Ask the Graft-verus-Host Disease Experts
February 13th, 2020
Presenters: Steven Pavletic, MD, Head of the GVHD and Late Effects Section in the Immune Deficiency Cellular Therapy Program, National Cancer Institute
Stephanie Lee, MD, MPH, Research Director, Long-Term Follow-Up, Fred Hutchinson Cancer Research and President of the American Society for Hematology
Sandeep Jain MD, Director of the Dry Eye and Ocular Graft Versus Host Disease Service at the University of Illinois Health in Chicago
Presentation is 1 hour and 12 minutes of Q&A.
Summary: Graft-Versus-Host- Disease (GHVD) is a common challenge for people who had a transplant using donor cells (allogeneic transplant). GVHD can impact many parts of the body including skin, eyes, mouth, GI tract, liver and muscles. The treatment for GVHD is rapidly changing and information can be difficult for patients to navigate. This webinar brings together three top GVHD experts to answer your questions about the treatments and therapies available today.
- Graft-versus-host disease (GVHD) is associated with a graft-versus-leukemia or graft-versus-tumor effect, which reduces the risk of relapse. However, the graft-versus-leukemia effect can be at work, even if you do not have active GVHD.
- Dry eyes caused by ocular GVHD can persist for life, even after GVHD is no longer active.
- GVHD can slightly increase your risk of developing a skin or oral cancer later on, but not other cancers.
Thanks to Pharmacyclics, AbbVie Company and Janssen Biotech, and Jazz Pharmaceuticals for supporting this event.
04:14: Joint stiffness, cramping and limited range of motion are common in GVHD patients. It is caused by scarring of the tissues. Current treatment options include extracorporeal photopheresis (ECP), Imbruvica and Jakafi, and retaining flexibility by stretching and massage.
06:36: GVHD of the kidneys is rare and treated in the same way as non-transplant related kidney damage is treated
09:31: Contact lenses can be an effective treatment for ocular GVHD. Soft contact lenses can help reduce pain associated with eyelid movement over the eye. Long-term, using a scleral contact lens that covers a larger area of the eye is preferable.
13:49: About 10% of GVHD patients develop a lung problem called bronchiolitis obliterans. This cannot be reversed, but may be slowed by early intervention. Frequent pulmonary function tests can help detect the problem early.
18:51: A combination treatment for dry eyes caused by GVHD is most effective and may include preservative-free anti-inflammatory eye drops, scleral lenses, serum tears and chamber glasses.
28:56: GVHD of the muscles is rare, but needs to be treated right away to avoid devastating side effects.
30:11: Changes in skin color are common with skin GVHD. There are no effective treatments, but the changes usually resolve over time.
O1:01:38: Jakafi is an effective treatment for acute GVHD and is being studied as a possible treatment for chronic GVHD
Transcript of Presentation
00:00:02 [Moderator] Good evening and welcome to tonight's Ask, the GVHD Experts forum sponsored by BMT InfoNet. My name is Sue Stewart and I will be your host, one of your hosts, for this evening.
If you're not familiar with BMT Info Net, we're a not for profit organization that provides transplant recipients or their loved ones was high quality, easy to understand information about bone marrow, stem cell and cord blood transplants. We have many publications, a peer support program and a website that has a lot of valuable information including information and videos about GVHD.
Before we begin, I would like to thank Pharmacyclics LLC, an Abbvie company, Janssen Biotech and Jazz Pharmaceuticals, whose support, in part, has made tonight's webinar possible.
So this is how tonight's session will proceed. For the first half hour our GVHD experts will respond to questions that you submitted at the time you registered. We will have them respond to as many of those questions as time allows. For the second half hour, we will take questions submitted by attendees on this call. If you have a question, please type your question into the chat box in the lower left hand corner of the screen.
This presentation is being recorded and will be available to review on our website at bmtinfonet.org after the webinar.
Now it's my pleasure to introduce to you tonight's GVHD experts. Dr. Steven Pavletic is the head of the GVHD and Late Effects Section in the Immune Deficiency Cellular Therapy program at the National Cancer Institute in Bethesda, Maryland.
Dr. Stephanie Lee is the research director in the long-term follow-up program at Fred Hutchinson Cancer Research Center in Seattle, Washington. She is also currently the president of the American Society for Hematology.
Dr Sandeep Jain is the director of the Dry Eye and Ocular Graft Versus Host Disease Service at the University of Illinois Health in Chicago, Illinois. Please join me in welcoming our guest speakers.
00:02:20 [Moderator] So, let's begin with the first question. Dr Pavletic, If I'm having GVHD symptoms, does that mean that the graft-versus-tumor effect is still working?
[Pavletic] Good evening, thank you for this question. Graft-versus-host disease is tightly connected with graft-versus-leukemia or graft-versus-tumor effect. And in general, we say that having little bit of graft-versus-host disease is actually a good thing and is associated with best leukemia or malignancy-free outcomes after allogeneic transplantation. It is important to know that if a patient doesn't develop signs of graft-versus-host disease, at the same time, graft-versus-leukemia or graft-versus-tumor effects could be an action. So this is another reason for concern. Just have to follow patients closely and do everything that's necessary in communication with their physician.
If the symptoms are exaggerated, more than mild, then often a concern is [whether] graft-versus-host disease should be treated aggressively with immunosuppression, and all the information we have is yes. If there is more than minimal graft-versus-host disease, then we do know that anti-tumor effects can go up, but then other risks associated with GVHD go up as well, and in principle, then, at that point, graft-versus-host disease has to be treated per treatment principles, and if needed, even aggressively with systemic immunosuppression.
00:04:14 [Moderator] Thank you Dr Pavletic. Next question, Dr Lee. Please address joint stiffness, limited range of motion, damage to ligaments and tendons, and hand cramping and stiffness caused by GVHD. Are there remedies? And then along the same line, someone else asked, "My daughter has had a locked arm at 90 degree angle for two years with blister-like sores on the arm, and now lymphedema in her hand. ECP, Imbruvica and Jakafi are not helping. Any recommendations to get positive results?"
[Lee] Hi, this is Stephanie Lee, and thanks again for inviting you to this forum. I'm sorry to hear about these two cases, because I think this is, unfortunately, rather common in chronic GVHD. So in both of these situations, these people are having what we call sclerotic graft-versus-host disease, which is basically when the tissue kind of scars down, and that leads to the joint stiffness, to the limited range of motion, to the contractor, this locked arm. And it can lead to these ulcers on the skin and to this lymphedema, which is if there's some scarring, then down below that scaring, you can get swelling.
In terms of the treatment of this, I think it's two fold. One is to try to find effective GVHD treatment so that the scarring process stops. And some of the things that have been mentioned here, ECP, Imbruvica, Jakifi, are things we try. There are many other things that we try and there's also clinical trials that are targeted towards this particular problem. And I think if any particular treatment is not working, I would encourage people keep looking for additional therapies that might be helpful.
I think the other thing that people can try to do is good supportive care. So whenever the joints and the skin are involved like this, trying to retain what flexibility you have already by stretching, by sometimes massage, and certainly by, in terms of the ulcers, making sure that you're on good antibiotic or antiviral, antifungal prophylaxis if that's indicated, and treating those ulcers aggressively. But this is a very vexing kind of graft-versus-host disease and you just have to keep trying one thing after another.
00:06:36: [Moderator] All right, thank you very much. For you, Dr Pavletic. “I was recently diagnosed with GVHD of the kidneys. I'm told this is very rare and there's limited clinical data to support treatment protocols. Is there any new research being done regarding GVHD of the kidneys?"
[Pavletic] Oh, well thank you for this question. Yes, it's still totally correct that GVHD of the kidneys is a very rare manifestation and it's certainly then very difficult to do large clinical studies and protocols in such a complication that affects maybe 1%, at most, patients after allogeneic transplantation. So classically, we don't consider GVHD of the kidney a classic manifestation of chronic graft-versus-host disease. But definitely we refer, with this term, to situations where kidney damage occurs as a consequence of autoimmune reactivity. So donor immune systems works against the recipient, and in this situation may cause all this hyper-activated immune system, the immune attack happens at the level of kidneys.
So it's important, in this situation, it's important to rule out other potential causes of kidney injury. There could be many other diseases, I mean, complications after transplant. They are often medications-related, like tacrolimus or the cyclosporine and some others.
But when chronic GVHD of the kidneys occurs, then it is associated with spilling lots of protein in the urine, most commonly. And typically it happens at a time of tapering of immunosuppression which occurs between 6 and 12 months after allogeneic transplant. It may or may not be associated with other signs of chronic GVHD, and then it has to be treated in the same way as are treated non-transplant patients with the same types of autoimmune kidney damage, usually called glomerulonephritis. Basically, in these cases we are using systemic treatments such as prednisone, rituximab, MMF, some of those drugs that also work for chronic GVHD in other organs. A reinstitution of systemic immunosuppression takes care of the problem. In some rare instances, it can be more difficult to get this kidney process under control.
00:09:31 [Moderator] Thank you, Dr Pavletic. Dr Jain, You're the expert on ocular GVHD, this is the one for you. What is the difference between soft contact lenses, bandage lenses, and scleral lenses, and how do you choose which one to try?
[Jain] Oh, thank you for the question. First, I think it is important to understand why a contact lens would work in chronic GVHD at all, and then the choices become easier to understand. What happens is that the eye surface gets inflamed in chronic GVHD due to lack of tear production and fibrosis and many other reasons, such that the surface becomes very irritated. And as the eyelids move over the surface, they can cause immense pain or light sensitivity, feeling of grittiness, dryness, [which] just makes the feeling from the eyes just miserable. Now, how do you take care of that?
Well, if we put a piece of plastic that covers the surface of the eye and separate the eyelid movements out, then one would not feel that pain, now, because the eyelids are moving on the piece of plastic. And that's exactly the rationale for using contact lenses in GVHD. To heal the surface under the contact lens and to reduce pain and discomfort that is due to eyelid movement on the surface.
So all contact lenses are basically pieces of plastic. The smaller soft contact lenses, the regular vision corrective contact lenses are fine. They are smaller, they cover primarily the transparent part of the eye, which is the cornea. They don't cover the white of the eye much, but they are very effective. They are easy to insert and they are the first choice, in fact, to rapidly help patients get better.
Long-term, we like to go to scleral contact lenses, which are much larger, so they cover the white of the eye also. But a very important difference is that the scleral contact lens, they vault over the transparent part of the eye, which is the cornea, as opposed to the soft contact lenses, which are in contact with the cornea. So if the surface of the eye, the cornea, is very diseased, then obviously you do not want the contact lens to be in contact with the surface of the eye.
And there are other strategies we can employ. For example, putting serum tears will help heal the surface under a scleral contact lens.
So which one to try? I think it's fine to go with the soft contact lens first, and there are some logistics involved and it's really not to fit the scleral contact lens. The fitting may need some time, but finally, our goal is to go to scleral contact lens. One thing that is very important to understand is that you cannot sleep in the contact lenses. That really increases the risk of infections, both for soft contact lenses and for scleral lenses.
00:12:56 [Moderator] Thank you. On to the next question. Dr Lee, "Can complications arise with GVHD when an IVIG is administered for a flu or a viral infection?"
[Lee] I think this person's asking about giving IVIG if someone has a viral infection, is how I'm interpreting this. And I think the short answer is essentially, no. There's lots of side effects that can happen with the IGG infusion, but I wouldn't think that a graft-versus-host disease flare or response to that would be concerning. I think this person might be worried because we do think that antibodies have some pathology in GVHD and causing GVHD, but I wouldn't, if IVIG infusion is indicated for someone's care, I wouldn't be worried about that.
00:13:49 [Moderator] Thank you. Next question, Dr Pavletic. "Please discuss treatment options for lung GVHD. Is there anything other than the FAM regimen? And is lung transplant an option if you have bronchiolitis obliterans syndrome?"
[Pavletic] So, GVHD, I'm talking about chronic GVHD of the lungs, it's a relatively rare manifestation of chronic graft-versus-host disease. About 10% of patients with chronic graft-versus-host disease develop lung manifestations, then we call that bronchiolitis obliterans syndrome. It is very important to follow regular pulmonary or lung function tests after allogeneic transplantation because symptoms can occur quite late when quite a bit of damage to the lungs has already occurred. So that's the one important aspect of approaching the lung chronic GVHD.
When these manifestations occur, they're reflected in a decreased lung function and narrowing of the small airways in the lung, sort of like an asthma-type of problem. This asthma can't be improved or reversed by interventions. These kind of changes are irreversible because of a fibrotic type of scar, type of changes on the small airways. Then we have what we call bronchiolitis obliterans, and it's one of the more difficult to treat manifestations of chronic GVHD. And usual medications like corticosteroids, prednisone in the initial therapy for chronic GVHD, which are often very effective initially, don't really work for bronchiolitis obliterans syndrome well.
We usually recommend very short courses of prednisone, and then the mainstay of therapy is, as you correctly mentioned here, FAM. So inhaled steroids with an oral anti-asthma medication and an antibiotic [such] as azithromycin has been shown as a very, very adequate therapy as a front-line for these kind of patients that keeps at least most of the patients stable with this kind of treatment.
And we don't like to give systemic steroids in this situation, that actually could be instrumental in the long run. It's a major focus of research and trying to come up with better approaches. If FAM is not effective there are many other options that can be tried, but they're even less effective than, in general, in second or third line therapy for usual chronic graft-versus-host disease. It's quite often we resort to using extracorporeal photopheresis for these kind of situations.
Common drugs like tacrolimus or cyclosporine can be sometimes used. There is some substantial evidence that anti-tumor necrosis factor antibodies can be helpful in patients who need something beyond FAM.
And you are asking a question about lung transplant. The short answer is yes, definitely, the lung transplant has been done. There are quite a number of cases with advanced bronchiolitis obliterans syndrome that ended up having lung transplants with very good success, but this is not something that we like to advocate. We like to find ways of preventing this situation coming to the point of having lung transplant. But in an unfortunate case, if somebody needs a lung transplant, actually nowadays, at least in the short term, they work very well and patients can get back to a very normal function at least for some time. But basically lots of research is growing in this area.
We have some drugs of interest called JAK inhibitors. One example will be Jakifi. We don't know anything conclusively about these new agents. How do they work? There's some other anti-fibrotics, anti-scarring agents that have been in research, or some other anti-inflammatory drugs that attack neutrophils. But the best recommendation would be to try to find a clinical trial around if assistance is necessary beyond FAM therapy for lung GVHD.
00:18:51 [Moderator] Thank you, Dr Pavletic. Dr Jain, "What else can I do for dry eyes? I'm six and a half years out from transplant. GVHD started nearly two years later. I've used steroid drops, blood serum eye drops, synthetic albumin eye drops, various over the counter drops and gels, cauterization of eyelids, and scleral lenses. The lenses work the best, but only for a short time before my eyes are dry again. I now have non-age related cataracts due the several years of steroid use.
[Jain] Well, thank you for the question. Indeed, ocular GVHD can be a very difficult problem, and the best way in our experience we've seen it respond to treatment is to use a combination of treatments in a step-down approach, which means that we don't add a starter treatment. If it doesn't work, then stop it and try something else. A combination of treatments generally gives a better success, using anti-inflammatory eye drops like steroids, along with scleral contact lenses, along with serum tears and so on.
Now, the question is what else can be done, because it seems that this patient has done practically everything that I've said. There are some guidelines, I guess some principles and things that can add to the effect.
For example, everything that is used on the eye in these patients should be preservative-free. We can't use any commercial eye drop that is dispensed in a multi-dose bottle and has a preservative inside, we should avoid that. Sometimes we may need to compound preservative-free steroids in other drugs, but that is slow.
Serum tears. We like to use 50% and so increasing the concentration can sometimes help, or going onto plasma rich in growth factors can help.
One thing that I feel has a good additive effect is just the way the eye drops are applied. We tell our patients to lay flat on the bed, and then put the eye drops on the eye, and then gently lift the upper lid so some of it tracks back under the upper lid. Now, that would make sense because if you were sitting up or just [had] the head a little bit tilted back and applied the eye drop to the eye, the gravity is working against you. It just goes into the lower eyelid and onto the cheeks. We want the eye drop to stay on the eye for some time, and that simple technique, our patients tell us, makes a difference.
The other thing that we also tell them is to use some non-pharmacological strategies, like wearing moisture chamber glasses. Now, these are sunglasses or eyeglasses which have a foam backing or a plastic backing which makes a seal around the eye so that the eye is now protected from the environment: it's windy outside, or you're driving and there's hair blowing on the eye, which can dry the surface out. So there are many other strategies that we can use.
In terms of what else can be done from a research perspective, from eye drops that are currently under development, there are eye drops that we are looking at. Brimonidine nanoemulsion is one which is in phase III clinical trials. Platelet cell lysates from Cambium is in clinical trials. At our institute, we use pooled human immune globulins as eye drops, which has given us some good results, but these are all investigational eye drops that are placed under protocols for clinical studies. So the answer, what else can be done? Yes, a lot can be done. We just can't give up, that's certainly one thing we can't do.
The second part of the question is that the patient now has non-age related cataract due to several years of steroid use. That's very common, but just the fact that the patient has a cataract does not mean that one should rush into cataract surgery. The indication for cataract surgery is if the patient is unable to do the things in life that they want to, and the quality of life is now reduced, and you're not able to do the daily activities that you would want to. What could those be? Driving at night, for example. Watching T.V. and it's blurry, even with your best correction of glasses.
Cataract surgery in ocular GVHD patients is fine. We've had hundreds of patients with ocular GVHD with cataracts who have undergone surgery, and they all do fine. Yes, there are some special considerations that are needed. The post-operative recovery may be likely more prolonged, there may be a little bit more discomfort. We may have to use contact lenses or not use certain eye drops like non-steroidals. So yes, there are some special considerations we have to keep in mind but overall, patients with ocular GVHD do fantastic after cataract surgery, so no problems with that.
00:24:38 [Moderator] Okay, thank you. Next question, Dr. Lee. How do you know when GVHD is completely gone? If I have no symptoms after eight to 10 years, is there still a chance it could come back?
[Lee] Thanks, Sue. I think this is a common question for people. The only way that you know GVHD is completely gone is that you really never have to deal with it again, unfortunately. A lot of people, even when you get off immunosuppression, will continue to have mild symptoms that come and go. You may need to get on some topical therapy or a little bit of therapy here and there, and so probably the GVHD is not completely gone, but it's at low enough activity that it's not really bothering the person.
If someone's had GVHD and they really have had no symptoms for eight to 10 years, and particularly if they've been able to get off immunosuppression, then yes it could still come back because it could always come back, but I think the chances are probably pretty low at that point. I think unfortunately, once you've had a transplant, anything that happens could be graft-versus-host disease, but it gets less and less likely as time goes on.
00:25:43 [Moderator] Thank you. Next question, Dr. Pavletic. Does GVHD increase your risk for getting other cancers?
[Pavletic] So we do know that having graft-versus-host disease, particularly having both acute and chronic graft-versus-host disease has been associated with higher risk of getting a cancer somewhere down the road after allogeneic transplant. Usually takes at least five to 10 and beyond years follow up. Fortunately in the big numbers, those instances are relatively rare so the risk only can be detected with a larger population of studies.
Some particular types of cancer, like skin cancers or oral cavity cancers, have been found to be more elevated in long-term survivors after allogeneic transplantation. And particularly if treatments were delivered with some older drugs like azathioprine, but even some more recent drugs like cyclosporine or sirolimus or prednisone, [these] have been associated with higher risk of skin or oral cavity cancers. So the good news is that many other common cancers that occur in general population have no increased association with chronic graft-versus-host disease.
And in general, the recommendation is, the bottom line is to adhere to usual healthcare maintenance prevention practices with your primary physicians. In case there's something else, some high risk indication detected like some special type of skin or some cancerous skin lesions and so on, then you can get more frequent skin checks or some other preventative measures could be pursued. So long story short is that yes, the risk is higher, but in the big numbers there's really nothing to be particularly engaged about. Just do everything and lifestyle measures and maintenance like any other person that's in population to follow for standard preventative measures.
There's some research going on. There's some cancers that could potentially be prevented, like using the HPV vaccines that have been started even after allogeneic transplant. At this time, we don't know if those could prevent certain type of cancers that are associated with HPV virus, but I'm just mentioning this as an area of research that may end up someday in our ability to actively prevent certain cancers in graft survivors.
00:28:56 [Moderator] Thank you, Dr. Pavletic. Dr Lee, a patient said “I received a BMT in September 2017. I was diagnosed with GVHD in February 2019 which manifested as myositis, polymyositis, as it affected many muscle groups. How rare is GVHD in the muscles?”
[Lee] Yeah, thanks Sue. So GVHD of the muscles is definitely recognized, but I would say it's very rare. It's probably less than 1% of people who will get it. However, when you get it, it needs to be treated right away and it can have devastating side effects. I will say, I haven't seen very many cases in my career, but the ones that I have seen actually have responded pretty well to our treatments.
The problem is that as you taper those treatments off, it tends to come back again. And one of the treatments that we tend to use is steroids, which can also cause muscle weakness. And so it's very important to be under the care of someone who can follow very closely. Oftentimes that is a neurologist who can taper the prednisone and the other immunosuppressants, and watch out for that balance between treatment side effects versus the actual polymyositis graft-versus-host disease.
00:30:11 [Moderator] Thank you, Dr Lee. Next question, Dr. Pavletic. “I have skin GVHD and the pigment in my skin has changed color. It's being treated with triamcinolone and tacrolimus. Will the skin color change be permanent?
[Pavletic] Changes in skin pigmentation and color, increased pigmentation or decreased pigmentation, is a disturbing manifestation that can go with chronic graft-versus-host disease of skin. It's something that's definitely a very prevalent concern among patients. From our end, as a physician, we're usually more alarmed when we see the more dramatic manifestations that are associated with substantial disability, and then it can be life-threatening with very active, extensive red skin rashes or contractures, or sclerotic lesions. They go with the typical active chronic graft-versus-host disease.
So for skin discoloration, this can be part of the active chronic graft-versus-host of the skin, in general, we still think that if it's only skin discoloration, the good news is that there's not necessarily too much active disease. So this is the good news and bad news. The good news is that it's not active disease, so it's unlikely to cause some major disabling symptoms and less problems, but certainly very disturbing to the patient. These kind of manifestations are, on the other hand, very, very difficult when it comes to trying to treat. We actually don't have very effective ways, and I would strongly recommend to connect with a very good dermatologist as well. But there are really no very effective treatments. There's corticosteroid creams or tacrolimus is similar and commonly used for the somatic cosmetic measures.
The good news is that over time, in general, those changes tend to become less intense, less contrasting, less disturbing, but it takes many years. It may never completely go away, but after years of fading of the GVHD process and after transplant. So the encouraging part would be that this can somewhat get improved. It's annoying, disturbing, and a problem that, again, doesn't go with active disease but it's very difficult at this time to treat effectively, unfortunately.
00:33:19 [Moderator] Okay, thank you Dr. Pavletic. Next question, Dr Lee. My daughter has severe scleroderma/fibrotic tissue. She's on Imbruvica for a year and also on Jakafi for seven months. She has very limited mobility. Do these medicines take a long time to have a positive effect to loosen her skin?
[Lee] I'm sorry to hear about this, just like the other two people who had their questions. Again, sclerosis is really, really difficult for us to treat. To address this specific question, chronic GHVD takes a long time, usually, to respond to our treatments, and particularly in sclerosis. I usually give any treatment that I'm trying at least three to six months to see if they're getting any benefit. Sometimes in sclerosis, just not getting worse is actually a benefit if someone's been progressing up until they tried a new treatment.
For these two treatments that are mentioned, so the Ibruvica and the Jakafi, we really think that if they're working, they're working by preventing future damage and ongoing damage. They're probably not directly affecting the sclerosis and the sclerotic tissue that's already there. It's probably just keeping additional damage from happening, and then hopefully the person's own body will, if we turn over all of our tissues, help to loosen and to soften, and to address the sclerosis. So I do think you have to give any treatment awhile. In this particular case, if someone's been on it for a year and for seven months and they're a person that's actually getting worse, in my mind it would be time to move on and to try something else.
00:34:53 [Moderator] Thank you, Dr Lee. Next question, Dr Jain. “Does ocular GVHD eventually go away, or is this a lifelong issue?”
[Jain] Thank you for the question. Ocular GVHD, the highest risk of developing it is around seven months after the bone marrow transplant, up to two years. And the reason why ocular GVHD develops is because of the immunological attack that's going on on the surface of the eye, due to the graft-versus-host disease processes that have taken place systemically. So the fuel that is driving this inflammation is the GVHD processes, and that's why these structures of the eye become damaged. The lacrimal gland, which produces tears, ceases to produce tears because it's destroyed with fibrosis. The surface of the eye is damaged, and so on.
Early on, it is the ocular GVHD processes that are causing the trouble, that are fueling the fire. About two years or so, maybe about three, four years as time passes, these immunological processes tend to burn out, but in the wake of what has happened, the patient's eye has become now dry. It is not producing tears, and it has lost the ability to, let's say, produce even oil on the surface, so it has become an inflamed, to your definition, dry eye and at that point, maybe it is not the GVHD processes that are driving the inflammation, but the dry eye processes that are driving the inflammation.
The ocular GVHD processes, I would say, would probably go away, but the inflammation due to its sequel, or it's consequences, will then continue to drive the inflammation forward. For that reason, the treatment, some form of treatment to treat the dry eye would probably be lifelong. Whether that treatment is just artificial tears or whether that treatment is artificial tears with some steroids or serum tears depends upon what is the extent of damage ocular GVHD has caused in its wake.
[Moderator] Thank you Dr Jain.
00:37:42 [Moderator] Okay. All right, next question please. What is the current standard of care for discontinuing immunosuppressants after an unrelated mismatched allogeneic stem cell transplant? Dr Pavletic, can you answer that?
[Pavletic] Yeah, thank you for this question. So I would say that after unrelated mismatched, allogeneic stem cell transplants, in general, the tapered end goal of the immunosuppression approach, it's no different than after any other conventional allogeneic hematopoietic stem cell transplant. There are some protocols that tend to delay tapering, where there are studies, but in general, the principle is the same. It's driven by the fact that unrelated mismatch allogeneic transplants are associated with more acute and chronic graft-versus-host disease.
So the rate of tapering immunosuppression is really driven, as usual, by manifestations. So graft-versus-host disease, in this particular setting, is actually more common and therefore it's more likely that patients would stay longer on an immunosuppressor regimen or treatments for graft-versus-host itself because if it's more common.
So in general, nowadays, when almost all patients have better choices of type of allogeneic donors, the focus is moving more into choosing transplants that would result in lower likelihood of complications associated with the mismatches. So in the future, with the evolution of the field, we are going to try to avoid this kind of [transplant], but the reality is some patients need it. Allo transplant, it's maybe the only option, so this is the case where tapering is driven by clinical activity of graft-versus-host disease. How much is present.
00:40:17 [Moderator] Thank you, Dr Pavletic. Next question. Dr Lee. How common is central nervous system GVHD? Can you recover from the CNS GVHD?
[Lee] Well this is a great question. I think a lot of people would want to know the answer to this. You know, for a long time we said that the central nervous system was one of the sanctuary organs and that we didn't think that it was involved with GVHD. I think more recently there's been an understanding that yes, people who have chronic GVHD do seem to have symptoms in their central nervous system. So when their brain is ranging all the way from, you know, thought disturbance all the way to actual strokes. But because we haven't really been collecting the data we don't really know how common this would be and we also don't know, in general, what the natural history of it is. I will say that I know a lot of people are actively studying this process ,actually both in humans and in mice, and so I hope we do know more about this in the future.
00:41:19 [Moderator] All right, thank you Dr Lee. Next question, Dr Pavletic, “Going into my BMT, very little was discussed about GVHD. It was offered up as a potential side effect that could be dealt with as if it weren't that big a deal. From what I've read, 40 to 50% of BMT recipients get GVHD. Is there any shift in protocol to talk more honestly about GVHD?” And to provide more support after BMT such as offering more GVHD experts at treatment centers.
[Pavletic] But this is a very important question that goes to all of us really, as a trust of community and as physicians and advocacy, and patient support groups. How can we better address these not uncommon comments and concerns we hear from patients, usually longer term later after allogeneic transplants, when graft-versus-host disease, particularly chronic, becomes a prominent problem. And short answer would be, we all need to keep in mind this aspect and all try to do best possible job. Not that we are not doing that, but there is always room for improvement and for joint action in this arena.
I would say education is a key word. And the good news is that moving into allogeneic transplantation, sometimes there is lots of acuity on how to treat cancer and focuses on leukemia and how to overcome lymphoma. But usually it's a process. And from day one, in the general oncology clinic to the transplant clinic , and all this counseling and planning of the transplant, there is still a substantial amount of time and golden opportunity that we all should be trying to be better using in terms of counseling, in terms of using amazing materials.
You know, we always try to emphasize how great materials are available, such as the resources from patient advocacy groups like BMT InfoNet and others. It's a team effort. Caregivers, care providers can provide maximum information and education and try to get this.
Now the reality is that everything is focused on how to treat cancer. It's really the main focus because 90% of our transplants are done because of cancer. And I have to say that sometimes, we have this number one objective, why we are doing allogeneic transplants. It [education about late effects] does fall a little bit behind in terms of focus, acuity. It's not even something that everybody necessarily wants to hear much about - what's going to happen three years down the road, and is this disabling chronic GVHD going to be active three or four years down the road when there's no leukemia anymore in sight.
So, very complicated, important issue that we all need to constantly keep trying to do, to keep in mind and education would be a word I would like to underline as we move forward with what you are doing in the transplant field.
00:45:29 [Moderator] Thank you Dr Pavletic. I think the next question will be the last question we'll take from the pre-submitted questions. So then we have time for the questions that people are chatting in now. If you are on the line and you have a question that you want to chat in, please use the chat box in the lower left, and we will try to get to them, as many of them as we can.
So Dr Jain, what are the options for opening up tear ducts? I can feel my tears but they just do not come out.
[Jain] Thank you for the question. As I understand this question, I'm going to answer. What ocular GVHD does, by the immunological attack and inflammation, is to destroy the lacrimal gland, the main lacrimal gland, which resides under the bone just above the lateral angle of the eye. And this gland produces tears as we cry or that reflex tearing. It is because of this gland. And this is destroyed, so this is not able to produce those tears.
There are some other accessory lacrimal glands that are present also in the tissues that cover our lids, and those may produce some tears. So maybe there is some feeling that there are some tears because of those accessory gland. But because the main lacrimal gland that produces what was the reflex - those profuse tears - that's damaged, that doesn't function anymore because it's destroyed by inflammation, and the tears one would feel just don't come out, although you can still feel some wetness because of some tears that are still hanging around over the surface of the eye.
Now discuss options for opening tear ducts. For the main lacrimal gland, there is no way we can open tear ducts because there is no purpose. The gland is not producing any tears. If the question refers to opening the nasolacrimal duct, which is the passage that leads from the inner angle of the eye to the nose, from where the tears plane, often times these are plugged with punctal plugs and are permanently closed by cauterization. Yes, of course there are surgical procedures to open the nasolacrimal ducts. But there is no option that I'm aware of that is used to open the ducts of the lacrimal gland, which is producing tears.
00:48:22 [Moderator] Thank you Dr Jain. Now we will jump to the questions that have been submitted this evening, just to make sure we get some of those in as well.
First question is, I understand that taking prednisone, an immunosuppressant, increases the risk that the transplant will fail. Is this true? All right. Whoever would like to take that question, go for it.
[Pavletic] Okay. I could take it. Prednisone is typically given for graft-versus-host disease when it needs to be treated. And that takes priority, and it's a given for a good cause. If the main promise is prednisone, it's not the drug we like, and has a many side effects. It's our best friend and our worst enemy in treating patients with graft-versus-host disease. But initially it works very well in the majority of patients. So, it's given for reasons.
In terms of engraftment concerns, if that's a question whether the transplant would fail, the short answer is that patients, when they have a graft-versus-host disease, are usually well engrafted. And losing a graft is the least of our concerns. So again, answer is no here.
And then the other question is, is it going to hurt graft-versus-leukemia effect? So should they give prednisone, get prednisone, is it going to hurt my chances of curing an underlying malignancy. And again answer is whatever evidence we have, the answer is no. The reasons that creates a need for giving prednisone are sometimes very serious reasons and can be life threatening, and those reasons can cause a transplant to fail. But once a necessity exists to give prednisone for treatment, there is absolutely no evidence that the likelihood of leukemia coming back is higher. Actually whatever information we have, that's not the case. So I would say it's a complicated answer, but a short answer is that no, we don't like to give prednisone. When the decision is made to give prednisone then, it's a for a good reason, and transplants don't fail because of prednisone itself.
00:51:32 [Moderator] Thank you, Dr Pavletic. Dr Lee, can you speak to the pros and cons of using low-dose IL-2 for GVHD treatments and doing UVB-1 while taking an IL-2.
[Lee] Sure. So, low-dose IL-2 has been reported to be helpful in people who have current GVHD. This is primarily work that was done by the Boston group. And it looks like this form of low-dose IL-2, which does have to be given by injection frequently, tends to increase regulatory T cells. So we think it has a kind of dampening effect on the immune system. So I think it's a very reasonable thing for someone to try.
In terms of combining it with other things. I know that there's some clinical trials that combine it with ECP. I'm sure you could do it with any other agent. UVB, I can't speak to that particularly other than that, it looks like the IL-2 was pretty safe and reasonably well tolerated and so it could be combined with other potential GVHD treatments.
00:52:36 [Moderator] Thank you. Dr Pavletic, does ECP, extracorporeal photopheresis, need to be done on consecutive days?
[Pavletic] So ECP is probably one of our most often use treatments for chronic GVHD beyond steroids. Of course, there may other options [for its use], it can be used for acute GVHD in certain circumstances. There is no predetermined schedule for ECP, whether once a week, twice a week, three times a week, a weekly, every two weeks. There are different schedules. Usually it's a more intensive in the beginning and then tapers off over time. But there's no evidence that one schedule is superior to another.
One of the most popular schedule is using two weeks or two days in a row as you know, as inferred in the question. So two days in a row, every two weeks for several consecutive months and maybe then going monthly. So that's a very common, and the schedule [with which we probably have] the most experience. But today there's no evidence that one schedule or the other is superior.
[Moderator] Okay. Thank you very much.
[Lee] Yeah, I think that can I just add, I think that that schedule came up when we were using the oral psoralen. And so people wanted to condense the time that they were sensitive to the sun and things. Here and at many other places we don't adhere to the two consecutive day requirements.
00:54:25 [Moderator] Thank you Dr Lee. While you're on the line, do you, can you speak to this question? Are there any biomarkers to follow for chronic GVHD? And perhaps in your answer you could explain what a biomarker is?
[Lee] Sure. Yeah, I think that's a great question and that's the focus of a lot of my research. So a biomarker is basically a biologic measurement that indicates the health and the status of the GVHD in a person. And so we've done a lot of work with trying to look at various biomarkers. We tend to do blood biomarkers, so things that you can measure proteins and cells and cell types that you can measure in the blood. But really a biomarker can be any other kind of measurement.
I think the short answer is that prior, the sort of more high tech biomarkers that we think might be associated with chronic GVHD, to this point have not reached anywhere near where we can actually use them clinically and follow them. Some people use less high tech biomarkers or some people follow, for example, eosinophil levels and, platelet counts and other kinds of things that can indicate whether someone's responding or not. But at this point, most of the biomarkers are still within the research realm. It is hopeful that at some point we'll be able to just draw someone's blood and be able to tell how serious their GVHD is and what kind of treatment we should put them on and whether their responding. But at this point we don't have enough evidence to do that with any of these.
00:55:56 [Moderator] All right. Thank you. Dr. Pavletic, maybe you could answer this one. When your immune system revs up to fight an infection, can it rev up the GVHD at the same time?
[Pavletic] Well, we don't have hard evidence that that's the case. In practice, we do not uncommonly see associations of some triggers that are followed by chronic GVHD flare ups. Even after one year or something not having any GVHD, and then he comes and there's a sense that any trigger to the inflammation and the immune system potentially could be associated. So anecdotally, yes, after systemic viral infectious, flares can be obtained. Sometimes even after topical interventions, like a surgery or local radiation or some injuries, certain areas it can flare up locally or systemically. It's not common, but the common external factors like exposure to sun, right? They tell everybody don't get sun exposure because then the case is you get a whole large portion of the skin being exposed to sun radiation and inflammation that can trigger. So the short answer is it could happen, but most commonly doesn't.
00:57:39 [Moderator] Alrighty. Dr Lee, can you address this question? What types of GVHD does Rituxan treat?
[Lee] Well, the most common thing, I think, that people try to use Rituxan for is actually the sclerotic form of graft-versus-host disease. That was reported by the Italian group as being very effective.
We actually did a randomized trial here where we looked at Rituxan and Imatinib, another thing that has been reported to be effective by the Italian group, and had some responses but [we] didn't see nearly the response that they [the Italians] had seen.
We tend to use Rituxan when we think that it's a type of chronic GVHD that is more associated with B-cells since that's what Rituxan treats. And so we tend to use it again in scleroderma or in sometimes the arthralgias or some other manifestations that we think are related to B-cells.
I think it's a very reasonable thing to try. It is important to realize that if you're going to give someone Rituxan, it's very important to check hepatitis B before you do that because people can reactivate if they otherwise have hepatitis B under control. And it's important to remember that Rituxan has long lasting effects in suppressing the B-cells, and so immunoglobulin levels can be low. And if people have frequent infections, that would have to be repeated afterwards.
00:59:06 [Moderator] Thank you. I'll throw this one out to both you. Dr Lee and Dr. Pavletic. I'm not quite sure I understand the question, maybe you will. What are the GI GVHD risks if I have a level one upper and level two lower, and my gallbladder has failed and needs surgical removal.
[Pavletic] Well, I assume you're referring to GVHD grade one and two and any connection with the gallbladder. I'm not directly aware of these two problems being connected, but certainly some symptoms. So the gallbladder or bile duct-related disease could mimic certain manifestations of GVHD, particular upper GI tract. So that in terms of staging grade one, upper grade two, lower. So that's what I mean in general that it's a grade two probably at minimum of overall acute. If we're talking about acute GVHD and that typically needs to be treated with some systemic immunosuppression. And if I exactly answered the question, please feel free to expand if you don't think it's answering exactly what you needed.
01:00:45 [Moderator] All right, thank you Dr Pavletic. And Dr Lee, how can you treat GVHD of the lips? I have sensitivity to sunlight and red sauces.
[Lee] That's a tough one because the lips are pretty sensitive. I think if it's an acute symptom, then we do sometimes use steroids. You have to use that very sparingly or you'll get atrophy on the lips. I think the most important thing actually is protection. So making sure that you have a good Vaseline coat, that you avoid the things, like this person has noticed, such as sun and different foods that can cause sensitivity. But the lips are tough. Sometimes we also try to use topical tacrolimus, and for some people they respond to that. But usually if it's a very sensitive area, a little bit of steroids very briefly is the best treatment.
01:01:38 [Moderator] Right, and then Dr. Pavletic Perhaps for you. What success have you seen using the drug Jakafi? My daughter was recently diagnosed with chronic GVHD, following her transplant in February of 2019. She had two bouts of skin, very serious but no scleroderma, and one bout of gut. She recently started on Jakafi.
[Pavletic] So Jakafi is one of the newer drugs that we use more commonly with chronic graft-versus-host disease. And response rate to Jakafi has been varying in different trials, but I would say it seems that the response rate is somewhere around 50, even up to 70 or so percent. So it's a very popular class of drugs with actual reasons. One, there's a need for better drugs for chronic graft-versus-host disease and whenever something new mechanistically comes, then there's lots of excitement about this. The other aspect is that these kinds of drugs, they're easy to take, it's a tablet. And in general they're quite well tolerated. They're not without side effects. They can reactivate certain types of viral infections, like cytomegalovirus, they can cause anemia, but in general they are well tolerated.
As far as we know, there is no particular system or type of manifestation of chronic GVHD that responds better or worse to this particular agent. And it's definitely something that has to be considered in an in patients needing next lines of therapies.
It has to be said that Jakafi is now approved for treatment of acute graft-versus-host disease. It was approved last May. So it's very good news because we have, for the first time in recent history, a drug approval for acute GVHD and it seems to be particularly promising in GI manifestations in that setting. I think it has to be said that, that studies in chronic GVHD, actually, controlled prospective trials are still in progress. So while there's a widespread enthusiasm and for good reason, it seems, to use Jakafi, we still don't have studies being published or even completed that are saying conclusively this is better than alternatives. So research is still going on, but the high promise of those agents is going ahead of the curve of research and it's been wildly spread into practice. There are other JAK inhibitors in research that may be coming, so it's a very active area of research and there may be new agents to come beyond Jakafi. But again, it's still something that studies are going on in terms of more conclusive assessment of the benefit.
01:05:09 [Moderator] Thank you, Dr. Pavletic. Dr Lee, is there any research going on about the impact on GVHD of probiotics and the microbiome?
[Lee] Yeah, that's a great question. I think that most of the active research in GVHD in the microbiome is in the acute setting where we have more data. It does look like, at least, there is an association between certain types of organisms that could be affected by antibiotics and the onset and the severity of acute graft-versus-host disease.
We know much less when it comes to chronic. I've seen a few abstracts that have looked at this that suggest a similar phenomenon is going on. The specific agent, specific microbes seem like they're a little bit different, but it's very, very early on in that field. This is something that we're studying as well and I think we'll have more information in the next few years.
01:06:07 [Moderator] Thank you, Dr Lee. Dr. Pavletic, does having chronic GVHD increase your body's daily caloric need to maintain your weight?
[Pavletic] Can you repeat the question, please?
[Moderator] Does having chronic GVHD increase your body's daily caloric needs to maintain your weight? Do you need more calories if you have GVHD in order to maintain your weight?
[Pavletic] Well I hate to say, but it is an interesting question. So we do know that in general, it's a complicated answer as far as I know, and I don't think it's being studied in terms of late. But there're clearly nutrition related problems that are associated with chronic graft-versus-host disease. And common sense tells us that, yes there's an increase the catabolism and nutritional needs in these kind of situations, to help the body overcome these challenges and regenerate. So everything that works for other people works particularly for patients in this situation in terms of nutrition and healthcare maintenance and so on, lifestyle.
Now there are two spectrums of nutritional manifestations. So on one end is a small percentage of patients. They have very little weight and low body mass index that particularly endangers. And it seems that, I have to say, I don't think it's fully understood the mechanism, but it seems that catabolic processes are at a high rate. The body mass index could be very low, survival could be impaired in some of this. It's more commonly in patients that have associated GI tract manifestations or pulmonary manifestations, but it's most likely due to the question that you're asking.
There's some little evidence that certain drugs can sometimes cause this situation, rarely. There have been case reports associated with CellCept, particularly in children, causing some kind of cachexia. So just keep in mind it's very, very rare, but it's been described as very complicated.
The other end of the spectrum, that's not necessarily good either, but it's overweight. So we've called this metabolic syndrome. That goes more with the overweight situation, with the increased inflammation in the body, with problems of lipid and glucose metabolism, cardiovascular risk factors are going to go with this and then certainly expose patients to risks associated with these kind of a metabolic syndrome problems.
And that's on the other end. And I would say they could go with the decrease muscle mass and so on, commonly with [inaudible 01:09:30] administration. So I would say there are two spectrums of extremes, maybe 10 or so percent on low weight and maybe 20 ish percent or so on the higher end that are associated with chronic GVHD. And we need to do much more effort in better understanding the processes and, even more, so what's the best intervention.
01:09:59 [Moderator] Thank you Dr. Pavletic. And I think we have time for one more question before we close and perhaps Dr Lee, you could close us out. Is there a role for Cannabinol CBD in the treatment of GVHD? I understood there was a study out of Israel and ongoing studies at clinicaltrials.gov.
[Lee] That's a great question because many, many people are interested in the medicinal components of this. There is a study in Israel, the one that I'm aware of is actually for acute graft-versus-host disease prediction. So it's not for chronic. I've seen some preliminary single patient kinds of cases where people have taken it and it looks like it's been beneficial, but those are just anecdotes. I think other people are trying to study this and I think it is quite worthwhile studying it, but at this point the data are very preliminary.
01:10:56 [Moderator] All right, thank you and with that I think we'll need to end the webinar tonight. Thank you, Dr. Pavletic, Dr. Lee and Dr. Jain for sharing your expertise with us and answering some of our questions. I know we didn't get to everyone's question. If you want to have your question answered and we didn't get to it tonight, email us at email@example.com and we'll see if we can get an answer for you.
I do want to point out we have a couple of resources that you might be interested in. We have a book called Graft-versus-Host Disease: What to know, What to Do. And it's a free publication which can help guide you through GVHD. All you need to do is order it online at bmtinfonet.org/product/graft-versus-host-disease-what-know-what-do or phone us at 888-597-7674 and we'll be happy to send you a copy. It's also available in Spanish.
Thank you everyone. And again, thanks to Pharmacyclics, AbbVie Company and Janssen Biotech, and Jazz Pharmaceuticals for supporting this event. Have a good evening.
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