Introduction to Chronic Graft versus Host Disease

Introduction to Chronic Graft-versus-Host Disease

July 13, 2020 Part of the Virtual Celebrating a Second Chance at Life Survivorship Symposium 2020

Presenter: Corey Cutler MD, MPH, FRCPC, Medical Director, Adult Stem Cell Transplantation Program and Director, Stem Cell Transplantation Survivorship Program, Dana-Farber Cancer Institute

Presentation is 38 minutes with 21 minutes of Q&A.            Download Speaker Slides  

Summary: Chronic graft-versus-host disease is a common complication after a transplant using donor cells (allogeneic transplant). Early detection and treatment are critical to successful management of the disease. Side effects from drugs used to treat chronic GVHD can increase the risk of health problems later in life.

Highlights:

• Graft-versus-Host disease (GVHD) affects approximately half of individuals who undergo a stem cell transplant using cells from a donor (allogeneic transplant).

• Skin, mouth, and eyes are the organs most frequently affected by chronic GVHD

• It is important for stem cell transplant patients to know the risks and signs of GVHD and seek appropriate treatment.

• Physicians not familiar with GVHD may incorrectly diagnose a patient with a more common autoimmune disease.

Key Points:

02:27     GVHD occurs when the transplanted immune system, or the graft, attacks recipient tissues, or the host.

03:39     Historically acute and chronic GVHD were distinguished by the number of days the stem cell patient was after transplant. Today, acute and chronic GVHD are distinguished by organs involved and symptoms.

09:34     Chronic GVHD is often called the great mimicker because it mimics signs and symptoms of some autoimmune diseases.

10:12     Symptoms of chronic GVHD of the skin include changes in pigmentation, stiffness of the skin, nail changes, and changes to the hair and scalp.

10:37     Symptoms of chronic GVHD in the mouth include sensitivity, pain with temperature (hot or cold foods), and discomfort with spicy or acidic foods.

10:51     Symptoms of chronic GVHD in the eyes include inflammation, redness in the eyes, pain, itchy, and or the sensation of sand in eyes.

15:24     Diagnosis of chronic GVHD requires a comprehensive physical examination led by a transplant physician and eye examination by an ophthalmologist who understands chronic GVHD. The mouth can be examined either by the transplant physician or an oral medicine specialist.

18:47     Treatment options for chronic GVHD depend on whether the GVHD is localized to one organ or affects multiple organs.

21:30     The majority of stem cell transplant patients with chronic GVHD will need a second line therapy beyond steroids. It will require trial and error to find a personalized treatment that works for each individual patient.

33:04     Long-term side effects of steroids used to treat chronic GVHD after can include immune deficiency, cataracts, chronic kidney disease, diabetes , high cholesterol, reduced muscle strength, adrenal insufficiency; the adrenal glands, osteoporosis, nerve damage and poor wound healing.

Transcript of Presentation

00:00     [Sue Stewart] Welcome to the workshop, Introduction to Chronic Graft-Versus-Host-Disease. My name is Sue Stewart, and I will be your moderator today.

It's my pleasure to introduce to you today's speaker Dr. Corey Cutler. Dr. Cutler is the Medical Director of the Adult Stem Cell Transplant Program at Dana-Farber Cancer Institute, and the director of the Stem Cell Transplantation Survivorship Program. He is also an Associate Professor of Medicine at Harvard Medical School.

Dr. Cutler is an internationally recognized expert on graft-versus-host disease. His research focuses on development of novel methods to prevent acute and chronic graft-versus-host disease, umbilical cord blood transplantation and decision theory in stem cell transplantation. Please join me in welcoming Dr. Cutler.

00:54     [Dr. Cutler] Thanks very much Sue. Welcome everybody. As you just heard, my name is Corey Cutler and I have been at Dana-Farber for about 20 years now, with a focus in graft-versus-host disease. Today, I'm going to speak to you about an overview of chronic graft-versus-host disease. Now, I realize that those of you who have been online over the weekend have already heard detailed lectures on GVHD of the gastrointestinal tract, and of the eye by my colleagues, but we'll take a step back today, and we're going to really start from square one and review the basics of chronic GVHD.

Chronic graft-versus- host-Disease (cGVHD) is common after a transplant using cells from a donor (allogeneic transplant)

01:38     Why is chronic GVHD so important and why are we spending so much time on it in this conference? Well, because it's common. It occurs in approximately half of individuals who have related and unrelated donor transplants. As we do better with early transplant outcomes, we are seeing more and more people develop chronic graft-versus-host disease.

The reason why it's so important is because it is a very important cause of morbidity or side effects in the later post-transplant period. It requires long term therapy, sometimes up to two to three years, and it's associated with real quality of life problems for patients who suffer with it in the long term.

Why does GVHD occurs after a stem cell transplant?

02:27     What is graft-versus-host disease? Actually, this applies to both acute and chronic GVHD. GVHD occurs when the transplanted immune system, or the graft, attacks recipient tissues, or the host. I like to think about it by using the example of kidney transplantation. If you required a kidney transplant, and that is a kidney right there on the screen, the immune system of the recipient, and those are white blood cells. Unfortunately, that's my artistic ability. White blood cells from the recipients would go and attack the transplanted organ, and we would all call that rejection.

In stem cell transplantation, the transplanted organ is the immune system, and the target tissues are things like the skin, the intestines, the liver, et cetera. In graft-versus-host disease, it is the transplanted immune system that attacks the target tissues and causes the syndrome that we recognize as GVHD.

Difference between acute and chronic GVHD

03:39     It's important to recognize that acute and chronic graft-versus-host disease are not the same syndrome, and they are not defined by when they occur after transplants, although historically they were, with the dividing line being 100 days.

It used to be said that anything that occurs before 100 days is acute graft-versus-host disease, and anything after 100 days is chronic. In fact, that is not true, and now we define two syndromes: classic acute and classic chronic GVHD with some overlap over time. Acute GVHD could definitely occur following day 100, and we call that late acute GVHD. There can be some individuals who have symptoms of both acute and chronic GVHD at the same time, and we call those people having an overlap syndrome, although, we treat them as if they have chronic graft-versus-host disease.

We also can differentiate acute and chronic graft-versus-host disease based on some of the clinical features and the organs that are involved.

On the bottom is a timeline of the incidence of both acute and chronic GVHD and you can see in blue acute GVHD tends to occur earlier. There's an overlap syndrome, roughly that occurs between days 100 and one year and then classic chronic GVHD occurs later. Some of the biology that goes along with these two syndromes is shown under the graph.

Very strictly speaking, one can look just at the clinical manifestations and decide if a patient has acute or chronic graft-versus-host disease. On the right, you see that acute graft-versus-host disease only involves the skin, the gastrointestinal tract and the liver. Whereas on the left, under chronic GVHD, you can see that there are a number of manifestations of chronic GVHD, and that's what would put a patient into the category of chronic graft-versus-host disease.

On this slide, which is not meant for any of us to decipher, we see the biology of this process of acute and chronic graft-versus-host disease. What this slide is really meant to demonstrate for you today is that this process, graft-versus-host disease, is extraordinarily complicated from a biological point of view. It involves multiple different types of immune cells and immune effectors, and it involves a number of different organs in a number of different biologic ways, be it with inflammation, or scarring and fibrosis. This is not meant to be a comprehensive review, but really just meant to demonstrate really the complexity of chronic graft-versus-host disease.

Three distinct biologic phases of chronic GVHD

06:51     As physicians, we recognize three distinct biologic phases of chronic graft-versus-host disease. It's important that we recognize these three phases of the disease because that is what we use to help design our therapeutics for the disease. So, we can target those individual phases if we know where the patient is in their disease course.

The first phase is early inflammation and tissue injury. This is typically what we would call the red phase. Inflamed things like skin rashes, inflammation in the mouth, with ulcers, inflammation in the gastrointestinal tract. You can see that there are a number of cell subsets that are involved and our therapeutics target those.

The second and longest phase is what we call the chronic inflammatory phase. This is the phase where the immune system learns to behave in an abnormal fashion in the long term. We need to stop this phase before abnormal immunity becomes the standard rather than the exception.

Then finally, if this is left to go on long enough, then one ends up in the tissue, fibrosis or scarring phase of chronic GVHD, and this is where people end up with literally scars. Scars in the eyes or in the mouth, or most commonly in the skin, in the subcutaneous tissues.

Organs commonly affected by GVHD

08:36     This slide demonstrates the distribution of organ involvement in graft-versus-host disease, and it's from three different surveys. That's why there are three bars with each organ involved. What you can see is that the skin, the mouth, and in my opinion, the eye are the three most commonly affected organs and most importantly, these are the three organs that patients self-report symptoms of. It's very hard for a patient to report that their liver has GVHD, but a patient can decide or can tell and report when they've developed skin problems, mouth problems and eye problems. Luckily, those are the common organs that are involved, and they present early, and so we can intervene early. Early intervention in this disease is associated with better outcomes.

Symptoms of chronic graft-versus-host disease in the skin, eyes and mouth

09:34     The next two slides go over some of the signs and symptoms of chronic graft-versus-host disease. Now, chronic GVHD is often called the great mimicker of other diseases. It is, in effect, an autoimmune disorder and many of you have all heard of things like psoriasis and rheumatoid arthritis and scleroderma. These are classic autoimmune diseases, and chronic graft-versus-host disease often mimics the manifestations of these diseases in the affected organs.

Under the skin, we see a multitude of different signs and symptoms that you might notice: the changes in pigmentation, be it changing in the stiffness of the skin, nail changes, changes to the hair and your scalp, because hair and nails at the end of the day are just fancy skin structures according to the dermatologists.

10:37     The mouth is very obvious from a patient point of view. There is sensitivity, there is pain with temperature, so either hot or cold foods, and then discomfort with spicy or acidic foods.

10:51    The eyes are very obvious from a patient point of view. It's inflammation or redness in the eyes, painful eyes, itchy, scratchy eyes, feeling like sand has been kicked in them. These are the things that patients commonly report.

Unfortunately, they often report it to physicians who might not be familiar with the concept of graft-versus-host disease, and patients might be labeled as having one of these other autoimmune diseases, when, in fact, all of the symptoms can be explained by GVHD.

The next slide goes on to show some of the other manifestations in the other organs, and I'm going to go through some photographs of some very representative things in the coming slides. But it's very important that patients recognize signs and symptoms with the lung, so shortness of breath, and the other organs involved.

Symptoms of chronic GVHD of the skin, nails and hair

11:50   Now, we get into the show and tell portion. Here we see very, very classic signs of skin involvement. You can see that the fingers here are somewhat sausage shaped and have what we call scleroderma or scarring, and then the nail beds and the ends of the nails are very abnormal with ridging and very fragile chipped nails. These are very common signs of graft-versus-host disease of the skin.

This is a young man who has chronic GVHD affecting his scalp. You can see the change in the pigment around the hairline. In fact, he's lost some hair where that pigmentary change is. If you look even closer, you can see that the skin has a little bit of a sheen to it, what we call lichenification. This is a very classic sign of chronic graft-versus-host disease.

This person has a red lichenoid rash on the majority of their body. Again, this is the type of thing that a patient might present to a dermatologist with. Unless the dermatologist recognizes that GVHD is a common occurrence after transplantation, this might be labeled psoriasis or another skin disorder.

On the top left is someone who has a very advanced version of graft-versus-host disease of the skin. This is what we call scleroderma, and this is when the skin becomes hide bound to the tissues below, and you can imagine that that is skin that's just not pinchable.

Symptoms of chronic GVHD in the mouth (oral GVHD)

13:31     Moving on to the mouth, this is the inside of the mouth of a typical GVHD patient. This person almost certainly has discomfort when eating and drinking because of the inflammation, and you can see a big red ulcer on the inside of the mouth, and then a whitish discoloration to the rest of the mouth tissue, and that is also what we call lichenification. This is the type of thing that should be picked up on an oral examination by a dentist but might be mistaken for something else in the mouth, typically a condition called leukoplakia, which has nothing to do with transplantation.

Symptoms of chronic GVHD in the eyes (ocular GVHD)

14:12     The eye is the hardest organ for us to visualize changes. There's some inflammation around this person's eye, one can see lots of extra blood vessels in the eye. But you had probably an excellent lecture over the weekend by my colleague ,Dr. Katie Luo, and so I'm not going to go into greater detail about graft-versus-host disease of the eye because I'm quite certain she's already covered it.

Patients with skin GVHD have limited flexibility and range of motion

14:39     Then finally, one of the other signs and symptoms is this limited flexibility that graft-versus-host disease patients can get. We measure the patient's ability to flex and extend at the shoulder, at the elbow and at the hands, and you can see on the right-hand side, what would be considered normal motion. And then as you move farther and farther towards the left, one gets limitations of motion from scarring related to... Scarring underneath the skin, an inability to move.

How chronic GVHD of the skin, eyes and mouth are diagnosed

15:24     A patient should have a very comprehensive physical examination to document and detail chronic graft-versus-host disease. This should be led by a transplant physician. Most of us can do a full chronic GVHD examination in about 10 minutes or less.

All patients need an eye examination. This, if there are signs or symptoms, should be done by an experienced ophthalmologist who is attuned to the signs and symptoms of chronic GVHD.

The mouth can be examined either by the transplant physician or an oral medicine specialist. These are dentists who have secondary specialization in oral medicine, and you'll hear from one of my colleagues, Dr. Treister, in a couple of days, I believe on Wednesday, and he really is one of the world's authorities on oral graft-versus-host disease.

The skin should be examined by the transplant physician or an experienced dermatologist, and I'm quite sure you had a dermatology review at some point. The muscles, the joints and the fascia. The fascia is the things that hold us together, if you will. It connects our muscles and joints to our skin. That should be examined by the physician, and that's where those images of the patient doing all sorts of the flexing and extending come from.

How chronic GVHD of the lung, liver and genitalia are diagnosed

17:00     The lungs are hard to examine, because one could have significant lung compromised without being symptomatic. The way to examine the lungs is with a pulmonary function test. This is a simple test that all transplant patients undergo before and routinely after their transplant and should be done as part of the comprehensive chronic GVHD examination.

The liver is examined through blood tests mainly.

Then, for women, there are genital urinary manifestations, generally of the vaginal mucosa that should be examined by an experienced gynecologist.

Scoring the severity of chronic GVHD

17:42     When we do these examinations, we as transplant physicians will give an overall score to each one of the organs that may or may not be involved. It's a very simple scoring system, mild, moderate, and severe, corresponding to scores of one, two and three for each organ. It stands to reason that the higher the score, the worse the impairment or the more affected the individual organ is.

We take the summary of all of the scores and give a patient an overall chronic GVHD organ severity score. The overall severity score is mild, moderate or severe, and the scoring system is shown here in the table. Anybody who has severe involvement is called a three. If you have very mild involvement with one or two organs, you're a mild and everybody else falls into the middle with what we call moderate chronic graft-versus-host disease.

Treatment options for patients with chronic GVHD

18:47     With that, we're going to move into how we actually deal with chronic GVHD.

The fundamental theories here in treating chronic GVHD are that if the patient only has local symptoms, we use local therapy. That means, topical therapy to the mouth, topical therapy to the skin, topical therapy to the eyes, and even topical therapy to the gastrointestinal tract.

One could administer things like immune suppressive therapy, to decrease the inflammation, or simply supportive measures, things like re-wetting drops for the eyes and lubrication for the mouth. Two subtypes of therapy, and one has to distinguish anti-inflammatory and supportive measures for individual organs.

I would point you to a published paper by what was then called the American Society of Blood and Marrow Transplant and now the American Society of Transplantation and Cellular Therapy, which really talks about ancillary therapy for individual organs. If you are affected, for example, in your eyes or in your mouth, you can go to this free document. It's accessible on the ASTCT.org website, and it talks about all the supportive care measures that can be applied to individual organs.

Treatment for chronic GVHD when multiple organs are involved

20:25     If you get into multiple organs involved, or what we call systemic symptoms, then you have to give systemic therapy. That means therapy to the whole body. In 2020, the accepted therapy for chronic graft-versus-host disease is steroids, and the medication that you're all familiar with is prednisone, and it's often given at about a milligram of prednisone per kilogram of you. So, 70-kilogram person will be offered approximately 70 milligrams of prednisone in general.

We often give it with drugs that you've heard of like tacrolimus and cyclosporine, and about half of individuals have a very nice response to that front-line therapy. Although it takes a long time to get patients off these drugs, one has to be very slow and methodical in weaning patients off of the drugs. Otherwise, the chronic GVHD will just come back.

Most patients require a second, and sometimes a third line of therapy to treat chronic GVHD

21:30     Unfortunately, as I said, only about half of individuals will respond to therapy upfront, and therefore we have to think about other types of therapy that we can give beyond just steroids.

Why do we give second- and third-line therapy? Well, if subjects have progressive symptoms after prednisone. If the symptoms are not improving within about one to two months of starting the prednisone therapy. If you can't taper the prednisone or if you are having side effects from the steroids. Then finally, if there's a clinical trial, or an insurance issue that makes you have to change therapy.

These are the reasons why we move between therapies.

Unfortunately, the majority of our patients will eventually require a second therapy. This is a table from a publication that looked at the likelihood or the incidence of requiring a second and third- and fourth-line therapy. You can see that that goes up over time. Only about 20% or so of our patients don't require a second or third drug for chronic GVHD over the course of their disease.

Second line therapies available to treat chronic GVHD

22:55     What do we use once steroids fail? Well, unfortunately, despite all of our efforts, there's no real standard or algorithm for us to apply in this disease up until very recently. There are a lot of drugs that we've tried to use in this setting, and there are a lot of drugs that actually work. The problem is, is that they work for some people, not everyone. We as physicians do not yet know which drugs is going to work for which patient. There's a lot of trial and error, once one gets beyond drugs like prednisone and tacrolimus or cyclosporine.

Listed on the right are some of the drugs that we've used, and some of the response rates. These are in uncontrolled studies. The numbers need to be taken with a grain of salt. But these are the things that we often reach for if steroids are ineffective in chronic GVHD.

Luckily, our field has been extraordinarily interested in better ways to treat graft-versus-host disease in the last 10 years or so. We have taken a number of steps to try to improve the way we actually treat the disease. There are a couple of different ways that we can think about this. We can try to turn down the cells that are causing graft-versus-host disease, the so-called accelerators of the immune system. The other approach is we can try to put the brakes on the immune system and try to foster what we would call the brakes of the immune system or the regulatory cells. This slide depicts some of the mechanistic approaches we've taken to try to address both the accelerator and the brakes of the immune system.

I'm going to go through a couple of important studies with you, because these are the drugs that you are most likely to encounter in the next few years.

New drugs to treat chronic GVHD: Ibrutinib (IMBRUVICA)

25:11     The first drug and study to know about is a drug called ibrutinib, which has a trade name of IMBRUVICA. This is a drug that previously was approved for treatment of B-cell lymphomas and chronic leukemias.

We did a study, and I was proud to be a part of this study, where patients who had failed frontline steroids, that means... Rather, I shouldn't say that patients failed steroids, but the steroids failed the patients. We gave to 42 such patients ibrutinib, which was FDA approved at that time, as I said, a 420-milligram tablet, one tablet once a day, 42 patients. And we waited to see how these patients would do over time. The endpoint of the trial was how patients did. What was the response for chronic graft-versus-host disease? Then we looked at other important measures like how long did that response last? Was it safe? Could patients get off steroids, et cetera.

What we found, as you can see on the left-hand side, is that about two thirds of our patients, out of the 42, 28, had what we would call a complete or partial response. Meaning the disease either went away a little or completely, and then a smaller minority had stable disease, and only a small, small minority, two out of 42, had chronic GVHD that progressed despite ibrutinib.

This was really promising, actually. What we found in this trial was it didn't matter what organ was involved. People with skin, with mouth, with gastrointestinal, with liver involvement, all of the organs responded in roughly the same proportion. Even a significant number of patients who had multiple organs involved had nice responses.

We then looked to see, well, it's one thing if the doctor decides, oh, your skin is better, but do the patients feel better? We use what's called the Lee Symptom Scale. This is a patient reported outcome scale, developed by a very important researcher in this field. Dr. Stephanie Lee was at the Dana-Farber at the time, and now is at the Hutch in Seattle. This is a questionnaire that we use very frequently. You've probably been handed this questionnaire dozens of times in the waiting room while you're waiting for your appointment.  

What we demonstrated here was that at six, and then at the time of best response, subjects who had responded, based on the physician assessment, also had a higher rate of feeling better, based on their symptom scores. It wasn't just that the doctor said they were better, the patient actually said they were better, and that's a critical part. This actually was very instrumental in getting the drug FDA-approved, and this is now the first and actually only FDA-approved therapy for chronic GVHD, based on this study.

New drugs to treat chronic GVHD: Ruxoltinib (Jakafi)

28:48     Another drug you should probably know about, because it's out there, is a drug called ruxolitinib, goes by the trade name of Jakafi. It's been used in other blood malignancies, most notably myelofibrosis. Individuals, largely in Europe, went back and looked at case records of patients who had chronic GVHD and who were treated with Jakafi or ruxolitinib for their disease, and they noted in what's called a retrospective survey, so not a controlled study, but just looking at medical records, that 85% of patients whom they found with chronic GVHD, who were treated with ruxolitinib actually responded.

This is extraordinarily promising. It's not great evidence as far as evidence goes. A number of clinical trials have been started to test this agent formally. The most important one, you'll probably hear about this trial as it is nearing its completion, is a trial called REACH3. And this is a trial for patients with steroid refractory chronic graft-versus-host disease who are, in this trial, randomized to either the drug ruxolitinib or the patient and physician's next choice. If ruxolitinib weren't available, what would you give this patient?

This is an extraordinarily large study by our standards. So, 325 subjects were enrolled. The study was completed over a year ago, and we are anxiously awaiting results. Just of note, ruxolitinib has been approved for the treatment of acute graft-versus-host disease, and therefore it might be prescribed for patients with chronic GVHD at this point already, because there is certainly good evidence that this drug is effective in this disease. But we formally are waiting for the results of the REACH3 study and we hope to hear about that soon.

New drugs to treat chronic GVHD: KD025

31:05     The final drug I'm going to mention, because this is the new kid on the block, and probably the greatest up and comer is a drug called KD025. The drug is so new, it doesn't even have a name yet.

This was a study that I was involved in, that we recently presented the results at our annual conference, looking at individuals who had failed two lines of therapy. Generally, steroids plus another drug, and we gave them in experimental fashion, two different doses of KD025.

We gave half the patients, about 65 patients, we gave KD025 once a day, and then the other half they received KD025 twice a day. It didn't matter which group the patients were in, what you can see here is essentially two thirds of subjects had a nice response after failing two prior lines of chronic GVHD therapy, and a small number of patients actually had a complete response, meaning all of their chronic GVHD manifestations, all the scarring et cetera went away entirely.

We are actually very excited about this drug in particular because it appears to work in subjects who have already progressed despite ibrutinib and despite ruxolitinib. The other reason why we're particularly interested in this compound is because it tends to work in other scarring disorders. This drug is being tested for diseases outside of graft-versus-host disease, where scarring is an important manifestation of the disease, and it tends to work there as well, suggesting that it might actually work to reverse the scarring manifestations of chronic GVHD.

Long-term side effects of drugs used to treat chronic GVHD

33:04     We can't talk about throwing all of these novel drugs with unknown long-term side effects at patients without really discussing the long-term side effects of being treated for chronic GVHD. We give a lot of prednisone for chronic GVHD, and that leads to lots of long term steroid associated complications and that is why the search for better drugs is so important in this field.

What do long term steroids give you? It gives you immune deficiency, it causes cataracts, it causes chronic kidney disease, diabetes is a risk, high cholesterol, people become weak or myopathic because chronic steroids affect muscle strength and tone. It causes adrenal insufficiency; the adrenal glands are important for maintaining blood pressure and vascular tone. It causes osteoporosis. It causes nerve damage, poor wound healing. The list really goes on and on. This is the most common things that we see on the screen here. But it's important to recognize that if we're going to cause these problems, we have to deal with them in the long term.

There are lots of health conditions that we have to deal with in the chronic GVHD patient. Chronic GVHD, and long-term survivors of transplant, are much more likely to have other health conditions than age matched controls or their donors, for example. We know they have higher incidence of mouth and eye conditions, of lung compromised, of gastrointestinal disorders, of neurologic disorders.

To quantify that, a group called the Blood and Marrow Transplant Survivors Study Group did a formal trial or a formal assessment, I should say, of the long term morbidity associated with chronic GVHD, and this is the result of one of their reports that was presented a couple of years ago.

They went to look to see the frequency of late effects in survivors with and without chronic graft-versus-host disease, and this is what they found. The incidence of the disorders is shown in the columns entitled no chronic GVHD and chronic GVHD. You can see that, just by eyeballing the incidence of eye and mouth and lung, et cetera, disorders, that the incidence in the individuals with chronic GVHD simply is higher than the incidence in individuals without chronic GVHD. Chronic GVHD itself is a risk factor for all of these long-term complications.    

The column on the far right denotes the statistical significance of those differences. The majority of them are very statistically significant. These are not just differences in incidents related to chance or fluke, these are real problems related to the therapy and the incidence of chronic graft-versus-host disease.

Conclusion and Summary

36:28     I think I'm actually going to wrap up here so we can leave lots of time for questions. What I hope I've conveyed to you is that chronic GVHD really is a common disorder after transplants. It's potentially very serious, unless we catch it early, treat it thoroughly and treat it aggressively. Even if we do that, one has to be wary of complications related to the disease and to the treatment of the disease.

The disease is treatable, and that is critical for people to recognize, so that presenting to your doctor or reporting your signs and symptoms early is of paramount importance to make sure that we can deal with this properly. We actually advocate for screening. I didn't really talk about what screening entails here, but that will be discussed in the survivorship portions of the lecture series. Screening for the complications is more important than dealing with the complications once they've already occurred.

There have been lots of advances in the drug therapy of this disease. We now have our first FDA-approved drug. We are likely to have two more FDA approved drugs in the coming 18 to 24 months. Most importantly, there is a renewed interest in research in this field, now that we see that we can treat it effectively, and we can improve outcomes. With that, I am going to stop, and I'd be happy to take some questions.

Question and Answer Session

38:12     [Sue Stewart] Thank you very much, Dr. Cutler. That was an excellent presentation. I know, I learned a lot, and I'm sure everyone else that was listening did as well. I will now go to questions. As a reminder, if you have a question, type it into the chat box on the left-hand side of your screen, and we'll try to get to as many as we can. Let's start with the first question, does graft-versus-host disease prevent hair from regrowing after transplant?

38:40     [Dr. Cutler] That's a good question, and the answer that is absolutely, you can. Hair growth is a complicated process. I would first start by saying that if you are sick, for any reason, be it a transplant, or associated complication or something else, hair doesn't grow. Why? Because hair's just not all that important to the body. If your body needs to focus on healing other tissues, then it's going to divert energy and resources away from frivolous things like hair growth, hair and nail growth, I should say.

However, it's important to note that if you have skin involvement on your scalp, on the legs, then one of the earliest signs of GVHD of the skin of those locations is the lack of hair. Hair will fall out. Then hair will stay out. When that skin heals, then the skin will reform the hair follicles and hair will regrow, and that's an excellent sign that the GVHD has been taken care of, and that there is healing going on. The answer to the question is absolutely, hair growth is affected by chronic GVHD.

39:54     [Sue Stewart] Thank you. Next question is, why after GVHD has run its course, does it return and does tacrolimus aid in suppressing oral and liver GVHD?

40:07     [Dr. Cutler] Okay, a two-part question. Why does GVHD return? Well, at the end of the day, you're still dealing with a foreign immune system in a recipient body. When we treat GVHD, we use anti-inflammatory or immune suppressant drugs to turn off that donor's immune system. What has to happen for GVHD to never come back, is you have to develop tolerance. The donor has to give up and finally say, I'm okay with this skin. I'm okay with these eyes. Until you flip the switch of tolerance, then GVHD can continue to come back.

We are actively trying to figure out how to induce tolerance. That is not a trivial fact. In fact, the goal of all GVHD research is, first define, what does tolerance mean? And how do we get there from an immune point of view? That is, in fact, the holy grail of transplantation, is understanding tolerance. Until we understand tolerance better, GVHD may continue to come back, even if it appears to be successfully treated.

The other thing to think about is that sometimes patients are left with the sequelae of GVHD, even after the therapy is gone. For example, if you develop dry eyes from graft-versus-host disease, even if you magically turn off all GVHD, the eyes might remain dry, because you might have destroyed the tear glands that lubricate the eye. Even though there might not be active GVHD in the eye any longer, if the damage to the tear gland has been done and is irreversible, then you'll end up with dry eye forever, and that's why it's so important to present early and to report symptoms early to prevent these long term complications.

Now, to the second part of the question, which was, can tacrolimus prevent the recurrence? The answer is yes, and that's why it's used in the long term. It's used until that tolerance is induced. At that point, it can safely be stopped. But the long-term use of some immune suppressants can prevent the recurrence of GVHD sometimes.

42:43     [Sue Stewart] All right, next question, I'm three years out from transplant. I developed a continuous clot at the end of last year, and my doctor has ruled out any relation of this clot to the lungs or respiratory tract. Could this clot be chronic GVHD?

43:00     [Dr. Cutler] Well, without knowing the specifics of your lung function tests and what things like a CAT scan of your chest look like, it's impossible to say. But there are very simple tests to determine whether this is GVHD. GVHD will always have a decline in lung function on pulmonary function testing. If pulmonary function tests are normal, then one could convincingly say that this is not, in fact, related to chronic GVHD. But without seeing tests and understanding your individual investigations, it would be impossible to really answer that question any fuller.

43:45     [Sue Stewart] All right. If GVHD is severe, do patients ever receive another stem cell transplant with stem cells from a different donor to hopefully eliminate GVHD?

43:58     [Dr. Cutler] That is an excellent question. That has been done in the past. It really is done exceptionally rarely these days. I personally can tell you that I have not done that ever, in 20 years, although I guess I have contemplated it in a few patients with very severe disease. The theory is, is that if the first donor's immune system is never going to quiet down, then why not replace it with a different donor in the hopes that the second donor will be more tolerant or more forgiving in terms of GVHD induction.

It's a big step to take. It is a "there are no options left" type alternative. I would say with the advent of our novel therapies, it's something we simply don't consider any longer.

44:52     [Sue Stewart] All right, next question. I'm three years out of transplant and has level four GVHD with third degree skin burns. My eyes have what I think you would call chronic ocular GVHD. I worry my skin will flare up again. Is there a way to know whether I should be concerned about this?

45:14     [Dr. Cutler] What this question is referring to is a mix of acute and chronic graft-versus-host disease. I refer to the staging of chronic GVHD as organs being scored one to three, and this person describes a four, and that implies, the one to four system is an acute GVHD staging system. This person is asking I had acute GVHD of the skin, am I going to get chronic GVHD of the skin?

Acute GVHD is one of the greatest risk factors for chronic GVHD but getting one does not imply you will get the other. If you are three years from transplant, and you haven't had chronic GVHD, it's very unlikely that you will get chronic GVHD at this point. I tell my patients, for the most part, if you have not had chronic GVHD by two years from transplant, it is unlikely that you will get it moving forward. This person sounds like they might have some ocular GVHD. It's a little harder to say, I'm not sure what therapy they're on. There's nothing much one can do to predict whether you're going to get chronic GVHD or not. Just vigilance for the recurrence of a rash, or changes in the nails or hair would be all that this person can do. They'll be on the lookout for chronic cutaneous or chronic skin GVHD.

46:44     [Sue Stewart] Right, next question, do the adrenals heal over time, and who would check those levels to know?

46:51     [Dr. Cutler] Another good question. The adrenal glands themselves are generally not affected by GVHD. The adrenal glands produce small amounts of prednisone or prednisolone like compounds on a daily basis. We need those, that small amount, it's normal. If you take big doses of prednisone, the adrenal glands sense that and say, "Well, if I'm going to take a pill of 100 milligrams, the body doesn't need my five milligrams." The adrenal glands just go into hibernation mode.

Eventually, if you stop steroids, if you stop the prednisone, the adrenal glands have to wake up and remake it, and restart producing the body's normal amount on a daily basis. This is the reason why we always tell our patients, do not stop prednisone suddenly, because your adrenal glands are not ready to take the challenge up of making steroids for the body. This is why we taper steroids very, very, very slowly.

The adrenal glands eventually wake up although there are some people who get permanent suppression of their adrenal glands. An endocrinologist is generally the type of physician who deals with chronic adrenal insufficiency. If the adrenal glands never wake up, then patients need to take small doses of a different type of steroid, basically for life, to replace the small number of steroids that the adrenal glands ordinarily would make. But if there's a real issue, then an experienced endocrinologist is who would be in charge of that process.

48:33     [Sue Stewart] All right, does the overall health of a patient before transplant affect the risk of getting GVHD after transplant?

48:42     [Dr. Cutler] That's a tricky question. The answer is maybe, but it's not entirely clear. We do think that people who have advanced malignancies have a slightly higher rate of GVHD. Individuals who might have a compromised organ already might have a higher rate of getting GVHD later on. But globally speaking, overall health is generally not considered a risk factor for the development of GVHD. It's considered a risk factor for the development of organ toxicity, but not so much for GVHD, because it depends mostly on the donor's immune system, which is unaffected by the recipient's health at the time of transplant.

49:29     [Sue Stewart] All right, what percentage of people don't get chronic GVHD, and is not having any GVHD after transplant a bad thing?

49:41     [Dr. Cutler] Not having GVHD is not a bad thing, it is a good thing from the patient's point of view. There is a very slight association with development of GVHD, and prevention of recurrence of malignancy. It used to be thought that people who get some GVHD have a lower likelihood of having their leukemia or their lymphoma come back. That being said, you have to be very careful what you wish for. Really, patients should be hoping for the least amount of GVHD possible. If a little occurs, that's probably okay. But one should never wish for great amounts of GVHD in hopes that it will be somehow beneficial.

I would say, almost half of subjects don't get GVHD, they should be happy and not be doing things to try to get GVHD at that point.

50:40     [Sue Stewart] All right, where does extracorporeal photopheresis or ECP, enter into the treatment algorithm?

50:49     [Dr. Cutler] As I mentioned, there's no real algorithm. ECP is one of the established therapeutics and I could scroll back to the slide that looked at second line therapy, and ECP is right here, it's the first thing on that table. ECP is therapeutic, for those of you who aren't familiar with this, where white blood cells are taken out of the body, treated with a photosensitizer, and then UV light to disable those immune cells, and then those immune cells are put back into the body to try to re-educate the immune system.

It sounds a little bit like witchcraft, and perhaps it is, but in fact, it does work, and there are some patients for whom it works very well. It's difficult from a patient point of view, because it requires lots of trips and lots of time at the transplant center. For patients who are living at a distance from the transplant center, it's not a great option. But it certainly is something that I use in selected patients and those who are motivated to come back and forth to the transplant center a lot.

52:04     [Sue Stewart] All right. Can you please discuss what GVHD patients should do in terms of exposing themselves to the sun?

52:14    [Dr. Cutler] Yeah, sun exposure, and sunburn in particular is a risk factor for chronic GVHD of the skin. There are other drugs that patients might be taking that also make them at risk for sun disorders or solar exposure. Things like the drugs that prevent fungal infections can be photosensitizers, making them more prone to some exposure to illnesses. Patients with chronic GVHD, or in fact, all transplant patients should use things like broad brimmed hats, long sleeve t-shirts, and always use at least SPF 30 reapplied frequently to prevent sunburns.

Patients who've had a transplant are at higher risk of getting skin cancer over the course of their life. These preventive measures are both for the short-term prevention of development of chronic GVHD, as well as the prevention of long-term complications, such as secondary skin cancers after transplant. Very important to take care of your skin.

53:25     [Sue Stewart] Okay, we have a couple of questions about GVHD and COVID-19. Are GVHD patients at any greater risk of getting COVID-19? If they do get COVID-19, should they be treated any differently than the general patient?

53:43      [Dr. Cutler] That is a question that we probably don't have real answers for. So, I'm not going to go out and tell you I'm an authority on the topic. For one thing, the reason why we don't have great answers is because our transplant patients are professional social distancers. The incidence of COVID-19 among our transplant patients is probably lower than in the general population. Having GVHD or having a transplant does not make you more or less prone to acquiring COVID-19. It's important.

The only public service message I will say here is that one should continue to wear masks at all times in public situations, if you must be in them. One should socially distance and do everything in one's power to not acquire COVID-19. That is my public service announcement right there.

Whether the outcomes of transplant patients with COVID are worse than the general population is really anyone's guess. We, as a transplant community, have established a registry of COVID-19 BMT patients that's being run through the CIBMTR, but at the moment, I don't have any data that I could pass on to you other than to say, be smart and wear a mask and do not put yourself in situations where you could acquire COVID-19.

55:15     [Sue Stewart] We have several questions that are somewhat similar. I've heard GVHD can burn itself out eventually. I have sclerotic skin GVHD for four years. Another person says they have had some forms of GVHD for 15 years. Does it ever burn itself out completely?

55:37     [Dr. Cutler] It's a tricky question, because one, we don't have a test that says you have active GVHD or not. My experience is that at a certain point, the GVHD stops getting worse. But if you have bad sclerosis, that scarring, and that fibrosis of your skin might take years or decades to reverse itself. You have to be careful to differentiate the active immune phenomenon of GVHD and the chronic sequelae, like having scar tissue under your skin or having chronic dry eyes. They're two very different things, and they're treated very differently. The short answer is, it might burn out, but you still might have the chronic signs and symptoms of having had chronic GVHD.

56:30     [Sue Stewart] All right, I've failed on at least five treatments for sclerotic GVHD, Jakafi has helped the most. I would like to try KD025, how do I get on this? I have scarring on my lower arms and legs and would like to try this new drug to see if it would help. Would my transplant doctor be able to put me on it? If not, when would I get an access to it?

56:54     [Dr. Cutler] At the moment, this compound is only available as part of clinical trials at a few select sites in the country. It is not available on a broader, compassionate use format yet. I understand that the company is going to go through the process of FDA approval, but this is a lengthy process, and I don't know that any of us will have access to it outside of clinical trials, at least for a year. I would again reiterate that many of these drugs are not going to take care of the chronic scarring and even KD025 might not. So that you have to make sure that you want to be treated with an immune suppressant drug only if your disease is progressing, if there's active scarring going on, things are getting worse. If things are stable, then sometimes the right thing is to do nothing and to focus on things like stretching, physical therapy, occupational therapy and retraining things rather than more immune suppressive therapy.

58:09     [Sue Stewart] All right. I'm 15 years out of transplant and still have blisters on my legs for a number of years. How do you suggest I treat this?

58:20     [Dr. Cutler] Again, that's not going to be a question I'm going to be able to answer without seeing your blisters, knowing what you had done. Whether these blisters represent GVHD or not. This is the type of thing that you'll have to address with your physician, maybe ask for a referral to a specialty dermatologist or a wound center. But I don't think I can answer that question without knowing more about your medical record.

58:46     [Sue Stewart] All right, and we're starting to run out of time. This will probably be our last question. Have you used Gleevec for skin GVHD? And did it produce any good results?

58:56     [Dr. Cutler] Yeah, that's a good question. Gleevec is something that was a fad for a little while. The theory was that Gleevec would actually help reverse some of the scarring and there was some biologic mechanism to go along with that. It probably works for a very small subset of patients. I have tried it in patients with very mixed success. Patients only with sclerotic or scarring forms of GVHD. It's on the list of things we can do. But it's not on the list of things we do commonly these days.

59:34     [Sue Stewart] All right, and with that, I think we'll need to end this session. On behalf of BMT InfoNet and our partners, I'd like to thank [Dr. Cutler] for a very helpful presentation today, and I'd like to thank you, the audience, for all of your excellent questions.