Introduction To Graft-vs-Host Disease

Presenter: Jonathan Gutman MD, University of Colorado Hospital Blood Disorders Center

43-minute presentation followed by a 10-minute Q & A session.

Summary:

Chronic graft-versus-host disease (GVHD) is a significant side effect of an allogeneic transplant (a transplant using donor cells). Learn the risk factors for developing chronic GVHD, organs it affects and treatment options.

Highlights of Talk:

• Chronic GVHD can affect many organs and tissues
• Treatment options depend on the location and severity of GVHD, as well as cost and proximity to treatment centers
• Treatment may be required for months or years after transplant
• Research is underway to better prevent and treat chronic GVHD

Key Points:

• 05:11  Types of graft-versus-host disease (GVHD)
• 08:39  Risk factors for developing chronic GVHD
• 12:15  Organs affected by chronic GVHD
• 21:18  Localized treatment for chronic GVHD (mouth and eyes)
• 23:25  Systemic Treatment for Chronic GVHD: steroids (prednisone)
• 24:18  Options if chronic GVHD does not respond to steroids (steroid refractory GVHD)
• 30:19  Side effects of prednisone at high dosages
• 32:56  Extracorporeal photopheresis
• 34:12  Long term complications from chronic GVHD
• 36:13  Tapering off therapy for chronic GVHD, managing flare ups
• 40:10  New therapies to manage GVHD

This recording was made possible, in part, by a grant from Pharmacyclics and Janssen, Incyte Corporation and the Meredith A. Cowden Foundation

Transcript of Presentation

00:00  Introduction:  I’m Happy to be here today. I always love to be able to see people who have been through the process and it's great to be able to catch up with a few friendly faces who I know from years ago and more recent and some of you who I don't. I'm going to talk today about chronic graft-versus-host disease. It's not the most easy topic to talk about in the happiest of ways, but it is absolutely something that we have to deal with and, of course, are trying to figure out ways to not have to deal with, but I'd like to just take you through with really an emphasis on chronic graft-versus-host diseases.

00:38  Two types of GVHD:  As you all are well aware, there's also a form of graft-versus-host disease called acute graft-versus-host disease, which we'll talk a bit about, but for those of you who are well out from your transplants and hopefully doing well in as many ways as possible, chronic graft-versus-host disease definitely is an issue we still have to unfortunately contend with more than we would like.

01:01  Outline of talk:    What I'd like to do today is to spend a few minutes on each of these topics and then hopefully have a little bit of time for questions and answers and do my best to help out with what I can, but spend a little bit of time talking about what graft-versus-host disease is, talk a bit about what its risk factors are, spend a little bit of time talking about how we, as physicians, assess graft-versus-host disease and try to understand how it's affecting people's lives, and then a bit of time talking about how we treat the disease, and then, of course, again, also, hopefully, some time for some questions.

01:42  GVHD is most significant side effect of an allogeneic (donor) transplant:   Graft-versus-host disease, and several of you I've had the chance to sit down and have a consultation about a stem cell transplant with, and you've heard my pitch about it in that more intimate setting. But graft-versus-host disease is what we always, unfortunately, have to talk about, I think, as being the most significant problem that we can cause with these transplants that we're always undertaking to try and cure you of very challenging diseases. Basic operating principle of an allogeneic stem cell transplant, the transplant where somebody else is the donor, is that we're relying very heavily on the curative effect of that transplant, we're relying on these donor cells hopefully seeing little bits of the disease that we're doing in the transplant for that are still remaining in the body and will come back if we do nothing more.

02:37  Graft-versus-tumor effect and GVHD:  So, the donor transplant, the positive side of the immunologic effects that we have from having someone else be the donor is what we call the graft-versus-tumor effect. We like the graft-versus-tumor effect. We want that. The flip side that comes with it though is that those donor cells can also see the normal body is foreign and they can attack the normal body. And when those donor cells attack the normal body, we call it graft-versus-host disease. Again, it I think it is fair to say, there's a lot of things that can happen in the aftermath of a transplant that could be problems. There's issues with infections. There's issues with the donor cells not taking. There's issues with toxicity from the chemotherapy. The disease can come back.

03:22  Impact of GVHD on quality of life:   But the single largest problem I think that we can cause with these transplants is this phenomenon of graft-versus-host disease and unfortunately, it can have potentially a very significant impact on the quality of life going forward out from the transplant and, I think, including quality of life, probably a lot of financial issues that can be raised by issues related to graft-versus-host disease. So it's really something that we are working hard to try and figure out how to improve upon.

03:55  Is a little bit of GVHD good?  I often get asked though, people will hear that maybe a little bit of graft-versus-host disease is potentially a good thing. I think this is a little bit of a debatable question that depends a lot on the nuances and details of this specific type of transplant that a patient is undergoing, but I do think that it's fair to say that there's a general consensus in the world of transplanters that a little bit of what we would have called mild chronic graft-versus-host disease, hopefully, not enough that it's really causing you any trouble, but maybe enough to know that it's there, might be a good thing because we think that it might correlate with a more potent graft-versus-tumor effect and might mean that there's less risk of the disease coming back, which of course is another huge risk of these transplants.

04:39  The two types of GVHD: So when we talk about graft-versus-host disease, we really talk about two different entities and there's overlap between the two entities and we are continuing to refine, and define, and better understand what exactly causes and defines graft-versus-host disease. But as it grows, in general rule, we talk about acute graft- versus-host disease and we talk about chronic graft-versus-host disease. And as I've said, I think the focus of our talk today is really going to be primarily around the chronic graft-versus-host disease.

05:11  What is acute GVHD:        Acute graft-versus-host disease is a phenomenon which usually occurs within the first three months after the transplant. Symptoms of acute graft-versus-host disease can develop later after the transplant, particularly in certain types of transplant settings, perhaps cord blood, which we do a lot of at our center a bit more. But acute graft-versus-host disease tends to be a fairly distinct phenomenon that's characterized by those donor cells attacking the skin, the liver, and/or the GI tract.

While acute graft-versus-host disease is quite a common thing to see after virtually every kind of stem cell transplant, donor stem cell transplant, and while it can, on occasion, become a very serious thing and occasionally can be a lethal thing, as it grows in general rule, I think that we are often able to control acute graft-versus-host disease without terribly toxic and terribly difficult treatments and it usually resolves and is not a long-term, ongoing significant dramatic issue. There are of course exceptions to all rules here, but that's I think a reasonably fair statement about acute graft-versus-host disease.

06:26  What is chronic GVHD:  Chronic graft-versus-host disease, in contrast, I think, we tend to think of as being more of a challenging phenomenon. It typically starts somewhere on the order of three to seven months after a transplant, though it can begin to develop later. Chronic graft-versus-host disease I think we understand ... not that we understand acute graft-versus-host disease so terribly well. Chronic graft-versus-host disease I think we understand more poorly and it is a function of lots of different irregularities and disregularities in the immune system of the donor versus the patient and the consequences of the therapies to get the disease under control for which we did the transplant. But what is generally true of chronic graft-versus-host disease is that it can affect lots of organs and it can do lots and lots of different things and we'll talk about all that in a little bit more detail.

But chronic graft-versus-host disease I certainly worry about as an entity that can often be more protracted, more long-term, having a more complex course than acute graft-versus-host disease, can be more challenging to treat. Chronic graft-versus-host disease affects a lot of patients. Depending on details of your transplant, depending on how you look at the numbers, 20 to 70% of patients might be expected to have some degree of chronic graft-versus-host disease.

I always try to point out to people when I'm talking about this, if you try and go and look at studies and things like that, the details of how the data is presented, and it probably gets beyond the scope of what we want to talk about in this overview but I'm happy to talk about it with anybody individually, the details of what the likelihood of chronic graft-versus-host disease is for a given patient can roughly be predicted based on the details of their transplant. But it can be a little hard to tease out exactly what those numbers might look like if you're just trying to go and look at general sorts of materials. So, I think it's just important to know that it's a very significant issue and, in many settings, it's almost an expected complication of transplant.

08:39  Type of donor affects risk of getting chronic GVHD:  Again, I'm going to focus now and here on out primarily on chronic graft-versus-host disease. Again, I'm happy to talk about acute with anybody who would like, and many of the basic principles are quite overlapping. But the real focus here is going to be chronic. So, when we talk about the risk factors for chronic graft-versus-host disease, what sets up a patient for risk of actually getting chronic graft-versus-host disease, there are a number of known factors for sure and what I would say for sure is to my mind, the most significant risk factor for graft-versus-host disease is who is used as the donor for the transplant. I think it is fair to say that unrelated donors and certainly mismatched unrelated donors re going to be associated with the highest risk of chronic graft-versus-host disease and that risk is higher than a sibling donor transplant.

09:29  Lower Risk of Chronic GVHD when using cord blood for transplant:   At our center, I'm not necessarily the best man for this task because we put enormous primacy in our center trying to avoid ever having to deal with chronic graft-versus-host disease, and cord blood is really associated with a much lower incidence of chronic graft-versus-host disease, and so we're a very big cord blood transplant center. But lots to talk about the issues around that for sure. Cord blood is certainly associated with a lower incidence of chronic graft-versus-host disease.

10:00 Risk of chronic GVHD after haploidentical transplant:  I know a few patients in the room who are haploidentical or half-matched donor transplants. That is an area of development in the world of transplant and in recent years, I think we've seen some very exciting data coming out around novel ways to do these transplants where we give doses of a drug called cyclophosphamide right after the transplant, and that intervention seems to really be decreasing risk of chronic graft-versus-host disease in the haploidentical population also, so it's an area of interest for sure to us.

10:31  Peripheral blood stem cells increase the risk of chronic GVHD:  When we talk about using a sibling or an unrelated donor for the transplant, we can get those donor cells either directly from the bone marrow, we can go and harvest it out of the bone marrow, or we can give shots to stimulate the cells to come out in the blood and collect them off a machine. That's what we call a peripheral blood stem cell transplant. We know that the risk of chronic graft-versus-host disease is higher when we do a peripheral blood stem cell transplant because we get more immune cells that we think are associated with graft-versus-host disease in that setting.

11:01  Acute GVHD increases risk of having chronic GVHD:  Patients who developed acute graft-versus-host disease earlier in their transplant course are going to at greater risk for developing chronic graft-versus-host disease.

11:10  Older age increases risk of having chronic GVHD:   As both donors and patients get older going through this process, risk of graft-versus-host disease starts to go up for sure.

11:18  Female donor increases risk of having chronic GVHD:  When we have a female donor and particularly, a female donor into a male recipient or a female donor who's have lots of kids, that's a risk factor for graft-versus-host disease because having those kids has done some stimulation to the immune system that can create a risk for sure. We know that there are a lot of different things that we can consider to be risk factor for chronic GVHD. At the end of the day, also whenever I'm talking to patients, we've got statistics but what really matters to you is what happens to you and even with all of these predictive factors, there's a lot of heterogeneity and individual experience.

When we talk about assessing chronic graft-versus-host disease, how do we figure out and come up with any kind of standardized way to talk about different people with this entity to help us learn to better deal with it, to help us better be able to help our patients?

12:15  Organs affected by chronic GVHD:  Well, as I mentioned, there are a lot of organs that can potentially be involved in chronic graft-versus-host disease. It can honestly really do almost anything, but there are a number of organs that are most commonly involved in chronic graft-versus-host disease and this slide just lists a variety of organ systems and the frequency and the percentage of the time that we see them when we see chronic graft-versus-host disease.

As I said earlier, having a bone marrow transplant. as opposed to a peripheral blood stem cell transplant, is going to be associated with a bit less incidence of chronic graft-versus-host disease. But very commonly, we'll see chronic graft-versus-host disease affecting the skin, the mouth, the eyes, the GI tract, the liver, the joints, muscles, both penis and vagina can be affected, esophagus. More rarely, it can affect the lungs, but when it affects the lungs, it can be a very significant issue for sure and again, there are even more places where it can cause problems, but it really has got potential to do lots, and lots, and lots of different things.

13:32  Photos of chronic GVHD: These pictures just show some common manifestations of chronic graft-versus-host disease. There are lots of pictures out there that one could look at, but I tried to pick a few that really are things we see very commonly.

13:48 Photo of chronic GVHD on skin:    This is an arm. You can see the skin is tightened down, and patchy, and its color and things. This is a classic finding of chronic graft-versus-host disease of the skin. It may also be associated with the underlying tissue called the fascia and the joints being involved too so people can lose flexibility in the joints as a consequence of GVHD. People can get ulcerations from graft-versus-host disease of the skin that can be painful and difficult to manage.

14:18  Photos of oral chronic GVHD (in mouth)  This is a typical finding of graft-versus-host disease in the mouth. This is a person's cheek on the inside there. This white, we call lichenoid, is very common. Patients can get dry mouths, get tenderness to foods, particularly spicy foods.

14:36  Photos of ocular chronic GVHD (in eyes):  The eyes can become very dry, irritated as a result of chronic graft-versus-host disease.

14:41  Photos of chronic GVHD and nails: Nails can very often be affected by chronic graft-versus-host disease. So, just some pictures and some of the things that can happen.

14:52  Grades/Scoring of chronic GVHD:  When we talk about assessing graft-versus-host disease and trying to grade it, it's been a real challenge because it's such a heterogeneous disorder, and because we think that probably different things can cause it to be occurring in different organ systems, and we don't entirely understand and it's probably got a very complex what we call pathophysiology, that is driving factors that are causing it. It's a real challenge for us to try and standardized and be able to assess patients in a uniform way, which is a really critical thing for doctors to be able to do in order to be able to really effectively come up with better treatments.

But this scoring system, which I don't intend for you to memorize, is just to give you an idea of the complexity of when we try and do this scoring ourselves, what the kinds of things that we're looking at are and what goes on here is, basically, all of the major organ systems that are likely to be affected by graft-versus-host disease - the skin, the mouth, the eyes, the GI tract, the liver, the lungs. For each of them, we can check what the manifestation looks like in that organ system and then we can score on a score of 0 to 3 how severe the problem is that we're dealing with, and our hope is that by doing that, we can get a little bit more standardized in our thinking about how we're dealing with this disease in different patients.

But I like to point out certainly to the fellows, and residents, and students who I'm teaching or working with who may not be terribly interested in transplant but are generally interested in medicine, and know all the different things that can happen in medicine, we've got all of our major systems here but then we've got this box here and every single one of these little elements in the box is some weird, unusual medical thing that can happen to virtually any part of the body, and any of these things can also be associated and seen in graft-versus-host disease. So, we go through all these check boxes to try and assign a grade to the patient and to feel like we're talking about them collectively in something of a standardized way.

And so, at the end of the day, what we come up with in our most modern iteration of scoring chronic graft-versus-host disease, which is constantly under evolution, we come up for a patient and we will say that they have mild, moderate or severe chronic graft-versus-host disease and we come to that by taking the individual sites involved and their scores and coming up with an aggregated score for the patient.

17:33  Mild, moderate or severe chronic GVHD:   As a general operating principle in terms of clinical relevance and what it means to a patient, patients who have that mild chronic graft-versus-host disease are generally functioning quite well, don't have a whole lot of problems associated with it, but if you go and look you can probably see something.

Moderate to severe chronic graft-versus-host disease tends to be the kind of chronic graft-versus-host disease that's definitely having a significant impact on patients and their lives and is what we are certainly more concerned about and love to try to avoid as best we possibly can.

18:06  Treatments for chronic GVHD:     So, that's a little bit of an overview of how we assess graft-versus-host disease. Now I think we can finish up spending a little bit more time here, hopefully, talking about how we treat chronic graft-versus-host disease because I'm sure that that's a topic of interest to anybody who's dealing with this entity. I think there are some basic principles that we think about in the context of talking about how we treat chronic graft-versus-host disease, and I'll say it's one of these things that for us, in medicine, and certainly I know for patients, can be a challenging and frustrating thing because there often aren't easy answers. There's often a lot of experimenting. The duration of things is often a lot longer than we would like to be. Things can move in very slow motion and things can change. It's a challenging area for sure.

18:53  Preventing chronic GVHD:  And so, as I've already alluded to, my personal, very strong view about chronic graft-versus- host disease, and our center's very strong focus with regard to chronic graft-versus-host disease, is that we try to avoid it from ever happening in the first place. And I think that donor selection, as I talked about, is a critically important issue on that front. And again, our emphasis on cord blood, we think, is quite important with respect to what we see with regard to chronic GVHD. But also, it is true that for virtually any transplant that's done, there's going to be some form of medication and/or manipulation of the cells that's intended to prevent chronic graft-versus-host disease that we would call prophylaxis. And the details of the prophylaxis program that any patient is going to be on to try and avoid chronic graft-versus-host disease and acute graft-versus-host disease is going to be highly dependent on the center where the procedure is being done, and what they think best, what they're investigating, but also the details of how the transplant is being done - how intensive is the transplant, what's the donor source, what disease are we dealing with, et cetera.

20:03  Treatment for chronic GVHD:  As a gross operating principle around the treatment principles of chronic graft-versus-host disease, if it develops, it can develop locally and just be in one area. In other patients, it can be much more systemic or be in multiple different areas. So some people will have it just in the eyes. Some people will have it just in the mouth. Some people will have it in the eyes, the mouth, the lung, the skin. As a general rule, if the symptoms are local and they're really only in one particular area, we really will try to focus the treatment on that local site and not get into drugs that are systemically active throughout the body because, as we'll talk about, there's all kinds of issues with those systemic type therapies.

However, if the disease is more systemic and it's present in multiple different places, or it's not amenable to local treatment alone, then we do talk about treating the disease systemically. I know that a number of the sessions at this symposium are focused on specific treatments for specific areas, and so I think I'd certainly encourage anybody who's suffering from a specific issue to attend the session related to that for sure.

21:18  Localized treatment for chronic GVHD:      When it comes to local treatment and how we approach local treatment, probably the areas in which it is most likely to be true that there's local disease that can be amenable to local treatment would include the skin, the mouth, and the eyes and when it comes to the skin, there may be very limited involvement that's amenable to just creams or ointments or there may be more extensive involvement, but a therapy called phototherapy where you sit under an ultraviolet light can be an effective local therapy for treating the skin alone.

21:59  Treatment for oral GVHD (mouth):  When graft- versus-host disease affects the mouth and is active and causing pain or difficulty in eating, steroid rinses and gels are potentially very valuable things in the treatment of flared chronic GVHD in the mouth. GVHD in the mouth can also cause a dry mouth. That's a very common symptom of GVHD of the mouth. That's a little more challenging to treat but again, there's devoted sessions on management of the mouth here and I would encourage you to attend for sure.

22:34  Treatment for ocular GVHD (eyes):  GVHD also very commonly affects the eyes, and can be isolated to the eyes. And even if it's in other places, local treatment to the eyes can be very effective, and we work closely with our ophthalmologist here at the University of Colorado who can help manage the dry eyes and associated problems that can occur with chronic graft-versus-host disease. And there's lots of things that can be done very quickly out of my scope. But eye drops, cyclosporine eye drops, steroid eye drops, putting in little plugs to prevent drainage of tears because the eyes get dry because the tear producing ducts get damaged in graft-versus-host disease. There are special lenses that can be put in that can be really retaining. So again, that's a whole area of expertise onto itself but lots of local things we can do for the eyes if they're affected by chronic graft-versus-host disease.

23:25  Steroids (prednisone) to treat chronic GVHD:       When it comes to the needs for systemic treatment in chronic graft-versus- host disease that's affecting multiple organs and organ systems, this is where it gets a little more frustrating rapidly both for us and for patients. It's pretty standard fare I would say, that anybody with systemic chronic graft-versus-host disease in need of treatment, the first thing that we try to do is treat them with prednisone, with steroids, potent immunosuppressive drugs, lots of bad side effects. Things that we don't like to use for a sustained period for time, but we think probably our best first line option with our available agents at this point. That's hopefully something that's changing quickly. But patients who need systemic therapy for chronic graft-versus-host disease will almost always be started initially at least on prednisone to try and control the disease.

24:18  Therapies if chronic GVHD doesn’t respond to steroids (steroid refractory GVHD):  If the disease is not responding rapidly to that prednisone, or even worsening on that prednisone, then we start to talk about the need to take on second line treatments, additional therapy for the treatment of the chronic graft-versus-host disease and there is absolutely no standardization of what second line therapy looks like for chronic graft-versus-host disease. There's a lot of stuff out there that can be tried and people experiment. The management of this is far, far more art than it is science and though we are hopeful that maybe we're making some innovations that are looking promising, the management of what we call steroid refractory, that is chronic graft-versus-host disease that isn't responding promptly and nicely to prednisone, is a real hit or miss proposition.

Just to give a sense of that, these are two relatively recent papers that just list ... these are all different agents that people try in the setting of steroid refractory graft-versus-host disease. Many of you may be familiar with a variety of them and the number of different studies that the authors were able to find that have been published on each of these different therapies. This is a similar kind of a deal just listing all kinds of different therapies that can potentially be used in the management of steroid refractory chronic graft-versus-host disease with a little bit of an incidence of reported response rates in each of these separate modalities, and how likely patients were to survive over the course of a year or two if they were in need of these kinds of therapies.

Again, not meant to be something that you memorize but meant to at least give you a little bit of a sense that there's lots of stuff out there and what I think is fair to say is true is that no matter what anybody might tell you, there is no magic bullet. We don't have the ability to reliably predict, with any particular type of chronic graft-versus-host disease, which one of these therapies is going to be the best therapy for an individual. All of the studies that have been done, I think, are unfortunately less ... they're not rigorously designed, well done studies. Conducting those kinds of trials in graft-versus-host disease for a variety of reasons is unfortunately a big problem.

26:41  Choosing best therapy for steroid refractory chronic GVHD:  And so, while there may be some data that can be looked at for each of these different options, there is no magic bullet and there isn't really a right answer on this question. Again, hopefully, we're making some progress on that issue but instead, I think, as we'll talk about, what become major issues and thinking about what their best option for patients look like depends on a lot of different things that include financial issues, that include logistical issues, that include details of the relative expected toxicities and side effects of each of these drugs, because the problem is that most of them have potential significant toxicities and side effects.

27:21  First drug FDA approved for chronic GVHD is Ibrutinib:  I will say though, for those of you who I'm sure have dealt with this disease have probably heard, in 2017, there was actually our first drug that was approved for use in chronic graft-versus-host disease. Chronic graft-versus-host disease is something of a little bit of an esoteric subject in the general world of medicine and so most drug companies aren't really trying to pursue drugs for chronic graft-versus-host disease. But Ibrutinib, which is a drug that was actually developed primarily to treat a kind of blood cancer called chronic lymphocytic leukemia, CLL, is a pill that is, relatively speaking, relatively non- toxic. There was some rationale for it that it might be effective in chronic GVHD.

I also like to tell the residents and the fellows that we understand chronic GVHD so poorly and there's so much going on that you can find a rationale for almost any drug to potentially have value in the treatment of chronic graft-versus-host disease. And so, these drugs work in ways across the board. But Ibrutinib, a study was actually conducted led by a group out at Stanford, that showed reasonable responses with Ibrutinib. I would honestly say that they're comparable to the kinds of responses we see with lots of these other drugs, but the study was done a bit more rigorously and I think the FDA, which approves drugs, is under some pressure to maybe approve something for graft-versus-host disease. And so Ibrutinib got approval as an agent for chronic graft-versus-host disease.

It's not a magic bullet and it's not the solution to everything. I think our general experience with it, and the consensus that I've heard from lots of people, is there may be some drugs we think are even better. But to at least have an approval which helps at least with insurance authorization, not necessarily cost but insurance authorization, is something a bit of a changer in the field for us.

29:13  Three things to think about when choosing therapy for chronic GVHD – toxicity, cost and logistics:  When we think about how are we going to treat a patient with chronic graft-versus-host disease with this heterogeneous set of options that we have, there are, I'd say, three main things that we have to think about: the toxicities that are going to be associated with the drug we use, the costs that are going to be associated with the drug that we might use, and the logistics that are going to be associated with the drug that we might use. And for each patient, we try and think about each of those issues as we decide how to move forward through this arsenal of potential options.

The first thing that I think about, all other things being equal, is the toxicity issue and what the potential negative effects of these drugs might be. As a gross rule, until more recently with some of these newer drugs that we'll mention, the biggest toxicity of virtually all therapies related to chronic graft- versus-host disease was that they were drugs that knocked down the immune system, and in knocking down the immune system, they set patients up for more infections and infection problems and so a vicious cycle of infection, graft-versus-host disease, infection, graft-versus-host disease can develop and it can be a very challenging thing to deal with for sure.

30:19  Side effects of Prednisone at high dosages:  Prednisone, the mainstay of initial treatment and, for a very long time, the primary treatment, we know that, particularly at any high doses, doses above 20, 30 milligrams a day for sustained periods of time, prednisone has terrible, terrible side effects that I will do almost anything in my power to get rid of prednisone, to get it down and get it down to a dose of certainly no more than 10 milligrams in patients as possible because, number one, the risk of infection on prednisone goes up, up, up but prednisone will also cause diabetes. It will cause osteoporosis, it will eat at your bones. It can cause this thing called avascular necrosis, that often happens in the hip where the blood vessels deteriorate and you get this bone on bone thing that can be incredibly painful and require replacement of joints.  It can cause high blood pressure. Most patients on high doses of prednisone will get what we call Cushingoid, will get these fat faces and maybe a hump on their back. Horrible things and I think we all hate them, but my personal bent, for sure, is that I will do anything in my power to get prednisone doses down rapidly. And if I meet patients who have been treated at other places and I see them, and they come in and they've been on 40 milligrams of prednisone for a year, I will do everything in my power to get that down as quickly as possible.

31:37  Cost of therapies for chronic GVHD:  Second hugely non-trivial issue is the costs of these therapies. Again, virtually none of them, with the exception of Ibrutinib, are approved, and so insurance companies, and dealing with them, and sorting that out, and figuring out what you can get for patients and what you can't get for patients is a whole battle onto itself. Anyone who's been through a transplant has had the opportunity to interact with our healthcare system in more ways, I'm sure, than they would like, but it is a challenging and frustrating thing for sure. I mean, I have a patient, recently, we tried to get a fancy drug for him in Wyoming and I don't even know how it happened but it ended up in court, and like my notes, and then the judge is referring to my notes, and then the judge authorized it but then somebody else took it back.  It's a nightmare and so we do the best we can with it. Even Ibrutinib, an approved drug which we can generally get, you probably know better than me, but frequently will still be extraordinarily expensive even if it's approved. So, we have an extraordinary pharmacy team in our group, but the resource needs that can go in to trying to optimize this are enormously challenging both for you and hopefully for the transplant center that you're working with, that they try hard, but it's a conundrum for sure. So we have to think about that issue also as we think about options for patients.

32:56  Extracorporeal photopheresis (ECP):  Then logistics is also an issue. If we go back to the previous slide, at the top of list, this thing called extracorporeal photopheresis seems to be the most used entity for chronic graft-versus-host disease. We like extracorporeal photopheresis. It's actually not really a drug, it's a procedure. You get hooked up to a machine, blood goes out through the machine back into you. While it's in the machine, it's mixed with this ultraviolet light and it's mixed with a chemical that synthesizes itself to the ultraviolet light. And then, through a magical hand waving, that modulates the immune system and makes things better.  We don't know much more than that, to be honest with you, but the nice thing about it, from my perspective, is it doesn't tend to have a lot in the way of side effects. It doesn't tend to knock down the immune system profoundly and it doesn't tend to have a lot of negative side effects. So we like to do it if we can. A big problem with it though is you have to be at a center that can do it, and it's not something that can be done at most places outside of major urban centers, and then also, you have to come in and sit there for several hours and we usually do it twice weekly for a month or two then back off to weekly. So, it's logistically challenging but it's a modality that we do like to use as possible.

34:12  Long term complications from chronic GVHD:  So, what do we think about in terms of the long-term complications of chronic graft-versus-host disease and the kinds of things that it can do to patients? For sure, as we've already alluded to and mentioned, it's the single most significant issue with regard to quality of life, and probably finance in the long-term after a transplant, if we get through all the other terrible things that can happen and the disease doesn't come back. People dealing with chronic graft-versus-host disease, though it's very variable, complex, and different from person to person, are nearly always dealing with some degree of these different types of issues.

Again, infection is number one reason that people die who have chronic graft-versus-host disease. Immune system isn't working because of the GVHD. The medicines added on cause problems. Infections can be a big issue. Poor nutrition, poor teeth.

Graft-versus-host disease again, itself, is a marker that the immune system isn't working very well and our own body's immune systems actually do a lot to try and survey and prevent cancers from developing within us. And so if the immune system isn't working well, that doesn't work so well, so people can get second cancers after having a transplant and it's not just a random thing that bad luck to the person. So, we worry about that.

Lung issues if they develop can be very significant and very challenging.

Eye issues, sexual health issues, skin and joint issues are all potential problems that can be a consequence of chronic graft-versus-host disease.

35:42  Scheduling treatment for chronic GVHD:  So, when we talk about how we treat this disease and a bit of a paradigm for how things often go, many of you may have experienced this if you've dealt with chronic graft-versus-host disease, and this is also true of acute graft-versus-host disease, though as I've said often a bit more protracted and complex in the setting of graft-versus-host disease, is that a patient may present with some sign of chronic graft-versus-host disease. And it may be something that we think warrants intervention. That's here at the beginning of the curve.

36:13  Tapering off therapy for chronic GVHD/flare ups:  So, we'll put them on to some kind of potent medicine and hopefully, we'll see things starts to improve. We'll try and taper down the medicine and we'll try and reduce the medicine, and then we hit some tipping point as we're reducing the medicine down and the symptoms may start to worsen again or spread or show up somewhere else. Then when that happens, we bump things back up. We try to be judicious. We try to think about all of the things we've talked about. We try to think of the arsenal agents to pick what the next appropriate therapy will be. But it is often the case that as we're trying to get the therapy down and off, which we are always trying to do, things may flare up and then boom, we have to bump things back up, and then we try and do the same thing again, and then maybe things flare, and then we have to bring it back up.

It can be a very, very frustrating, long, challenging process to go through this again. It is art, it's not science, and there are lots of things we have to think about for every patient. Our hope is that we can get to a point where we can actively get rid of any immunosuppressant medicines, but it is often the case for patients with chronic graft-versus-host disease that it may take years, and years, and years, and years, and years to accomplish that and there are many patients who, I find, have chronic graft-versus-host disease who we can get down to a low dose, maybe 10 milligrams, 5, 10 milligrams of prednisone, maybe a little bit of a drug, Tacrolimus or cyclosporine, which most of you who have been through transplant have probably seen. But we can't get much lower than that and it maybe years, and years, and years, and years.

Ultimately, the entity tends to burn itself out and by years after transplant, we may be able to get rid of things, but there may be just some residual stuff there that's never going to actively get totally better and it just sort of is what it is. I will say again, it is not the focus of today or anything, but what we do find, for sure, at our centers is that - it began primarily because of the cord blood issue - we are able to get the vast majority of our cord blood patients off all immunosuppressive medicines within a year of their transplant, and we just don't see that to be true at all with unrelated and frequently even sibling donor transplant patients. So, if you're talking to people or whatever, I think it's an important issue.

38:33  Clinical trials for chronic GVHD:   To finish up with just a couple of points here, novel areas of investigation. As I mentioned, for a lot of different reasons that we could get into if you're interested, it's very challenging to run clinical trials around graft-versus-host disease. To conduct organized studies - that is the best tool that we have in medicine to really try and understand how effectively we're impacting things and how effectively drugs work. Because it is unbelievable to me, and I only understand it or see it more and more the longer I do this, is how easy it is for us through unconscious bias, subtle bias, perhaps deliberately convince ourselves that certain things work when they might not actually work at all, if we aren't able to study them in very organized, organized ways.

So, the notion of clinical trials for graft-versus-host disease, as with all areas of medicine where we haven't fully come to fix the problem, and certainly in the minds of people who are at academic medical centers, but I think across the board, is very appealing to us. And we are seeing more and more efforts at better clinical trials around graft-versus-host disease, but it's a challenging area and that makes it hard for us to understand how we best treat folks. I mean, obviously, if someone comes up with a pill and it just goes away, great. We don't have to worry about that. But that's not on the immediate horizon, and I think that we are likely looking at incremental steps in dealing with this disease and trying to best manage it.

40:10  Cellular Therapy, CAR-T therapy, and Chronic GVHD:  There are lots of things going on. I've harped on cord blood, but there are lots of things going on in a variety of centers where there are efforts being undertaken to manipulate the cells that are given back to patients, or to manipulate them in the early post-transplant period to take out subsets of cells that we think might cause graft-versus-host disease; to put in subsets of cells we think might be very powerful and helpful at preventing graft-versus-host disease. So, this whole area of what we call cellular therapy, manipulating the products, is an area of great interest, and enthusiasm, and excitement across the board in the world of cancer treatment particularly blood cancer treatment. Some of you have probably heard of these CAR T cells, which is a really exciting thing in the world of cancer [inaudible 00:40:54] and is an example of a cell therapy. But manipulation of donor cells is certainly something that is ongoing as an effort also to try and prevent graft-versus-host disease from developing.

41:04  Ibrutinib to treat chronic GVHD:  I think the two things around, which there's the most enthusiasm in the current environment, are these new drugs to treat graft-versus-host disease.  Ibrutinib, which we talked about already and I've already told you, in my experience and again from what I've heard, it's not a magic bullet. It is effective for some patients and if it's effective, I think it's a very good option. But it is nice in the sense that its toxicity profile is lower than a lot of the traditional agents though it's not a non-toxic drug for sure.

41:39  Jakafi (ruxolitinib) to treat chronic GVHD:  There's a drug called Jakafi or ruxolitinib which is in a class of drugs that are called JAK2 inhibitors and this JAK signaling pathway is another one of these things where it's involved in inflammation, it's involved in immune response.   It might be a targetable area in graft-versus-host disease, but I would say that there's been a fair bit of enthusiasm around ruxolitinib and preliminary data that's come up around in both in the setting of acute and chronic graft-versus-host disease and we're pretty enthusiastic about ruxolitinib as an agent that again has a relatively mild toxicity profile, probably less toxic than Ibrutinib, and really does seem to be having a positive impact on a lot of graft-versus-host disease patients. We've got a number of long-standing complex chronic graft-versus-host disease patients who I think have really had an appreciable change in things getting them on to ruxolitinib. So, it's a drug about which we have some enthusiasm.

There are variants of it, sister drugs, that are in clinical trials right now. We have some going on at our center. Inhibition of this JAK signaling pathway is an area, for sure, of enthusiasm. There are variety of other things out there, but I think these are the things around which there's probably the most enthusiasm.

42:58   Suicide genes to treat GVHD:  It occurred to me, I threw in this thing, suicide genes, to treat GVHD which I think this is my last ... oh, not quite my last slide. It occurred to me that this is more of a thing about acute graft-versus-host disease but it's cool so I like to talk about it.  The concept is that when we collect the donor cells, before we put them in, we can put a gene into them so that we can give some benign drug and it will cause those cells to die. So the idea is that if you do a transplant, you start having horrible graft-versus-host disease, we could just give you a marshmallow and that marshmallow will cause all those cells to die, and it's a cool strategy. Kind of complicated, kind of gets into the cellar therapy. A bit more of an acute GVHD than chronic GVHD thing.

43:46  Managing chronic GVHD requires a multi-disciplinary approach: But to finish up, I think I have two more slides, critically important in thinking about the management of this disease over the long term that it is a multidisciplinary thing. Hopefully, having an effective access to an integrated community of doctors that can help with all things is important. I mean, I very much appreciate the complexity of, again, our healthcare system. You go to one person, they tell you one thing. You go to another person, they tell you a different thing. All their little piece of the puzzle. I like to try and be as holistic as I can around the management of patients and try and keep it as focused as possible.

But there are critical roles, I think, certainly in patients who have issues in those areas, for specific team members in the long-term management of graft-versus-host disease and the well-being of patients after transplant. Critically important for sure, I would say, is the primary care doctor because all the kinds of things that normal people get, people who in the aftermath of transplant, even without chronic graft-versus-host disease, are at a bit more risk developing - heart disease, second cancers, all kinds of issues. So, integration with a primary care team, with the oncologist is always a very valuable thing for sure.

45:05  Summary of Talk:  So, just to summarize, chronic graft-versus-host disease, an unfortunately very common issue after stem cell transplant, can affect lots and lots of organs and can be a very, very, very challenging both in terms of quality of life and finances. It's a complicated thing. Multidisciplinary approach is necessary and, as with all things transplant related, taking advantage of your support network and hopefully having a team behind you is such an important thing to help get through it all. But hopefully, this is something that's going away soon and I guess I'll leave it at that and I'm happy to answer any questions [crosstalk 00:45:47].

45:47  Moderator thanks Dr. Gutman:  Thank you, Dr. Gutman. You can repeat the question.

45:48  Can stress cause a rash?: Can stress cause rash? I don't think you'll mind me telling you, this is a patient of ours from years ago who currently lives in Hawaii and just flew out to see us. So, he's very interested in not being stressed. But I think stress, and its consequences on physical well-being and physical health, is somewhat of a poorly understood relationship. But I'm certainly a believer in sound mind and sound body. I don't know that rashes, per se, are typically caused as a consequence of stress, but we see rashes for so many different reasons. It may be a contributory element for sure.

46:39  Question about how to get off prednisone: Hi. My name is Margie. I had my transplant in 2015 and I've been trying to get off the prednisone, but I can never get below 15. I've tried so many times and then I'll have horrible flare-ups and I'll have to end up going back to 40 or 50 and wean my way down. It's happened like three times. I'm down to 17 and a half now and I'm terrified to go back to 15 because I always have such a hard time. I've been taking Jakafi and I think that helps and I was just wondering what you would suggest.

47:19 How to get off prednisone:  Sure. Obviously, every person here has a story and has their special circumstances and I said it's such an individualized art to manage this that I think it's ... I'd obviously want to know a lot more details to understand a bit more of the exact circumstances, but as a general operating principle, I think it's fair to say that if you're having problems and you're on the combination that you're on, there's other things out there to try and that you might have to just keep trying to add other adjunctive agents to help facilitate the prednisone coming down. It really is artful management.

As a general operating principle for how we do things, we like to, if we get in a situation where we have to think about adding other things, add another thing without bringing things down, give a little bit of time, you know a few weeks for the new thing to be in system doing its thing, And then if we're seeing at least stability, if not improvement, trying to taper down the prednisone and get it down. But it's art and there's lots of things out there. I don't know what you have and haven't had.

Another truism of prednisone, that isn't necessarily true in your circumstance from what you're describing to me, but can become a very real issue as you get down to lower doses of prednisone and trying to get rid of lower doses of prednisone, is that our bodies actually make prednisone and we need it for lots of things. If you are chronically on doses of prednisone, your body stops making it. And so it can very significant challenge as we get down to lower doses. This usually starts to become an issue around 10 and dropping below 10 or so. But just taking prednisone down from those kinds of doses can cause people to feel really, really lousy because they're not getting the prednisone that they need. And so that has to be tapered very slowly and very delicately. It's individually very heterogeneous too. We've dropped some people off of 10, no problem at all. Some people have to go to 9, to 8, to 7, to 6, to 5 and goes on, and on, and on. As a bit of a side point but I would just mention it.

49:33 Question about when risk of getting chronic GVHD declines:  If one hasn't shown symptoms of chronic GVHD by the seven-month time period, what does the risk graph look like after that for doing it?

49:42  Gutman response to when does risk of getting chronic GVHD decline:  Well, that's an important, and good, and interesting question. Again, every center is a little different in terms of how their transplants are done, the prophylaxis it's offered, et cetera. But I would say it's generally true that most of you probably were on some kind of program where the intent was to taper the immunosuppressive medicines off over the course of about six months, maybe a year after the transplant. I think that as we're tapering the immunosuppressive medicines down, that's always a timeframe in which it is very common to see things flare. We may go down a notch and then we start to see the GVHD develop. If you get off of immunosuppressive medicines and you are truly off of immunosuppressive medicines, after several months off immunosuppressive medicines, we start to think that maybe we're not going to have a problem with chronic graft-versus-host disease.

50:37  Late flare-up of chronic GVHD:  That said, though, there are certainly situations where I see patients who have been off immunosuppressant for months, and months, and months, even years, and may start to flare some chronic graft-versus-host disease symptoms. Sometimes, it happens in the context of maybe having had an infection or some sort of inflammatory state that might trigger it. Another thing that we deal with, it's not terribly frequent but it's I think a reality of the lives of post-transplant patients in many situations, is it's very often, certainly here in Colorado where we have great distances and things like that, that people may go back to places that are much smaller and then may have a lot less experience with this entity. It can come on rather subtly and it can come on slowly. And if it's not being watched for, and it's not being looked after, and people aren't paying great attention they can come back to us three months after we last saw them and have some really significant stuff going on that just wasn't picked up because it's a subtle thing.

51:40  Be vigilant looking for GVHD symptoms:  So, I think I would encourage everybody, for sure, also if you're not in a place where you have access to transplant doctors 24/7, that being wary of symptoms and calling them to people's attention is an important thing to do, for sure, because I think we have at least the sense that we might have a better chance of controlling this disease if we catch it when it's first starting than if we have to deal with it when it's fully developed. And I can think of cases over the years, we've had patients come in just unable to walk. I don't quite know how they got to that state without drawing it to anyone's attention, but it can be very frustrating and challenging.

52:20  Question: Are muscle cramps considered GVHD?   A lot of people seem to have random severe muscle cramping after transplant. Is that considered GVHD and, if it is, are there any treatments for that?

52:33  Gutman response to muscle cramps associated with GVHD:  Yeah. It's very often a phenomenon associated with GVHD. One of the things I also say about GVHD in the post-transplant setting is almost any symptom someone's having, in fact, you don't have an easy answer, I'll just say it's GVHD. But that's certainly something we see and is described frequently. Inflammation of the muscles or the fascia, the tissue underlying the skin, can certainly contribute to that. I do think that one of the things that can be a little bit challenging about that muscle ache issue, though, is that sometimes a consequence of all the treatment that you've been through, and perhaps sometimes, just the steroids and the prednisone, can contribute to this.

53:11  Drugs for GVHD can cause symptoms of GVHD:   One of the issues that we deal with, as another issue around these drugs, is that many of them can sometimes cause symptoms similar to graft-versus-host disease also, particularly I think the MMF or CellCept, which some of you might have taken in the early aftermath of a transplant, classically can cause nausea, vomiting, diarrhea and we use it to prevent nausea, vomiting, and diarrhea. So, it's a little bit of a tricky issue, for sure, but definitely muscle cramping is something that we see as a phenomenon that is graft-versus-host disease related. But there isn't a magic bullet either. I think, again, it's experimenting and trying to find what works for you with the options that are out there.