Graft- versus-Host Disease of the Gastrointestinal System: Symptoms and Treatment

Transcription:

[00:00] Moderator: Welcome to the workshop, Graft-versus-Host Disease (GVHD) of the Gastrointestinal System: Symptoms and Treatments. My name is Michala O'Brien, and I will be your moderator for this workshop.

Before we begin, I'd like to thank Incyte, whose support helped make this workshop possible.

It's my pleasure to introduce today's speaker, Melissa Cochran. Melissa is the Director of Advanced Practice Nursing in the Hematologic Malignancies Division at Dana-Farber Cancer Institute. She has been at Dana-Farber for over 20 years and has volunteered with the American Society for Transplantation and Cellular Therapy and previously served as an advisory board member for the Bone Marrow Foundation. 

Please join me in welcoming Melissa Cochran.

[00:48] Melissa Cochran: Thank you so much.

I'm delighted to be here this afternoon to talk with you about GVHD of the gastrointestinal system. I want to thank the organizers. This is a very special symposium that meets a very important need for all of us.

[01:14] I've put together a few learning objectives for us this afternoon.

We’ll learn more about GVHD when it affects the gastrointestinal system.

We’ll also cover the risk factors, what makes it more likely to happen, the symptoms for both acute and chronic GVHD and their onset, how long GI GVHD typically last, what some treatment options for GI GVHD are, strategies patients can use to minimize these symptoms, and potential outcomes for patients who are struggling with gastrointestinal GVHD.

[02:07] Our gastrointestinal system is comprised of our mouth, throat, esophagus, stomach, small intestine, large intestine, pancreas, gallbladder, and liver. This system allows us to eat and drink, absorb nutrients that provide us with the energy to do all the things we want to do in life, and support our quality of life.

So, we need to eat and drink to have the energy to do the things we want to do. It is very critical for anyone undergoing an allogeneic stem cell transplant. And this is how we process and eliminate waste.

[03:05] What is GVHD?

GVHD (GVHD) is something that happens to people who've had an allogeneic stem cell transplant [a transplant using donor cells]. They've likely had a blood cancer and have been offered a curative therapy in the form of an allogeneic transplant.

Unfortunately, part of the transplant risk is something called GVHD. This is a problem arising from donor cells, particularly donor T cells. After donor T-cells are infused into the patient, they recognize the patient’s tissues as foreign. They then activate and proliferate, causing inflammation and immune system dysfunction in the patient.

[04:19] Is GVHD the same as graft rejection? Does this mean my transplant is not working?

Really, it's the opposite. When you think about a solid organ transplant, you think of organ rejection. You may have a kidney recognized as foreign, and then it can't stay in that patient any longer.

Whereas when stem cells are infused into a patient and are proliferating and recognizing the tissues as foreign, they're not going anywhere. So, it's not a rejection. However, that doesn't mean that it's not a problem that we need to fix.

[05:27] There are two types of GVHD: acute and chronic GVHD.

Risk factors for developing GVHD include the conditioning regimen (chemotherapy) that prepares a patient for transplant. Radiation is also a common part of the conditioning regimen. 

The conditioning regimen makes room for the donor cells to take up residence in the patient’s body. Before one can have a transplant, you really need to get the body ready, and that's called the conditioning chemotherapy or chemotherapy plus radiation regimen. The conditioning regimens are really toxic to the body.

[06:27] Gastrointestinal GVHD is a toxicity affecting the lining of the mucosa of the GI system. So, the mouth, esophagus, stomach, and colon, all of these delicate mucosal tissues, are irritated by chemotherapy or radiation, and that makes them more vulnerable to GVHD.

Another risk factor is the degree of the donor and patient match. You want the best possible match. You want a perfect match, but that is not always possible. If you have, for example, an unrelated donor mismatch, that's going to be a much higher risk of GVHD.

[07:17] Female donors to male patients increases the risk of developing GVHD. Unrelated donors increase the risk. It's less of a risk if you have a sibling-matched donor.

[07:35] The source of cells is also an area of risk. We can obtain stem cells from donors' peripheral veins. So rather than going directly into the bone marrow to get stem cells, we can get them from donors' veins.  That process makes the cells richer in T-cells, increasing the risk of GVHD when they are infused into the patient.

When you get T-cells directly from the bone marrow, there is less of a T-cell component and less risk of GVHD. The lowest risk, which is much less common these days, would be a cord blood transplant.

[08:50] How often do we see GVHD when patients are receiving donor cells?

Acute gastrointestinal GVHD occurs in 40% to 60% of patients who receive GVHD prevention regimens. We'll talk a bit more about mandatory prevention strategies.

[09:20] Everyone gets a GVHD prevention regimen upfront right after conditioning, chemotherapy, or chemotherapy plus radiation. Despite that, up to 60% of patients develop acute GVHD. 50%-60% of patients who receive classic GVHD-prevention regimens develop chronic GVHD.

Many, many centers are now using a newer type of GVHD prophylaxis regimen. When I say "newer,” I mean the early 2000s.

Post-transplant Cytoxan reduces rates of chronic GVHD to 20% or lower. Unfortunately, it doesn't have a significant impact in the acute GVHD setting.

[10:34] Why do we have two different types of GVHD?

In the olden days, and I've been in the transplant world, in my view, since the olden days, although transplant dates back to the 50s. But when we go back to even the early 90s, we still thought that anything before day 100 was acute GVHD and everything after day 100 was chronic. We now know that's not the case.

[11:11] Diagnosis of acute or chronic GVHD is now based on symptoms and how people present.

Acute GVHD is characterized by specific symptoms. When these symptoms appear doesn’t really matter, although acute GVHD often occurs earlier after transplant, from the time of engraftment. Engraftment is when donor cells first take hold and start blood cell count recovery.

After conditioning chemotherapy, the patient's cell counts will drop, and then the donor cell counts will take over. And when you see the counts are improving, those are really the donor cells that are causing the count recovery. Because donor cells are recovering in the bone marrow, GVHD can occur once they have fully engrafted.

The GVHD that occurs during the first few months after transplant is most commonly acute GVHD, but we also know people can have late-onset, acute-looking GVHD symptoms.

[12:59] What do the symptoms of acute GVHD look like?

They look like a lot of watery diarrhea, very frequent trips to the bathroom, and a lot of crampy abdominal pain. People will say, “Everything I eat and drink goes right through me. I can't keep anything down. As soon as it's in, it's out.” They'll have nausea, vomiting, and decreased appetite.

If there is a liver abnormality, there can be yellowing of the skin, also called jaundice.

So, people who are suffering from acute GVHD feel really unwell. They're dehydrated, and they have irritation of the skin at the rectum. They really don't feel well at all.

[13:46] There are ways to stage and grade acute gastrointestinal GVHD for the liver. It's based on the bilirubin level.

For the lower GI system, it's based on the volume of diarrhea someone has.  Less than 500 milliliters per day is consistent with normal output. So that would be stage zero. Stage three would be 1,000 to 1,500 milliliters of stool per day, or up to five to seven episodes per day. No matter how many episodes you're having, if you're having severe abdominal pain, plus or minus blood in the stool, then that is stage four. If you're having any symptoms in the upper GI system such as nausea, vomiting, or lack of appetite, that would be stage one.

[14:57] After acute GVHD has been staged, it can then be graded.

I've highlighted, in purple, examples of what a GI staging might look like. For example, if you had a stage two level bilirubin and a stage two amount of diarrhea output, you would then be an overall grade three of acute GVHD.

And why does this matter? It's helpful for the clinicians caring for you and your family to understand how serious this is. 

Grade three and grade four have a higher risk of mortality after transplant. Grades three and four acute GVHD can cause up to 25% of what we call non-relapsed mortality after transplant. That's really high. So, these grading systems can help your clinician understand the severity of what is going on, and also help guide treatment.

[16:25] Acute GVHD is a clinical diagnosis. That means it isn't necessary to do a biopsy to prove that this is GVHD. That being said, if you or your loved one is experiencing these symptoms, your clinical team will likely test you.

If you have symptoms of nausea, vomiting, severe heartburn, or loss of appetite, they will likely consider an upper endoscopy. The gastroenterologist will insert a flexible tube with a camera down your esophagus to look and take biopsies. Those biopsies may very well provide a diagnostic pathology report consistent with GVHD, but they are not always 100% accurate.

If you're having a lot of diarrhea, a colonoscopy or flexible sigmoidoscopy will be done.

If there is significantly high bilirubin or abnormal liver tests, liver biopsy could be considered. Those are fairly risky, so the risk of bleeding may lead your team to opt not to do this, but it is sometimes considered.

Imaging of the abdomen, including ultrasound or CT scan, is performed very frequently. Testing of the stool for infection. While it may look like GVHD, the team will also want to know if this could be an infection. Could this be something like cytomegalovirus infection or norovirus infection? Many infections can mimic GI GVHD.

Blood work is also very important for understanding blood counts, the chemistry panel, electrolyte levels, and liver function tests.

[18:43] Supportive care is paramount when someone has acute GI GVHD. Very often, people need to be in the hospital for this type of care. They may need intravenous hydration. They may need bowel rest. 

They may need a period of time where they aren't taking anything by mouth at all, so no food, no liquids, no medications. They're not absorbing them anyway, so we give those medications through the IV instead, and sometimes consider giving nutrition through the IV for short periods.

The best way for people to get nutrition is orally by eating, but a short period of bowel rest can go a long way toward helping the bowel recover.

When things are improving on treatment, we start giving clear liquids and a very bland diet

Malnutrition and poor absorption of medications are major concerns in acute GI GVHD.

During this treatment period, screening for and treatment of potential infections will be performed weekly.

[20:21] Chronic GI GVHD looks different than acute GI GVHD. It can occur anytime after the transplant, after the engraftment period starts. While chronic GVHD can occur at any time, it most often occurs after three months and up to two years after the transplant, with 90% of chronic GVHD cases occurring within the first year.

If you have no GVHD, and it's been five years since transplant, and you start to have some GI symptoms, you definitely want to think about whether this could be something related to your transplant. You should talk to your transplant center about it, but it's much less likely to be chronic GVHD at that point.

[21:11] The symptoms of chronic GVHD tend to be much more subtle, not as dramatic, and with a slower onset than acute GVHD. This tends to be a bit of a problem because sometimes chronic GVHD is not picked up in the community setting as quickly as it could be, because people are having milder symptoms. So, it may be going on for weeks to months before treatment starts, because it's just not as dramatic as acute GVHD.

A prior history of acute GVHD is a risk factor for chronic GVHD.

[22:08] Common symptoms of GI chronic GVHD are mouth sores, difficulty swallowing, weight loss, decreased appetite, swelling, nausea, vomiting, and diarrhea. While these things tend to be more subtle and have a slower onset than symptoms of acute GVHD, they tend to have a very significant impact on people's quality of life.

Acute GVHD was recognized very early in the 1950s, but chronic GVHD was documented a bit later. There was a paper written by a Seattle pathologist in 1978, noting that chronic GVHD of the skin caused thickening of the skin, the sclerodermatous type of GVHD.

Chronic GVHD is a relatively new phenomenon, a little less well understood, and slower to reach consensus on how to treat it. The first consensus panel was convened in 2004 at the National Institutes of Health (NIH), and transplant experts from all over the country met and talked about , head to toe: “What are we seeing for chronic GVHD and what should we do about it?”

Then they met in 2014 to refine those criteria and developed a global severity scoring system. What really struck me about this scoring system is its focus on people's functional ability. It really tries to get at how chronic GVHD affects people's quality of life. 

[24:28] The global severity scoring system for chronic GVHD is very simple. If you have no organs involved, your score is zero. And if you have three or more symptoms, you're severe. So it's mild, moderate, or severe.

If you or your family member has chronic GVHD, and you go through the global severity scoring paperwork, it's really long and involved. It covers the head through the toes. It'll go through your mouth, esophagus, your appetite, nausea, vomiting, diarrhea, and the bowels in detail. It'll take a while to complete this assessment.

[25:31] Chronic GVHD of the mouth is very impactful on people's quality of life.

There can be a lot of pain and irritation. It can affect the gums, the mucosal lining of the mouth, or the pink part of the mouth. You can see the white, lacy picture showing what classic oral GVHD of the mouth looks like.

The dry mouth associated with chronic oral GVHD is really hard on people's teeth. We recommend that people stay in very close contact with their dentist. Whether you have GVHD or not, it's really important to keep that connection with your dentist. We find that people end up with many cavities, needing extensive dental work and, unfortunately, sometimes dentures at some point too. So, it’s uncomfortable and can impact quality of life.

[26:57] Chronic GVHD can affect the esophagus and a patient’s ability to eat and to swallow, due to stenosis or webs in the esophagus. Going to the gastroenterologist for an endoscopy can be helpful to stretch that.

Other symptoms of chronic GVHD in the GI system include nausea, vomiting, diarrhea, decreased appetite, and weight loss, as well as abnormal liver labs. When the liver is not working properly, you can have some edema [fluid retention] associated with that.

[27:37] Whether you have acute or chronic GVHD of the gastrointestinal system, your team will want to rule out some other diagnoses, including infection and medication interactions. Many medications can mimic GI symptoms, including antibiotics and some immunosuppressants. 

Lactose intolerance is a big issue. So, anytime someone comes in with possible GI GVHD, we'll want to know what they have been eating. We’ll conduct a 24-hour dietary recall to assess how much dairy is consumed.

Infections are also a major culprit behind GI symptoms.

And then sinusoidal obstruction syndrome (SOS), formerly known as veno-occlusive disease (VOD), can affect the liver and kidney function, and can mimic acute liver GVHD early after transplant. So that's something that would be ruled out if you had liver dysfunction early after transplant.

We talked a bit about GVHD prevention being mandatory after transplant. We know that if we didn't try to prevent GVHD, it would happen 100% of the time.

[29:07] Everybody who has a transplant needs to have a GVHD preventative strategy with their conditioning regimen. The timing is typically after chemotherapy. The goal is to suppress the donor T-cells.

The classic GVHD-preventative regimens are methotrexate with tacrolimus, or methotrexate with tacrolimus and sirolimus. Depending on your transplant center, there are lots of variations on this.

There's also a way to manipulate donor cells to deplete donor T-cells. Our center has not been super in favor of it, but it is one strategy for preventing GVHD.

The duration of regimens to prevent GVHD is about six months after transplant, but it can be longer. So, if you go through your initial preventive doses of methotrexate and tacrolimus, and you've had a small amount of GVHD early on, they may keep you on tacrolimus longer than six months. So, it may be closer to the one-year mark before you get off your immunosuppressive therapy.

The good news is it's not like a solid organ transplant where you need to stay on these medications for life. There is a light at the end of the tunnel to potentially be able to come off these medications.

[31:17] Post-transplant Cytoxan is a new way of preventing GVHD and is incredibly popular in the transplant community.

Most centers are using it. The reason is that it has dramatically improved the rates of chronic GVHD.

Cytoxan is given as an infusion after conditioning chemotherapy and after day zero of cell infusion. Then, typically, a medication like tacrolimus and mycophenolate mofetil will be given as pills after the Cytoxan for many days and months afterward.

[32:13] The other really great thing about post-transplant Cytoxan is that it has expanded the donor pool for patients.

Previously, we were not able to use half-matched donors. So, if you had a sibling who was not a perfect match, we really could not consider them as a donor for you. And when we used unrelated donors, we really had to think hard about using any mismatched unrelated donors.

But with the advent of post-transplant Cytoxan, it's been much, much safer to do this. So, now over 99% of patients who need an allogeneic donor transplant have a donor option.

[33:10] This slide shows you how post-transplant Cytoxan has really not made a difference in grades 2 to 4 acute GVHD, which is unfortunate.

But the following slide will show how post-transplant Cytoxan has made a significant impact on chronic GVHD, which is really remarkable.

And again, it's expanded the donor pool in ways that just were not possible 20 years ago.

[33:47] So we've talked about prevention. We've talked about what GVHD is, but how do we treat it?

I personally find it a bit frustrating that the first line of therapy for both acute and chronic GVHD is prednisone, and it's been the first-line therapy for more than 30 years.

It's not a targeted therapy. It's a potent anti-inflammatory that's used for all kinds of things beyond transplant. So if you have a frozen shoulder, your orthopedic surgeon will prescribe prednisone. It's used for all kinds of things.

[34:36] Prednisone has lots of side effects: high blood pressure, high blood sugar, changes in mood, decreases in muscle strength, and decreases in bone density.

It's best used short-term, which means we need to have second-line and sometimes third-line therapies for both acute and chronic GVHD.

[34:58] If your symptoms persist on prednisone, or you're not getting a complete response, then we need to add additional medications.

There are lots of options to consider. They're all either immunosuppressive or immunomodulating medications. 

I've listed a bunch here: ruxolitinib, mycophenolate, mofetil, infliximab, etanercept, and extracorporeal photopheresis, which is a very time-intensive phototherapy treatment that requires you to come to a transplant center twice a week. It can be very expensive due to the time that you need to spend doing that therapy.

Non-absorbable steroids can be an additional therapy to these other therapies.

[36:02] For chronic GVHD, there are FDA-approved second-line therapies, including ibrutinib, ruxolitinib, belumosudil, and axatilimab.

And then there are additional medications for chronic GVHD. Each transplant center has different algorithms for what to try, and the data isn't always very compelling on what the best strategy is. So, it can be a bit of trial and error.

Other treatments to consider include topical steroids for oral GVHD, swish and spit topical tacrolimus that can be used for the lips and the mouth.

And supportive care is really important for pain management, things like magic mouthwash for the mouth and throat.

How do people do on treatments? This is also a bit frustrating.

[37:20] About 50% of patients with acute or chronic GVHD will respond to steroids alone. Usually, less than 50% respond to second- or third-line therapies. 

Treatments will last many months, and more than 80% of patients with chronic GVHD will require treatment for two to three years, which is a long time.

[37:53] So when you have GI GVHD, you need a whole village to take care of you.

You need your transplant team, and that may not be easy because you may not live down the street from your transplant team. But they're really critical because they know best what these symptoms mean and how these treatments work and what the best strategies will be for you.

Your caregiver is also essential for getting you to and from your appointments, helping with your nutrition, and getting you your meds. Your caregiver will also need support. So, layers of caregiver support, if possible.

You will need active monitoring for infection and nutrition support. We'll highlight that again for a moment.

[38:59] It's becoming more and more evident how critically important nutrition is for our well-being. So a healthy diet, lots of fiber, vegetables, healthy proteins, and not too much sugar.

A nutritionist is critical. A gastroenterologist is likely a good person to have on the team. A dentist as well.

Throughout this process, you want to maximize your quality of life. So, maintaining your ability to exercise, do physical therapy, and manage financial considerations. All of this is incredibly challenging for patients and families.

[39:52] If you develop complications after transplant, the cost of taking time off work, traveling to the transplant center, hotels, gas, and food, bills, and arranging for pet care, those types of things add up exponentially and can be extremely challenging.

A ray of hope is what's going on in the research sector.

[40:30] When I last looked, there were 93 GVHD-focused clinical trials in the U.S. that were open and actively recruiting, and they're trying to look at GVHD in a variety of ways.

Some look at new therapies for both acute and chronic GVHD, new ways to prevent GVHD, the biology and natural history of GVHD to better understand it, prevention and treatment strategies, including non-prednisone treatment strategies.

And very exciting to me is that there are supportive care and quality of life-focused clinical trials going on to help us better support and understand those critically important issues.

[40:57] So a brief summary of this presentation:

GVHD prevention requires a prophylaxis regimen.

Post-transplant Cytoxan has significantly reduced the incidence of chronic GVHD.

Early reporting of symptoms is important.

Close follow-up with the transplant team is essential, and treatment may involve a long-term relationship with your transplant team.

Acute and chronic GI GVHD remain significant issues requiring continued research.

A ray of hope is that we have post-transplant Cytoxan in our arsenal, and nearly 100 actively accruing clinical trials in the U.S. 

The leaps and bounds in supportive care that the transplant community has gained in the past 20-30 years are incredible.

People are living good quality lives longer than in the past, but there's still a lot of work to be done.

There is a lot of hope. And with that, I really thank you for joining me this afternoon, and I will take questions.

[43:14] Moderator: Thank you, Ms. Cochran, for this excellent presentation.

[43:27] Our first question is, “I'm five years post-BMT and have mostly mouth chronic GVHD symptoms. Will this be a permanent condition, or can this condition still improve after this length of time?”

[43:45] Melissa Cochran: That's a great question. It can still improve with time.

Five years is a really long time to deal with this. But I do believe that there is hope that things can improve.

I would suggest, not knowing what you've done so far, reaching out to an oral medicine specialist at your transplant center and having regular follow-ups with them, trying different topical preparations.

And stay closely connected with your dentist as well, because hydrating and caring for the gums and the teeth is really important while you're managing GVHD of the mouth.

[44:58] Moderator: Is the mouth skin similar to the rest of the GI tract? [

45:14] Melissa Cochran: So that mucosa, it's sort of all connected, but it is different, and you don't necessarily see it happening at the same time in the mouth and in other parts of the GI system. Sometimes it's isolated to the mouth, and you don't see it at all in the esophagus, stomach, or colon. You may see it just in one area.

[45:47] Moderator: If you have upper and lower GI GVHD, do you typically see mouth GVHD as well?

[45:59] Melissa Cochran: Not necessarily. They can occur distinctly separate from each other, or you can have all of them.

[46:11] Moderator:Could you go into more detail about the esophageal webs? This person had grade one acute GVHD and still feels like foods, such as thick breads, are getting stuck in their esophagus. The problem goes away after drinking water. They're one-year post-transplant.

[46:35] Melissa Cochran: My understanding of it is that if they're persistent, you really do want to have another look with the gastroenterologist.  I would say have an endoscopy to reassess what's going on there, and then also get their opinion on what to do about it.

I think it's encouraging that it seems to be clear, but I think it's probably worth getting that looked at by the specialist.

[47:21] Moderator: Butyrate is the preferred fuel for colonocytes. What is your professional opinion of the butyrate supplement?

[47:30] Melissa Cochran: I know that there was data presented at ASH last year regarding butyrate, specifically after transplant. My understanding is that it's very promising. The safety profile was quite good.

That being said, I would 100% talk to your transplant team about your specific situation and whether that type of supplement is safe for you.

As a general rule about supplements, we recommend managing these on a case-by-case basis directly with your transplant physician.

Some of the supplements are iffy, depending on where they came from and how they were manufactured. So, I would be very cautious about having a good discussion with your transplant team before taking anything.

[48:59] Moderator: You mentioned preventative GVHD measures. Can you talk a bit more about how I could learn more about T-cell depletion of donor cells?

[49:11] Melissa Cochran: I would  go to PubMed and look for open-source articles using the search term T-cell depletion. That way, you can find free research-based articles.

You could also search Google Scholar and use the T-cell depletion search term. You'll get a lot of both history and current thinking on the topic.

[49:58] Moderator: Is having a hoarse voice in the throat a symptom of GVHD?

[50:05] Melissa Cochran: It can be, but hoarseness can also be a symptom of lots of things.

Usually, if someone has hoarseness, we consider an ear, nose, and throat referral, so they can do visualization. They have an ENT endoscope, so they can take a look and then consider imaging if needed. But it's possible.

[50:42] Moderator: Does a longer duration of GVHD raise the cancer risk of the affected organs?

[50:53] Melissa Cochran: The rates of secondary cancers after transplant don't necessarily correlate specifically with the site of the GVHD itself. The most common secondary cancers after transplant are skin cancers, predominantly squamous cell carcinomas.

If you have GI GVHD and have been immunosuppressed, that doesn’t mean that the risk for a secondary cancer would be in that area.

But it raises an important point: that’s another good reason to stay connected with the transplant team for long-term screening for secondary cancers. You want to make sure to have a good assessment for oral cancers and skin cancers as well. So, annual skin checks or sooner if you have any skin lesions that look concerning.

[52:28] Moderator: This person noticed that under risk factors for developing GVHD, there was a female donor to a male recipient. Is there a correlation with the reverse, male to female?

[52:39] Melissa Cochran: There is not, which is good.

[52:46] Moderator: My mother is six years post-allogeneic transplant, and she found out she has chronic GVHD of the esophagus. She's just off prednisone and started the new med Jakafi. She's had two EGDs to stretch her esophagus. It might be starting in her intestines. Any suggestions that you might have based on your experience would be appreciated.

[53:13] Melissa Cochran: From what you describe, it sounds promising that she's off the prednisone. So that's actually a good sign.

Jakafi has quite a good profile for success in treating GVHD. If it's a new medication, we like to give it some time. So, a good four to six weeks to see some benefit, which probably sounds slow, but we want to give it some time to work and then watch those lower GI symptoms closely.

In the very short term, try to prioritize a healthy, high-fiber, bland diet, and closer follow-up if those lower GI symptoms are acting up.

[54:21] Moderator: Can you speak more in detail about elevated liver enzymes in relation to chronic GVHD? Have you seen any cases where enzymes are high, but bilirubin remains at a relatively normal level?

[54:39] Melissa Cochran: Yes. We see that all the time in chronic GVHD, where the bilirubin will be normal, and the transaminases, the AST, ALT, and the alkaline phosphatase are high.

It's much more common in chronic GVHD to have those numbers elevated. And it's tricky because other factors can affect those numbers, such as medications and infections.

Depending on the levels of the numbers, we sometimes just monitor them and keep an eye on them.

Sometimes, if they're high enough or bad enough, they do need treatment. Or if you have other organ involvement, then you would need treatment. Typically, we would see those numbers improve if they are related to GVHD. But yes, very common.

[55:43] Moderator: My GVHD just flared. What things can cause these flare-ups?

[55:52] Melissa Cochran: Flare-ups can happen for a number of reasons.

Sometimes it's because you've been on treatment, things are better, and your team starts to lower the medications that you're on. That's a common time for symptoms to flare.

Another common time to see symptoms flare is during viral infections. Those are probably the top two.

And then there are also flares that have no explanation. People have been going along for months, things are calm, and there seems to be no good reason, but things are flaring up anyway. It can just happen.

Very often, flares become less frequent and less severe over time. That is a common trend, but not an absolute.

[58:01] Moderator: Does liver GVHD usually accompany GI GVHD?

[58:07] Melissa Cochran: It's not uncommon for them to occur together, but not necessarily. There's not an algorithm or a rhyme or a reason to this, but yes, it can happen, but is hard to predict.

[58:32] Moderator: On behalf of BMT InfoNet and our partners, I'd like to thank Ms. Cochran for a very informative presentation, and thank you, the audience, for your excellent