asking. It’s one of the best ways to take care of yourself. For the providers, it’s a good idea to ask patients to do a quick scan of their body to get the whole picture because it’s easy to forget stuff. Is there anything that’s going on that we haven’t touched on that you noticed?

The backbone of therapy for both acute and chronic GVHD is corticosteroids.

Dr. Satyajit Kosuri

Current GVHD Treatments

Stephanie: Dr. Kosuri, what are the current standard treatments for GVHD?

Dr. Kosuri: The keyword is current because this is something that’s changing and we hope will continue to change as we go through the years.

The backbone of therapy for both acute and chronic GVHD is corticosteroids. Many patients and their family members will have heard of the medication called prednisone or various types of the steroid.

The degree of the GVHD matters. If you have a mild, acute graft-versus-host disease, this could be potentially managed with topical corticosteroid. As it becomes more severe or involves more organ systems or more of the skin, we start graduating from topical steroids to systemic steroids.

Depending on where we are in the transplant process, our patients will already have been on another immunosuppressive agent, like tacrolimus, sirolimus, or cyclosporine. The goal is to treat with steroids plus or minus this other agent and then taper them off once we have a response.

With steroids, over a period of time, you can accumulate some of those side effects that we don’t like to see in patients, like insomnia, jitteriness, and fluid retention. Those are for people who are in the category of steroid-responsive.

Another category of patients are those who are steroid-refractory, which is where the graft-versus-host disease may be a little bit more sticky and not respond to steroids, or steroid-dependent, where patients are unable to get off steroids. In those cases, we go further down on immune suppression choices. There are other medications available. One that’s FDA-approved and works for both is ruxolitinib. There are also other various options. That becomes more of a longer term treatment.

There isn’t a blood test that can diagnose graft-versus-host disease right now, but we can use biomarkers to help us understand the severity of the immunologic reaction and how much damage has been done.

Dr. Shernan Holtan

Challenges of Existing Options for Managing GVHD

Stephanie: Dr. Holtan, what are some of the key limitations or challenges with the existing options for managing GVHD?

Dr. Holtan: The greatest challenge is understanding how much therapy to give for graft-versus-host disease. We base our treatment upon the severity of symptoms, but that isn’t adequate. There are still some patients that we are over-treating and some patients we are under-treating.

This is where the role of biomarkers can come in. There isn’t a blood test that can diagnose graft-versus-host disease right now, but we can use biomarkers to help us understand the severity of the immunologic reaction and how much damage has been done internally that we can’t detect clinically. This is a huge challenge because even though we examine patients fully and they reveal all their symptoms, we still can’t know how bad things are, so biomarkers can support us in helping to guide that therapy.

This is particularly under investigation right now using biomarkers such as ST2 (suppressor of tumorigenesis 2), REG3α (regenerating islet-derived 3-alpha) known as the MAGIC (Mount Sinai Acute GVHD International Consortium) biomarkers, and then the one that we developed at the University of Minnesota, amphiregulin or AREG. Both of these biomarkers can be used to understand how severe the graft-versus-host disease is.

I have patients who have had severe infections of the GI tract, like C. difficile colitis or viral gastroenteritis such as adenovirus gastroenteritis. An allogeneic transplant recipient might have these infections and we’ll treat the infections, but they’ll have persistent severe diarrhea so you won’t know if you’re still dealing with the infectious process and the healing that has to occur or if graft-versus-host disease developed as a result of the immune system trying to target the infections. Even a biopsy can’t always tell you this, but we can use biomarkers, especially amphiregulin, to help sort this out.

When we’re treating patients with these symptoms, it’s almost like it’s graft-versus-host disease until proven otherwise.

Dr. Satyajit Kosuri

I had a gentleman who had severe adenovirus gastroenteritis and was having 15 to 20 bowel movements a day. We used an amphiregulin test to know if this could be graft-versus-host disease. The result was normal. It was not elevated. I continued to check every week because his gastroenteritis went on for a long time, even though we treated it.

Clinically, he had weeks of diarrhea, but we followed that test every week and the number was always low, so we never gave him prednisone. If I didn’t have this reassurance, someone might say it’s GVHD. It took some time, but he made a full recovery. This is how we can use these biomarkers to help support our clinical decision-making. We need more trials along these lines because the real world is messy.

Dr. Kosuri: I can’t emphasize how important what Dr. Halton is mentioning because oftentimes in transplant medicine, we’re operating in the gray and we have to make guesses. Sometimes when we’re treating patients with these symptoms, it’s almost like it’s graft-versus-host disease until proven otherwise. When you have that type of thought process, it can be difficult and we can actually hurt the patient with the GVHD management in and of itself.

The example that Dr. Holtan mentioned, most transplant physicians would say, “This has to be GVHD and we have to give them prednisone,” and that could lead to other infections or it can worsen the infection the patient already has. We get into these situations that are difficult to manage and if we have something like these biomarkers, it can make our lives as well as the patient’s life much easier and with less toxicity than what we would say is the normal kind of approach.

We had no human data to support how we manage steroid-refractory GVHD. Out of decades worth of work, there were no studies.

Dr. Shernan Holtan

Stephanie: A lot of this is addressing the symptoms that come with GVHD. This may be a rookie question, but I’m trying to understand. Is there research going into how to address the drivers of what’s happening with GVHD?

Dr. Holtan: We know what causes graft-versus-host disease. The donor T cells are attacking tissues and organs. However, we can’t always tell when that attack is over. The whole field of steroid-refractory graft-versus-host disease has developed out of an assumption that the T cell-mediated attack is still happening, so all trials for steroid-refractory GVHD involve intensification of immunosuppression without actual knowledge that there are T cells still causing damage.

This was something that bothered me. These are things that drive you crazy about the field and want to change it. I realized that we had no human data to support how we manage steroid-refractory GVHD. Out of decades worth of work, there were no studies that justified that this is the right path.

I performed a study where we had rectal biopsies of patients with grades 3 to 4 gastrointestinal GVHD. They were steroid-refractory and received other therapy. I wanted to look at the biopsies for a sign that it was the donor immune system still doing the damage to prove what we’re doing is right and I found absolutely no evidence to support our practices. There was no increase in T cell infiltration. There was no immune signature at all that suggested that it was out of control T cell-mediated damage in the steroid-refractory patients. All we saw were signs of tissue damage.

I’m hoping that the field will evolve. Instead of intensifying immunosuppression, give something more immunomodulatory, support immune tolerance, and give something to help heal the damaged organ. Change the paradigm. That was a huge frustration that I had as a fellow and I hope more people read that paper now.

Clinical Trials for GVHD

Stephanie: We’ve talked about the current landscape of GVHD and treatments, and some gaps of need. Before we go into them, what are clinical trials?

Ashley: Clinical trials are carefully controlled research studies that may be conducted by scientists, doctors, or researchers to either test new treatments or test treatments that have been used in the past in a potentially different way. Trials can also compare new treatments to existing treatments or to various combinations of treatments to find out which treatment might work best or which would be better tolerated, all with the goal of improving care and treatment for patients.