Navigating Graft-versus-Host Disease: What You Need to Know

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[00:00] Dr. Holtan: Hi, everyone. I am Shernan Holtan.  I'm the Chief of Blood Marrow Transplant at Roswell Park Comprehensive Cancer Center. I'm going to the slide tab here to make sure everything is okay, and we're all set to go.

[00:14] Moderator: Thank you for joining us, Dr. Holtan. Before we begin your slides, I just want to thank our corporate sponsors for making this workshop possible. They are Incyte and Sanofi, and we are so grateful for their support.

Dr. Holtan is the Chief of Blood and Marrow Transplantation and the Professor of Oncology and Medicine at the Roswell Park Comprehensive Cancer Center.

She specializes in blood and marrow transplantation and cellular therapies, including CAR T-cell therapy for patients with leukemia, lymphoma, myeloma, and other blood disorders. Dr. Holtan's research focuses on improving the safety and effectiveness of stem cell transplantation using donor cells, which are called allogeneic transplants, by reducing the treatment-related toxicity and preventing GVHD.

Please all join me in welcoming Dr. Holtan. 

[01:14] Dr. Holtan: Thank you so much for the introduction. I wish I could see you all in person, but I think it's so great that so many could be on this call, and we have such a wide reach. I think that is absolutely wonderful.

It's my pleasure to talk about navigating GVHD today. We'll boil it down to the essentials you need to know. I've been in this field for about 20 years, and GVHD is something that I have really dedicated my career to, lessening the burdens, reducing the risks, and mitigating the side effects.

It's a very challenging condition, one that we have made great strides in and one that we need to continue to focus on to improve the quality of life and to help people really live their fullest lives after transplant. That's why we do what we do. We want people to be living their lives completely and fully after their transplant.

[02:06] The learning objectives today are on the screen now.

By the end of this talk, you should feel confident that you know the basics about what GVHD is and what it is not, when it can happen, and who is at risk.

We'll talk about which organs are affected and the main symptoms to watch for.

We'll talk about self-monitoring. This is really important, including when to call your team if symptoms just don't make sense.

And then we'll talk about how prevention and treatment work, including the benefits and the side effects of both.

[02:38] So the roadmap. We'll talk about GVHD in plain language. We'll talk about the difference between acute versus chronic GVHD, the symptoms and organs involved, the self-monitoring, and when you need to call now versus when you can talk to you physician or physician assistant nurse practitioner in the coming weeks.

We'll talk about prevention and systemic treatments, including multiple new FDA-approved options, but we'll also touch on some interesting areas that are evolving through research: microbiome, exercise and strength training, as well as substance safety.

We'll also talk about information literacy, community, and research partnerships. And at the end, we'll have time for questions and discussion.

[03:23] What is GVHD?

This happens when the donor's immune cells recognize parts of the patient's body as foreign and trigger inflammation. This can lead to organ and tissue damage.

So basically, when we infuse a bag of donor cells into the patient, there are also mature immune cells in that bag that can recognize organs and tissues as foreign and attack them. The immune system is just doing its job. It doesn't know that these organs and tissues are actually healthy, so it can be difficult to control.

GVHD can be mild or it can be severe. It can be brief or long-lasting. There are many different ways it can show up. Most importantly, it's treatable, and early recognition is very important.

So, to summarize, GVHD is an immune complication caused by donor cells. It's not an infection, and it's not exactly a rejection either, although we sometimes think about that in organ transplant terms.

[04:21] So why does GVHD happen?

These donor immune cells enter the body. They circulate around. Their job is to surveil and attack anything that looks like it could be infected or foreign. And when they receive signals that something is not what it's supposed to be, they attack it, which triggers tissue injury.

[04:44] Then we have to give immunosuppression, and sometimes that lowers the ability to fight infections.

So, infections can result from GVHD because of a lower immune system and the medicines we're using to suppress it.

But infections themselves can trigger immune activation as the body fights them. The immune system seeks to contain and control it, but in the process, it can cause more inflammation.

This can shift the microbiome, which can then perpetuate GVHD further.

This can sometimes be a vicious cycle of inflammation that can involve really any organ or tissue: the skin, the gut, liver, eyes, mouth, lungs, so on and so forth. This can affect any part of the body, and sometimes multiple parts at the same time.

[05:35] So the take-home point here is that GVHD risk and severity are influenced both by transplant factors as well as what happens during recovery.

So, infections that occur, medications we use, our gut health, and how our immune system is functioning as it recovers can all influence GVHD risk and severity.

There are some elements we can control, but others we can't.

But importantly, you can control early reporting, medication adherence, and healthy recovery habits that can help with this.

[06:09] So now let's dive in a little bit deeper and learn about the difference between acute and chronic GVHD.

Acute GVHD is a GVHD reaction that happens very early post-transplant.

Usually, we consider GVHD that occurs within the first 100 days as acute GVHD, although this is a general guide, not an absolute rule.

[06:38] Acute GVHD has a typical appearance. Most commonly, it's a red skin rash, but it can also cause nausea, vomiting, diarrhea, and liver problems.

When we see acute GVHD, symptoms often evolve rapidly over days. It's a rapid process, and early reporting is absolutely essential.

[07:08] Chronic GVHD typically happens after day 100, although it can happen earlier.

It can involve any organ or many organs. There's inflammation that occurs with it, but there can also be scarring.

The symptoms that develop can be very insidious and develop very slowly. The symptoms often manifest over weeks or even months. Sometimes it's difficult to notice that there's a problem until there's quite severe damage because it can be so subtle.

Acute GVHD is very inflammatory and occurs very quickly. Chronic GVHD can take many months to fully manifest and is often inflammatory, but it can also lead to scarring.

[08:01] GVHD risk is unique to every person going through a transplant.

The risk factors that go into developing GVHD include the type of donor and how closely genetically matched the donor is to the recipient. The closer the match, the less likely the GVHD.

For example, if we have an identical twin, the risk is extremely low compared to if we have an unrelated donor that's a full match. Even though it's a full match, there are still minor histocompatibility differences between the two individuals that can lead to GVHD.

And then we have more mismatched transplants than that. We can have mismatched related donors. Often, that's a parent or a child donating to the other.

We can have cord blood transplants, which often have more mismatches.  So that degree of matching correlates with the risk of GVHD. The closer the match, the less the risk.

[09:08] Graft source plays an important role in this.

Peripheral blood has a higher risk of GVHD than the old-fashioned bone marrow transplant. Peripheral blood contains about 10 times more T-cells or immune cells that could potentially cause GVHD than bone marrow. So that graft source is associated with a higher risk.

[09:30] Conditioning intensity plays a role in risk.

What this means is how strong the chemotherapy or radiation or both that we're using prior to the transplant is.  The more intense a treatment before the transplant, the more organ and tissue damage there may be because of that chemo or radiation. And that damage itself can trigger the immune system because it senses that there's a problem. So, more intense conditioning can increase the risk of GVHD.

[09:59] The GVHD prevention approach also matters.

There are prevention approaches that are pretty minimalist. We use one or two drugs to try to restrain GVHD, versus doing something more drastic, like graft manipulation that we call CD34 selection. We're only selecting the stem cells themselves, and we're trying to remove the T-cells from the graft.

And then there are other ways in between where we can give medications that deplete the T-cells that can cause GVHD.

So, the type of prevention will weigh into how much risk there is of GVHD.

This is tricky because we also want that immune system to fight the cancer, so we have to try to individualize this for every person. It's not always a cookie-cutter approach.

[10:54] Post-transplant events can also increase the risk of graft versus host disease. One of the most important transplant events would be infections.

For example, C. difficile colitis, an infection that can cause diarrhea, can sometimes trigger GVHD of the GI tract.

A severe respiratory illness from influenza, RSV, or COVID, could cause lung inflammation that's like GVHD.

 Something that triggers the immune system might also influence the risk of GVHD.

[11:33] If you're preparing for transplant, I think it's important to ask your transplant team, " What are my top few risks for GVHD given my unique situation?”

And what should I watch for most closely? Because the answer can vary from patient to patient. So, know what your risk factors are and what you should be watching for.

So we talked about those most common risk factors.

[11:57] On the transplant side, we do have some control over risk factors, although not always, but we do our best to control the match degree, whether we're using an unrelated or a haploidentical donor, whether we’re using a peripheral blood graft versus a bone marrow graft, and how intense the conditioning is.

If someone had previous acute GVHD, they're at risk of developing chronic GVHD down the road.

 [12:23] And then recovery factors are not always 100% in our control.

Infections can change the microbiome with antibiotic exposure.

Missing medications important for controlling the immune system may increase the risk of GVHD, gut injury, dysbiosis, and delayed immune reconstitution.

Overall, know that this is a framework that really leads to differential risk for different patients. Be aware of factors that may be influencing the risk balance, and stay informed and talk to your team about what you can control.

Now let's do a deeper dive into what GVHD looks like.

[13:04] Acute GVHD often occurs in the first 100 days, is often very inflammatory, and most often affects the skin.

Eighty percent of the time, if this develops, patients will notice a new red skin rash that's often spreading. It can be on the trunk, it can be on the extremities, or it can even be on the palms of the hands or soles of the feet. It can be on the face, really anywhere.

This is typically a red rash. It can be blotchy.  It can blanch. When you put pressure on the rash, it turns a lighter color and then becomes red again.

Sometimes the rash can be itchy. Sometimes it can be burning. In severe cases, there can be peeling or blistering. And if that happens, that is urgent.

[13:49] So if you're a transplant recipient and you notice that you have a new rash that's rapidly spreading, call your transplant team the same day. 

They're going to want to know about this. Especially call if there's a fever, if you're feeling unwell, or if you notice any blistering or skin pain. This can be a clue that we need to treat that day.  So, if you notice these changes, it's very important to call the transplant team right away.

[14:19] The next most involved organ with acute GVHD is the GI tract.

Patients will most often notice new or worsening diarrhea, cramping or abdominal pain, nausea, vomiting, or poor oral intake.

If this occurs,  it's sometimes difficult to tease apart whether this is GVHD versus just dealing with recovery from the conditioning chemotherapy or radiation, or medication side effects.

What is often the clue is that things are getting worse, not better, after the blood counts come back in, or the symptoms are not going away when you expect to be recovering from the conditioning toxicities.

It's difficult sometimes to tease out what's actually happening, but if you are having nausea, vomiting, and diarrhea, that's also a phone call the same day. If you're having these symptoms on the day you're having them, you need to let your transplant team know, and they'll help evaluate and figure out what the next right thing to do is.

[15:22] Now, the least common organ involved with acute GVHD is the liver, and sometimes this can be silent.

Often, we pick this up on routine blood tests. Sometimes people don't have any symptoms at all. What we're watching for are changes in your liver numbers. Classically, it's bilirubin that elevates in acute GVHD, but AST, ALT, and alkaline phosphatase (Alk Phos) can also be elevated.

Symptomatically, this only shows up clinically if people have quite advanced GVHD of the liver, causing jaundice, dark urine, or itching. That would mean that this is already pretty severe. Often, we see it much earlier through routine blood testing.

Now, importantly, other medications can contribute to this risk.

[16:10] Liver function elevation is not always caused by GVHD.

It might be medication. It might be an infection. There might be a blockage in the biliary tree that we need to manage with surgery. So, we're watching for these things.

Routine monitoring is really the key here. And just note that it is common to have an elevation in liver function tests, but we're going to be watching for that clinical picture to help determine whether this is GVHD. And sometimes, if it's not clear, we have to do a biopsy of the liver to sort it out.

Now let's pivot to chronic GVHD.

[16:53] Chronic GVHD can sometimes be more difficult to diagnose because it can show up anywhere with any severity.  The most common target organs are listed here, and it really could be anything.

The skin is the most commonly involved organ. This can cause a rash, tightening, or a change in skin pigmentation.

There can be diarrhea, vomiting, and difficulty swallowing. With scarring of the esophagus, there can be difficulty getting food or fluids to pass through the esophagus, a condition called a stricture.

With the liver, laboratory changes can occur. But if it's severe, there might be yellowing of the skin or the whites of the eyes, causing jaundice.

In the mouth, there may be mouth sores, pain when eating, dryness, or changes in taste.

With the eyes, most commonly, there's dryness, grittiness, or light sensitivity.

With lungs, there can be cough, shortness of breath, or low oxygen levels.

With joints or fascia, there can be stiffness or reduced range of motion.

And then with genital GVHD, there can be dryness, pain, ulceration, and scarring.

So, chronic GVHD is difficult because it can show up anywhere at any time, and it might be really mild. It might be rapidly progressive and become severe quickly. So chronic GVHD is tricky.

[18:22] I think the most common thing I tell my patients is if something doesn't feel like it should, I want you to tell me, no matter how minor. Because if we see signs of chronic GVHD, often we can intervene early and reverse some of the signs and symptoms.

So, diving into each organ just a little bit more.

[18:42] With chronic GVHD, the skin and the mucosal surfaces can have both inflammation, so redness, as well as scarring (fibrosis). 

Normally, if you pinch the skin on the back of your hand, you’ll notice that you're able to pick up some of your skin and roll it between your two fingers.

But someone who has really tight, thickened fibrotic skin might not be able to pinch that skin at all. It might be so stiff that the skin can't even be pinched. This can affect any part of the body. And there can be ulcers as well. 

Poor wound healing is a common problem. 

There can be fatigue. It's tiring being in a tight, stiff body. And that might mean functional decline, which means you're not able to do the activities you used to do. You might not have the energy that you once had.

So, if you notice any changes in inflammation, redness, or skin color or texture, it is important to report them at any time.

[19:57] Now let's go into the mouth and the eyes.

With the mouth, patients will report sores or burning pain, sometimes with sensitivity to spicy or acidic foods. I've had patients say that ”I really wanted a nice plate of spaghetti, but the sauce was just too painful. I couldn't eat it.”

Dry mouth or changes in taste are very common.

And there can be white lichenoid-like patches along the inside of the cheeks or along the tongue. When we look in your mouth, this is what we're looking for: any signs of these changes.

[20:27] With the eyes, dryness or a gritty sensation is what patients most commonly report. This can lead to redness or pain, blurry vision, and light sensitivity.

If these things happen, tell your team early, because there may be topical treatments and supportive care that can significantly improve these symptoms.

If you're experiencing anything like this, don't suffer. Let the folks who care for you know, because there's something that can be done.

[20:55] Now let's go deeper into the body with the lungs.

This can be much more serious, but also more difficult to diagnose. What we often do after someone has had an allogeneic transplant is schedule pulmonary function testing, which involves blowing into a tube and measuring your lung volumes and oxygen diffusion capacity. 

We often schedule that because patients sometimes don't know there's a decline in their lung function. By the time you have symptoms of lung GVHD, you've often lost about 25 to 50% of your lung function. So, we don't want it to get to the point where you actually develop symptoms. 

If symptoms are present, they might include a cough and a fever. That's called cryptogenic organizing pneumonia, often occurring after an infection.

[21:51] There's another form called bronchiolitis obliterans syndrome (BOS), which is what happens after long periods of smoking or COPD. It can develop with shortness of breath and exercise intolerance. There might be chest tightness. There might be just a general decline in how much exercise someone can do.

So, we should be tracking your pulmonary function through repeated testing, and if we see any abnormalities, intervening upon that quickly. It's important if you notice something, don't assume it's just because you're out of shape. Report symptoms so this can be investigated, and if we see any signs of GVHD affecting the lungs, it can be appropriately treated.

[22:37] Self-monitoring, I've been highlighting this a lot. This is your early warning system. And I wouldn't worry about being too cautious, too concerned, or annoying to your healthcare team. 

Honestly,  early intervention can really make a big difference. And if you're questioning a symptom, it's easy to run it by your transplant team and have them help you troubleshoot to determine whether it's nothing or needs investigation.

[23:06] As you're monitoring yourself, things you want to be doing daily to weekly, are looking at your skin, seeing if there's any new rash, itching, or whether there is tightness. With the GI tract, watch for diarrhea, pain, nausea, or vomiting,. For lungs, watch for difficulty breathing or difficulty with exercise.

If you're having a hard time eating, or if you're getting dizzy, please tell your team.

If there's a rash or blistering, worsening diarrhea, shortness of breath, any yellowing of your eyes, dark urine, can't keep fluids down, or fever or sudden decline in how you feel, I've been harping on this a lot. Tell your team the same day.

[23:44] You can make your visits efficient by bringing information.

Keep a log of your symptoms. Keep a medication list with over-the-counter medications and supplements. Talk about any cannabis use or alcohol use. This is important to talk about openly.

If possible, take photos of your skin or areas you find abnormal, as these symptoms can wax and wane, and photos can be helpful. This helps your team determine whether we're dealing with GVHD or other problems. It's very, very helpful.

[24:19] Most patients will receive a prevention regimen starting at the transplant. It reduces the risk but doesn't eliminate it entirely.

Medication adherence and lab monitoring are absolutely crucial. Don't stop the drugs that the transplant team gives you suddenly or change them without talking with your transplant team, because missed doses of medication can trigger the immune system and cause severe GVHD. So, medication adherence is extremely important.

[24:52] Once we've assessed symptoms, we've confirmed the cause, we know this is GVHD, then how we approach it is also unique for each patient.

We'll use supportive or local care for something to which we can apply a topical medication.

We'll also talk about nutrition and rehab support, which are important, especially for any skin tightness, decreased range of motion, or exercise intolerance.

[25:18] If there are severe enough symptoms, or the organ function is being threatened, that's when we talk about systemic therapy - medications that treat GVHD from the inside.

And we're going to watch to see how the response goes. If it's not as robust as we expect, we'll add or increase the treatment to help prevent irreversible damage to that organ. So, we will risk-adapt treatment for each patient based on what we see.

[25:53] The first line of treatment for GVHD is, unfortunately, often still corticosteroids such as prednisone. I think its days are numbered, though. 

I'm doing a clinical trial to try to eliminate prednisone from the first-line treatment of GVHD.  Others are, too. I think it's actually going to happen pretty soon that the first treatment won't be steroids, but for today, it still is.

We like steroids because they can reduce inflammation quickly, but they come with a host of other side effects we don't want, such as increased risk of infection, higher blood sugar, mood or sleep changes, muscle weakness, bone thinning, fractures, fluid retention, and weight changes. There are lots of things we don't like about prednisone and similar medications, and so we are all keen to get rid of steroids for GVHD.

[26:44] In the acute GVHD setting, ruxolitinib or Jakafi is FDA-approved for steroid-refractory acute GVHD. It is also approved for chronic GVHD after prior systemic therapy. 

Interestingly, it's actually being studied right now for the prevention of GVHD as well.

So currently, that medication is a pill, and it is being used when steroids are not enough or if other agents can't control the GVHD the way we want.

[27:16] Over on the right, Ibrutinib or Imbruvica was the first ever FDA-approved drug for chronic GVHD after inadequate response to at least one prior therapy.

Often, this is not used as much because of the side effects. It has a slightly higher side-effect profile than we’d like. So, we can use it sometimes, but often this is not the one that we go to first, if steroids are not enough.

[27:42] Now, other agents that are FDA approved to treat GVHD down on the lower left, belumosudil or Rezurock, is an FDA-approved pill for chronic GVHD after at least two prior therapies haven't worked.

It’s an oral medication that's easy to take. It is a good anti-inflammatory and can also reduce fibrotic manifestations or scarring.

[28:02] The newest kid on the block is axatilimab or Niktimvo.

This is an IV medication, now FDA-approved to treat chronic GVHD after at least two prior systemic lines, and patients must weigh at least 40 kilograms.

Unlike the other medications that target lymphocytes, this actually targets a different cell type entirely, called macrophages, which are important for fibrosis.

So, we have more FDA-approved options than ever. It's amazing that before 2017, literally everything we used in this field was off-label.

So what to expect?

[28:41] If your treatment team decides it's important to give systemic therapy, expect that there are going to be more frequent check-ins.

There'll be decisions about tapering off therapy or adding therapy that are symptom- and organ-based.

We're going to be watching your blood counts very carefully, including your CBC, chemistry panel, and liver tests. Sometimes we're checking medication levels.

We're watching things like your blood pressure, your glucose, what your muscle strength is, and how your mood is doing.

Sometimes there's a need for increased preventative medications, especially those to prevent infections. And sometimes vaccines have to be delayed because it might not be safe to give vaccines, especially live vaccines, when you're receiving systemic therapy.

And then we'll be talking about nutrition, oral and eye care, skin care, and sometimes physical or occupational therapy to help deal with the side effects as well.

Now, let's go a little bit into some of the research.

I'm sure you've heard that we have a whole community of microbes that live in us, and they contribute significantly to health and disease.

[29:48] The gut is a major immune organ, and after a transplant, the antibiotics and inflammation, the chemotherapy, and all the nutrition changes can really change what your gut microbiome is doing. If it's behaving in a way that's not healthy, it is called dysbiosis.

Dysbiosis can increase the risk of GVHD. Newer preventive therapies are being developed to specifically maintain healthy gut microbial communities.

This is all currently research, but there are things you can do to help your healthy gut microbes grow, like eating a wide variety of fruits and vegetables.

Our intestinal tract loves fiber. The good bacteria love fiber and starch. And so, giving them what they need to thrive is something you can do even before we have specific microbiome-targeting interventions 

[30:49] So some practical do's and don'ts to try to keep your microbiome healthy.

 Take antibiotics only as prescribed. We really take a minimalist approach now.

Tell your team about diarrhea.

Try to eat adequate protein.

Stay hydrated.

Eat fruits and vegetables because of those healthy fibers.

[31:08] Now, things to avoid. We don't recommend starting probiotics because we don't think that they are helpful in this space.

Most research says that they're not very helpful, actually. They can be harmful even. So, we generally do not recommend probiotics.

We don't recommend non-sterile microbiome products during heavy immunosuppression. 

And don't just assume that diarrhea is diet-related without checking. Always talk to your providers about your symptoms, and they can help you sort it out.

[31:39] Now, this is my favorite aspect, something that you can do to help mitigate your GVHD risk, as well as improve your overall health, and that is exercise.

If exercise were available in a pill and I could prescribe it to you, I'd be the richest person on the planet. But there's nothing as good as exercise right now for rebuilding your muscles after hospitalization and steroid therapy.

I've done research, as have others, that shows that exercise can actually improve your immune system. It can improve your immune function as well as your overall health. 

So, it's a therapy that's not just for your muscles, but also for your immune system as well. It has the added benefit of reducing fatigue and supporting quality of life.

A safe place to start is to go low and slow. As we say, consistency beats intensity. Start light. Start with something you can do 8-10 reps of easily, and very slowly,  add reps, sets, or weight as you feel able. Start low and go slow.

Some of you know that I briefly held a national record in powerlifting, and I didn't start out being able to squat over 300 pounds on day one. It took me five years to get there.

So basically, over time, you can build more and more muscle, which helps you feel better and better and helps your immune system work better and better as well.

If you need help, physical therapy or rehab can be employed. Personal trainers are a great option, but there's also a ton of information available online. I would not wait for the perfect training regimen. It's great to just get started. And again, just start low and go slow.

[33:29] Alcohol and cannabis are something that some people do use. It’s important to disclose everything to your team because there can be important medication interactions.

There might be effects that we notice on your liver. This might increase your infection risk. This might impair your decision-making and put you at risk for being overly sedated and falling. So, if you're using these products, please talk to your team about them.

So, things that we really would not want.

[34:00] Cannabis and CBD products can interact with our drugs and cause spikes or lows in these blood levels, and that's not good.

Some of the products that are inhaled can also be very damaging to the lungs or increase the risk of infection. So, we don't recommend inhaled products at all.

We would avoid starting new over-the-counter immune booster supplements. We often don't really know what they are. These are not regulated. If anything could increase the immune system in a pill, we would give it to you.

And again, avoid alcohol use with active liver issues and know that there can be interactions with medications.

[34:35] So there's a lot of information that's available.  The quality of the information can be variable.

So, when you're trying to decide if you want to take your health into your own hands and look to sources online, think about who the source is. Whenever you can, seek transplant-specific expertise and consult your multidisciplinary team.

Ask yourself what evidence supports this. Is this based on peer-reviewed studies or just someone's story?

And then think carefully, is this safe for me? Might this interact with my medications? Might this influence my GVHD or infection risk? Because this is always unique to your situation.

So, influencers can offer community. They can offer ideas and motivation, but they're not a substitute for specialized transplant teams.

Now, back to community. This is really important.

[35:26] Care partners are a part of the treatment team, as well as your peers. They can support you, reduce isolation, and improve follow-through.

Exercising with friends is the best therapy I've found. So, you could potentially develop an exercise cohort to work out with, and also ask about support groups, survivorship programs, and available counseling.

[35:48] It is normal to feel like you're not yourself, and you may need help. It's absolutely practical to reach out and know that there is a community there to support you whenever you need it.

[35:59] And lastly, research is still going on to improve our outcomes. It's paramount.

Whenever we're doing research, we're trying to improve upon the standard of care. I would never write a clinical trial that knowingly increases someone's risk.

So, whatever we're doing, know it's because we want to drive the field forward and help people live even healthier, happier, better lives.

[36:21] Patients and caregivers have a big role to play in research.

You can actually participate in the design of clinical trials where we're testing new drugs or prevention strategies. If you're interested in getting involved in clinical trials, you can reach out to me, and I can help connect you.

Registries and long-term follow-up studies are important for collecting data to better understand the lived experience and develop targeted treatments.

And then lend your voice. What outcomes matter most to you? We can incorporate that into clinical trials.

It's really important to share feedback and real-world barriers to care. As a researcher, I might say I want a blood test every single day so I can track these little variables throughout the study. But as the patient going through that, you don't want to go to the clinic every single day to get your blood drawn.

So, it's important to lend your voice to say what is actually practical and manageable, and to help us figure out how to meet in the middle to meet the research goals while also making the research not so burdensome that it's difficult to participate in.

So with that, I want to thank you for your time. This was a very high-level overview, and I wish I could go into deeper detail about anything, but we can always continue the conversation online.

The QR code links to my public Instagram account, Blood Cells and Barbells. I'm not selling anything there whatsoever. But as I mentioned, I really do focus a lot on strength training. And through that Instagram account, I'm sharing my training. I'm sharing ideas and would love to continue to interact with you online.

So please feel free to check out that Instagram page, and we can continue the discussion both here on this forum, as well as online.

Question and Answer Session

[38:11] Moderator: Thank you so much, Dr. Holtan. This was an excellent presentation. We do have many very good questions in the chat. 

Just before we get to them, I want to mention how important community is. Thank you so much for bringing that up. We at BMT InfoNet are part of your community as well. If anyone needs help with our resources, we are here to assist.

Now, on to the questions in the chat.

[38:49] Are there any biomarkers that you're looking for to help determine whether or not a patient is at higher risk of GVHD or GVHD complications?

[39:00] Dr. Holtan: Great question. There are blood tests being developed to help us understand GVHD risk, but there's no biomarker yet that can help us with early diagnosis of GVHD, distinguishing it from an infection or another inflammatory condition.

So, the MAGIC consortium is looking at biomarkers called ST2 and Reg 3-alpha. I've studied a protein called amphiregulin. We recently showed that when we test blood levels in someone with diarrhea, if they have viral colitis, their amphiregulin will not be elevated. But if they have GVHD, their amphiregulin will be high. That's just one small example where we might be able to differentiate infectious colitis from GVHD using that blood test.

But overall, there's no test that can actually predict when GVHD will occur. These tests, what we have now, are really designed to help us understand what's happening when symptoms are present.

So, we are excited, and we hope that one day we'll be able to have a blood test to see if GVHD is coming. But as of today, that does not exist.

[40:23] Moderator: There are a number of questions about GVHD risk and experience for someone who's had one transplant or someone who's had multiple transplants. Can you speak to that?

[40:35] Dr. Holtan: There is a slightly higher risk of GVHD with subsequent transplants. That relates to the risk of underlying tissue damage that can occur from repeated chemotherapy and radiation exposure. So, there's a possibility that someone going through a second transplant will have a little bit higher GVHD risk this time.

But even with that, we have excellent, excellent prevention these days. So, I wouldn't use that as an argument to not do a second transplant. They can absolutely be life-saving.

Our preventions and our treatments are so much better today than they were even five years ago, so that we can still make that GVHD risk extremely low.

[41:24] Moderator: There are some questions about rashes that appear after transplant and whether or not they might be GVHD.

So, one person mentioned that about a month ago, about four months post-transplant, a skin rash appeared, and they were using over-the-counter topical hydrocortisone, which has improved it but hasn't cleared it yet. And so, not sure if they should raise this as GVHD or just a rash.

There's someone else who experienced something similar and said they were concerned that a rash was skin GVHD, and their doctor said it was their body adjusting to or reacting to the new stem cells. Can you speak about when people should be concerned about GVHD?

[42:24] Dr. Holtan: Honestly, anytime you see a rash, it's good to talk about it. And the questions are spot on.

Not every rash is GVHD, so trust your team to help sort that out. Sometimes, when the new immune system is just starting to grow, it can cause what we call engraftment syndrome, and that can cause a rash. So just the appearance of the new immune system can cause some inflammation.

There can also be rashes for a variety of reasons. Viruses that you had as a kid can come back and cause a rash.Medication side effects, allergic reactions to topical things. So many different things 

Your transplant team will be able to take all of that into context and help figure it out. And often the treatment starts with just a topical steroid. But if that's not doing the job, after a while, they'll sometimes recommend a biopsy of that tissue to see what's going on and help identify the proper treatment.

So, any rash is very reasonable to tell your transplant team about. If you can't get in to see them, send photos so they can check it out and help with your symptoms, so everyone can sort through it together. You know, no rash is too minor.

[43:44] Moderator: There's a question about long-term side effects from transplant and how those might differ from GVHD. So, there is some confusion about kidney scarring, vision loss, and other aspects that they think might be a post-transplant complication versus GVHD, and how they navigate that.

[44:06] Dr. Holtan: Very good question. Sometimes, the chemotherapy exposure, the radiation exposure, medications, and infections can all influence organ function long-term. Depending on your health pre-transplant, you might have more significant side effects with these organs as well.

For example, if someone has had many years of diabetes, they might be more susceptible to developing kidney problems after a transplant or heart problems, even. There is the possibility that some of the medications or infections might increase the risk of organs not working as well after the transplant.

But GVHD differs in that it's a specific immune attack against that organ. It starts with inflammation, which can lead to scarring and disruption of the organ's function. And we can usually tell the difference because there will be signs of inflammation in the body. 

We can pretty well differentiate GVHD from other effects by taking a careful history, understanding their risk factors, and reviewing their medications. 

And we can also do some blood tests to see how much inflammation is actually active in the body. If there are high levels of inflammation, it might suggest that the organs are suffering from GVHD. Sometimes we'll also do biopsies of those organs to sort it out.

So, it's an excellent question that can be difficult to tease out, but working with your clinical teams, they'll often be able to sort out clearly whether an organ is not working well because of the effects of the transplant versus GVHD itself. It is pretty solvable.

Moderator: [45:49] How do we find out about clinical trials and how close or far from transplants should someone be to consider clinical trials?

[45:57] Dr. Holtan: Great question. The best source in the United States is clinicaltrials.gov. All clinical trials must be registered on that website. So if you're in the United States, that is the best place to look.

Nationally, I'm sure there are registries as well.

Patients can participate at any place they feel comfortable. Prevention studies, monitoring studies, treatment studies. There are clinical trials that really span the entire journey.

Some transplant centers have multiple studies available. Others are more limited.

Some require in-person participation. Some might be available through telemedicine. So, all kinds of options are out there.

If you're interested in research, and I hope you are, it's how we advance the field, and we want your input on it.

[46:53] Moderator: There are questions in the chat about very specific things having to do with eye or ocular GVHD and drops about lung GVHD. And so I just want to let everyone know that they can look at the agenda. We have a number of talks over the course of the week that address these organ systems, skin and fascia, so musculoskeletal.

And so if you want a deeper dive into any of these areas of GVHD, we have that information available. And they will be a little bit more extensive than what Dr. Holtan can address in this Q&A.

[47:48] We have a number of questions on long-term survivorship. So, this comes in a couple of different ways. I'll present these questions one at a time.

For someone who is a five, seven years out from transplant, what is the likelihood that at that point they might develop GVHD?

[48:11] Dr. Holtan: So that far out, it is quite low, but the risk is never zero. So over half of the patients who are going to get chronic GVHD get it by about nine months post-transplant, up to 12 months.  And then by the time we've gotten to 18 months post-transplant, most of the people who are going to get it will have already gotten it by that time. So, GVHD was destined to happen because of the stem cell transplant and all these factors that can kind of get the immune system revved up.

If we've gotten past that, and let's say we're beyond 18 months, chronic GVHD can still happen, but often it will have been triggered by something: a sunburn, an infection, a new medication, potentially, just hypothetically speaking, something that triggers the immune system to wake up. That risk never goes away.

So, any potential inflammatory insult down the road always has a small risk of triggering GVHD. Even if you're five, seven, or ten years out, something doesn't feel right, just get it checked out. Because if it is GVHD, there's so much we can do about it.

[49:32] Moderator: There are folks who are a couple of years out from transplant, and their doctors are referring them back to a GP or PCP for care. What do you think about that transition? I know that that could be a little nerve-wracking for people.

[49:52] Dr. Holtan: Yeah, absolutely. I would say it's super important to have a good primary care physician. I fully recognize my limitations. My focus is on transplant, blood cancers, and GVHD. And what I know is really a small portion of overall medicine.

I'm not the best person to manage high blood pressure, diabetes, heart disease, all these other things that are very important to long-term survivorship. So, I think partnership is always critical.

Often we'll involve other specialists if we're concerned that we're not able to get a handle on symptoms, and we want some additional advice. Often I'll refer my patients to a lung doctor, to a heart doctor, to a kidney and liver doctor, and an endocrinologist. And so, it is possible for some patients to have quite a community of people who all need to work together for their care.

But honestly, a general practitioner is the most important coordinator of all that multidisciplinary care. No matter what, I think it's very important to maintain close contact with a primary care provider.

[51:03] Moderator: And then this question came up, and my heart goes out to this person so much and to all of you who are dealing with this. My transplant was a number of years ago and I've been dealing with ocular and skin GVHD for two years. Will it ever go away?

[51:20] Dr. Holtan: Really great question. When we're treating acute GVHD, our goal is to make it go away 100%. Gone. What we call complete response.

With chronic GVHD, while that's what we hope for, it often isn't possible if it's been there for months or sometimes years. So then, what we hope for is improvement in organ function and quality of life as much as possible, while also giving medications that are least likely to harm someone.

So, in chronic GVHD, it might not be possible to fully reverse the scarring or fully heal the tissues with our current medications. Keep in mind, our current medications are just trying to suppress the immune system. 

So right now, we might, at best, hope for improvement, if not a complete reversal. But down the road, through regenerative medicine, I hope we can fully restore organ and tissue function and develop medicines that actually help the body rebuild itself. Right now, what we give is something just to lower the immune system. I hope one day I can actually give something to someone that will help build them back up.

You've already heard me talk about this, but it's true. Exercise is an important medication here. And so stretching, resistance training, aerobic conditioning, even just walking. If you're not able to walk, even just the slightest movement, whatever you can do and build upon it from there, that can have restorative effects on the body that are beyond any medication I could ever give.

If I can give anyone any hope today, it is to start whatever exercise regimen you can, because what it will do for your body and your mind is so much better than what we have to offer.

Now, that's not to say medications aren't important. If we have life-threatening GVHD, I need to give medication. Exercise alone will not treat it. I say that, recognizing that sometimes we do have to use these medications.

But if we're on a stable regimen and there are no emergencies, just know that simply exercising is an important therapy. And if we had it in a pill, it would just be an absolute miracle.

[53:41] Moderator: There are a couple of questions about exercise. One is, is exercise better for dealing with GVHD as you have it? Or do you think of it more as a preventative measure? 

So, exercise can help normalize your immune response. If you have GVHD, it can help manage some side effects and potentially reduce inflammation. But it can also be preventive, helping your immune system learn to do its job properly without leading to excessive inflammation or tissue damage. So, it is beneficial no matter where you are in your journey.

[54:25] Moderator: And how can PT be helpful for improving the range of motion or being able to get to a point where one can exercise if someone already has chronic GVHD?

[54:39] Dr. Holtan: Physical Therapy can be very helpful. I myself have a physical therapist for a little nagging shoulder issue. I think we can all benefit from PT, but recognize that they're often not going to be able to be there as long or as much as you want.

So, take PT, learn from it, learn the tools, and then know that at some point you're going to have to continue on your own and build upon what you learned from PT. So, I say they're the starting point.

They'll help people work through current issues, but for overall health and to keep moving your body forward, PT alone is not enough. You'll have to implement an exercise program on top of it long-term.

[55:25] Moderator: And then we have time for just one more quick question, which is, does chronic GVHD ever transition back to acute GVHD?

[55:38] Dr. Holtan: Sometimes it doesn't transition per se, but something might trigger the immune system to behave like acute GVHD again, and that's commonly an infection.

So, someone may have stable chronic GVHD, and an infection comes in, and all of a sudden, we have a bright red rash that looks a bit more like acute GVHD.

So established chronic GVHD doesn't naturally, on its own, revert back to more of an acute form, but something may trigger it to appear acute and may need specific new therapy to bring that back under control.

[56:17] Moderator: On behalf of BMT InfoNet, all of our partners, our sponsors for this wonderful workshop, I'd like to thank Dr. Holtan for her wonderful presentation and for her really important work.

And thank you to the audience for your excellent questions.