Graft-versus-Host Disease: What to Know, What to Do

Transcript of Presentation:

(00:00): Jordan Sexton: Introduction: Good morning. My name is Jordan Sexton, and I will be your moderator for the workshop. Welcome to the workshop Graft-versus-Host Disease: What to Know, What to Do.

(00:09): Before we begin, I'd like to thank Incyte Corporation and Sanofi, whose support helped make this workshop possible.

(00:15): It is now my pleasure to introduce our speaker, Dr. Farhad Khimani. Dr. Khimani is an associate professor in the Blood and Marrow Transplant and Cellular Immunotherapy Department of Moffitt Cancer Center in Tampa, Florida. His clinical work focuses on treating patients with Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPNs). His research and clinical trial activity are focused primarily on graft-versus-host disease (GVHD). Please join me in welcoming Dr. Khimani.

(00:53): Dr. Farhad Khimani: Overview of Talk. Thank you for the kind introduction and invitation to speak at this symposium. I am briefly going to talk about what graft-versus-host disease is, what are the types of graft-versus-host disease, and then we'll briefly talk about why it happens and how it affects patients. Lastly, we'll briefly go over whether there is any way to prevent graft-versus-host disease and, if it occurs, how do we treat it?

(02:22): GVHD is one of the major complications for patients who receive a donor stem cell transplant (allogeneic stem cell transplant). You may hear these terms: bone marrow transplant, peripheral blood stem cell transplant, allogeneic stem cell transplant, donor stem cell transplant. All these terms mean more or less the same thing.

(02:56): There are two different types of transplants that we do: One is from a patient's own cells, called an autologous transplant, and the other one uses cells from a donor, called donor stem cell or allogeneic transplant.

(03:16): In an allogeneic transplant or donor stem cell transplant we want the donor cells to go into the patient's body and start fighting the cancer or malignancy. Most commonly, we do these kinds of transplants for patients with acute leukemias, lymphoma, or myelodysplastic syndrome. We want the donor cells to go into a patient's body, make a new immune system, and start fighting with the cancer to beat that malignancy.

(04:00): These same donor cells may also start fighting with the patient's own organs, and that is what graft-versus-host disease is. Graft, meaning donor cells, and host, meaning the patient's body organs. We want the donor cells to fight cancer but at the same time, they have the potential to also fight the patient's own organs. Graft versus host disease is essentially an immune disease and has a lot of similarities with other autoimmune conditions. If you have heard of diseases like lupus or rheumatoid arthritis, graft-versus-host disease symptoms can be very similar to some of these autoimmune diseases.

(05:00): What do we want from an allogeneic transplant using donor cells? We want the donor cells to be active enough to fight off the malignancy, but we don't want the donor cells, especially in a severe form of GVHD, to fight with the patient's body organs.

(05:23): This is just a simple diagram and I'm going to go through it to explain what happens. So whenever we are doing a donor transplant, we are first collecting donor stem cells. We collect directly from the bone marrow (usually the hip bones where most of the bone marrow formation occurs) or, mostly these days, we collect these stem cells from the blood.

(05:52): There's a process called stem cell mobilization or apheresis. With help of a medication, stem cells are pushed out of the bone marrow into the circulating blood, and then we collect them from the peripheral blood (bloodstream). Once we have these stem cells collected from a donor, we infuse them into the patient.

(06:17): When these cells go into the patient, they form a new bone marrow and a new immune system.. The immune cells from the marrow (the white cells) can also start fighting off the patient's organs such as the liver, bowel, and skin, and that's what graft-versus-host disease is and that's how it essentially works in the patient's body.

(06:52): Now we all have an immune system, and our bodies are able to fight off essentially any foreign object or material that comes into our body. For example, let's just say we get an infection from a bacteria or a virus. When a bacteria or virus somehow gets into our body, our white cells recognize it as foreign material and start fighting it off, and that's the normal process of the immune system.

(07:27): Chemotherapy facilitates the engraftment of donor cells but can also damage patient’s organs. When we are doing a transplant from a donor, we prepare the patient’s body to take the donor cells by giving some form of chemotherapy or radiation. That chemotherapy or radiation suppresses the patient's immune system so that the donor cells can engraft, but at the same time, the chemotherapy and radiation also cause some damage to the patient's body organs.  

(08:01): An example may be our intestines. When the damage happens, the bacteria in the intestines gets broken down and damage, and they release a lot of proteins and foreign material inside the blood.  That triggers a response from the donor cells that we injected into the patient.

(08:35): Now these donor white cells are hovering around. When these proteins from the bacteria go into the blood, special cells in the blood recognize that protein, present it to the donor immune cells, and when these donor immune cells recognize these proteins as foreign they start attacking the patient's intestines. That's how graft-versus-host disease manifests.

(09:09): GVHD can be acute or chronic. Now what are the types of graft-versus-host disease? Essentially there are two major types of graft-versus-host disease: One what we call acute graft-versus-host disease and the second is what we call chronic graft-versus-host disease.  

(09:23): If graft-versus-host disease happens early on after stem cell transplant in the first hundred days, it is usually acute graft-versus-host disease If it happens after the first hundred days, it's usually chronic graft-versus-host disease.  

(09:48): But there is a small caveat. Some symptoms of acute and chronic graft-versus-host disease are very peculiar to either acute or chronic graft-versus-host disease and may or may not follow this time-based division. For example, dry eyes and dry mouth are very peculiar to chronic graft-versus-host disease, not acute. So, in some rare situations, if dry eyes or dry mouth develop at day 90 or day 80, for example, that would still be a form of chronic graft-versus-host disease that happened early on.

(10:30): There can also be overlap GVHD or late acute GVHD. This happens in some patients and that's why there are some other terms that we use. If somebody develops both chronic graft-versus-host disease and acute graft-versus-host disease within a hundred days after transplant, we may call it overlap graft-versus-host disease. Conversely, it acute graft-versus-host disease occurs without chronic graft-versus-host disease more than a hundred days post-transplant, we call it late acute graft-versus-host disease.

(11:22): Acute GVHD usually affects intestines, skin, and liver. Now what are the symptoms of acute graft-versus-host disease? The classical acute graft-versus-host disease affects three body organs: the intestines, the skin, and the liver.

(11:39): On the skin, graft-versus-host disease mostly causes red rashes which can be very itchy. In some patients, it causes nausea, vomiting, diarrhea, and appetite loss if it affects the gut. It can also cause abnormal levels of liver enzymes, aspartate transferase (AST), alanine transaminase (ALT), and bilirubin.

(12:03): Chronic graft-versus-host disease, on the other hand, can virtually affect any organ, including the organs affected in acute graft-versus-host disease such as skin, liver, and the gut, as well as other organs like mouth, eyes, lungs, joints, etc.

(12:25): Acute and chronic GVHD and their respective symptoms can overlap or present in various time periods. On this slide you can see how frequently chronic GVHD affects various organs. Skin involvement is very common, as well as mouth, liver ,and eye involvement. Some patients may only have weight loss. We use a term called GVHD anorexia when they may not have a lot of other symptoms, but they're losing weight. So that's why it's very essential, if you have any symptoms that are not normal, you should let your transplant team know as soon as possible no matter how trivial those symptoms seem. Lungs, esophagus, joints can certainly be involved with chronic graft-versus-host disease.

(13:20): When you develop acute graft-versus-host disease symptoms like diarrhea, nausea, vomiting and/or skin rashes or liver abnormalities after Day 100 post-transplant, we call it late acute graft-versus-host disease, whereas overlap graft-versus-host disease is the term used when you have symptoms for both acute and chronic graft-versus-host disease.  

This is just a simple diagram to describe the classification of acute graft-versus-host disease versus chronic graft-versus-host disease versus overlap and late acute. So if the symptoms of nausea, vomiting, diarrhea, rashes or liver problems happen within a hundred days after a stem cell transplant it's called classic acute graft-versus-host disease. If the same symptoms of nausea, vomiting, diarrhea, and skin rashes happen after Day 100 without any symptoms of chronic graft-versus-host disease, we use the term late acute graft-versus-host disease.

(14:47): If patients experience graft-versus-host-disease symptoms after Day 100, and most of these are chronic symptoms, such as dry mouth, dry eye, skin changes, and nail changes —classic chronic graft-versus-host-disease symptoms —then that's considered classic chronic graft-versus-host-disease. But if the patient also has acute graft-versus-host disease symptoms, like red rashes or diarrhea, nausea, vomiting, which is attributable to acute graft-versus-host-disease symptomatology, we call it overlap graft-versus-host-disease, meaning the patient has both acute and chronic graft-versus-host disease symptoms.

(15:30): Why does graft-versus-host disease happen? The donor cells are supposed to fight off the cancer, but they can also start fighting off the patient's body organs. The chemotherapy, radiation, and infections that happen around the time of transplant damage the surface of the gut or skin, and bacteria or other foreign objects go into the patient's blood and release different kinds of proteins that the donor's immune system does not recognize, that triggers a chain reaction where a variety of different white cells from the donor start releasing all kinds of chemicals that can damage the patient and cause inflammation and fibrosis vis-a-vis graft-versus-host disease.

(16:44): Chronic graft-versus-host disease can affect virtually every organ, and acute graft-versus-host disease essentially affects skin, liver, and intestines for most patients. It has been described in the literature that even acute graft-versus-host-disease early on can affect some other organs. It's very rare but it has been described in some patients and can affect the brain, the lymph nodes, lungs, thymus, kidneys, ovaries, testes, and bone marrow.

(17:27): With new treatment regimens, severe GVHD only happens in about 5 to 10% of transplant patients. How often do we see acute and chronic graft-versus-host disease? First of all, it does not happen in everybody, and if it happens, not all graft-versus-host disease is bad or severe. There are grades 1, 2, 3, 4 - mild, moderate or severe. With current standard regimens that we use for transplantation, the bad graft-versus-host disease or the higher grade graft-versus-host disease, such as Grade 3 to 4 acute graft-versus-host disease, or moderate to severe chronic graft-versus-host disease, happens in about 5% five to 10% of the patients, which is very good in terms of what we used to get back in the days. In the past five to 10 years, newer and more effective regimens have been designed that have really reduced the incidence of acute and chronic graft-versus-host disease.

(18:34): Now, what are the risk factors for graft-versus-host disease? Are there any situations that put a patient at a higher risk of graft-versus-host disease? There are certain risk factors that can increase the risk of risk of graft-versus-host disease. As I mentioned earlier, every patient gets some form of chemotherapy or radiation right before transplant to prepare their body to receive the donor cells. If we do not give them that chemotherapy or radiation, the patient's body will reject the donor cells right away, and we cannot do the transplant.  

(19:17): The risk of developing GVHD varies with the intensity of chemotherapy and radiation, the quality of the donor match, and the type of graft used. There are different types of chemotherapy and radiation regimens that we use to prepare the body for transplant. If we use a very intensive or very high-dose chemotherapy regimen as opposed to a lower-intensity chemotherapy regimen, the risk is higher for graft-versus-host disease.  

(19:41): Another important factor is the type of donor we use. If we use a fully matched sibling donor that has a lower risk of graft-versus-host disease as opposed to using an unrelated donor, a mismatched donor, or a haploidentical donor.  

(20:21): Also, if the patient or the donor is older, that also increases the risk of graft-versus-host disease. If the patient were to develop any infections, that puts the patient at a higher risk of graft-versus-host disease.  

(20:19): Also, the type of graft we use matters. If we infuse stem cells collected from the donor's peripheral blood (bloodstream) as opposed to directly from the bone marrow, that also increases the risk of graft-versus-host disease. There are a variety of reasons why one might use peripheral blood stem cells, rather than marrow, for the graft.

(20:44): GVHD can cause various skin-related issues. Now, this is just a picture that shows patients with skin rashes caused by graft-versus-host disease. They may have some red rashes, they may have some skin thickening, or other manifestations of skin graft-versus-host disease. The purpose of presenting this slide is to highlight that many organs can be affected by chronic graft-versus-host disease.  

(21:40): It can cause dry eyes, dry mouth, white lesions or ulcerations in the mouth, shortness of breath, and difficulty swallowing. It can cause vaginal scarring in females, or problems with phimosis or stenosis in males.  

(22:17): GVHD can cause all kinds of skin rashes, hyperpigmentation, discoloration, skin thickening, and leathery skin. It can also cause joint stiffness, and joint pain. These are the classic symptoms of chronic graft-versus-host disease and are easily recognized by our team.

(22:44): Less often, chronic GVHD will affect the lungs, nervous system, muscles and brain. Then there are what we call atypical organ involvement, symptoms we don't see very commonly. It can affect the brain and may cause memory issues in some patients, as well as meningitis or vasculitis, and our nervous system can be inflamed causing problems. It can cause neuropathy, numbness, and tingling in various areas of the body, and can muscle weakness similar to myasthenia gravis.

(23:19): It can cause restrictive lung disease in some patients. Serositis is a very interesting manifestation of chronic graft-versus-host disease that affects the layer that covers our heart, lungs, and intestines. It causes fluid around our heart, lungs, and stomach which we call effusions or ascites. It can also affect the kidneys.

(23:52): A small percentage of patients develop muscle cramps that can be very severe. It can also cause joint pains, and blood counts to go down. Those are some atypical manifestations of chronic graft-versus-host disease. Essentially, the message I'm trying to get through is chronic graft-versus-host disease can essentially affect any organ.

(24:14): That's why we tell our patients that no matter what type of symptoms you have, how trivial or severe or non-severe they are, if you're noticing anything at all that is not normal, share it with your transplant team right away. They can advise you if any of those symptoms are concerning, investigate whether or not the symptoms are related to GVHD, and help you to solve the problem.

(25:20): Here are other pictures of a patient with graft-versus-host disease. So symptoms of  skin graft-versus-host disease may persist even after graft-versus-host disease goes into remission. For example, this is a red, active erythema or erythematous rash, a manifestation of graft-versus-host disease. There can also be some hyperpigmentation that is a residual change from graft-versus-host disease that has been treated.

(26:05): It's essential for your healthcare provider to examine you at short intervals of time to assess whether changes you notice on your skin are active graft-versus-host disease. That will help guide them on whether the patient needs treatment or not.

(26:32): On this slide you see the joint graft-versus-host disease. That patient is not able to extend his hand joints properly. There is some sclerosis or leathery skin on the stomach, scarring in the forearm of the skin and so on. Graft-versus-host disease on the skin can present in variety of different forms. It's not a straightforward type of skin change. It could be any variety or types, and it's essential that you share anything you notice with your doctor.

(27:10): These are some of the common examples of graft-versus-host disease of the mouth. You may see these white spots (what we call lichenoid changes) on the tongue and the roof of the mouth. In some patients they can be painful. It may affect your taste buds, causing problems with tolerating spicy foods or hot or cold temperatures.

(27:35): Some patients may have no symptoms. So the key is to keep an eye on these things. If you notice something, speak up and let your team know so that they can follow up on these symptoms to make sure they don't require any other treatment.

(27:54): Sometimes patients have changes on the lips such as ulcerations, which can be painful. These may be related to GVHD, but there are other potential reasons for these changes. For example, patients can have a herpes infection or cold sores on the mouth. If patients have a history of cold sores, they may believe that what they are seeing is a cold sore and not report it to their transplant team. But as I said, any symptoms that happen, should be shared with your healthcare team, your transplant team, and let them help guide you about symptom - whether it is related to graft-versus-host disease or not - and how to control it.

(28:56): Chronic GVHD can also affect nails, hair, and joints. This slide shows some examples of chronic graft-versus-host disease involving your nails, hair, and joints. Nails, and hair are appendages of our skin. GVHD can cause patchy hair loss. Nail changes and scarring can all be part of graft-versus-host disease. Not being able to extend joints in your hands, or your shoulders and any tightness, pain, restriction of motion, etc. can be caused by graft-versus-host disease. Graft-versus-host disease can also cause dimpling or thickening of your skin, changes in skin color, discoloration, and a lack of skin pigmentation.

(29:51): Now can we prevent this graft-versus-host disease from happening? The answer is yes. We certainly can prevent graft-versus-host disease from happening in at least some patients.

(30:09):  When doing a transplant, some medications can prevent or reduce the risk of GVHD. Whenever we do a transplant, we give patients a cocktail of medications called graft-versus-host disease prophylaxis. These medications are supposed to prevent and/or reduce the risk of graft-versus-host disease.  

(30:33): We have come a long way in the past four or five decades to improve these regimens to prevent graft-versus-host disease. Just to give you a brief idea what we used to do back in the day, compared to where we are now: In the 1970s there was a single agent drug called methotrexate that we used to prevent graft-versus-host disease. This was very early on when transplants to treat patients with an allogeneic transplant was just beginning.  

(31:07): In the 1980s, another drug came about called cyclosporine, and then in late '80s the a combination of both of these drugs that became standard of care to prevent graft-versus-host disease. That did make some improvement. And then later on, a drug combination of cyclosporine and methotrexate or tacrolimus and methotrexate became standard of care. Still, the incidence of graft-versus-host disease remained quite high.

(31:44): Recent advances in posttransplant medications like cyclophosphamide have dramatically reduced the incidence of GVHD. In the past five to 10 years, a new regimen has come about that is now the standard of care, called post-transplant cyclophosphamide-based graft-versus-host-disease prophylaxis (PTCY). That has improved and reduced the incidence of graft-versus-host disease quite a bit. This has been one of the major advances in prevention of graft-versus-host-disease in the past four or five decades.  

(32:16): There was a very large randomized phase three clinical trial. In medicine, whenever a drug is approved, it's based on all the clinical trials and studies that we do in the background and one of the highest levels of evidence is a randomized phase three trial. If it's positive, it shows us that the given study or the new regimen is better than the regimen that we have had before. So what this trial did was compare the then standard of care, the two drug regimen, tacrolimus and methotrexate, with this new regimen that combines three drugs: post-transplant, tacrolimus, and mycophenolate (MMF). Matched related sibling donors and matched unrelated donors were part of this trial. It was a pretty decent-sized large trial and they all received reduced intensity chemotherapy.  

(33:25): What did the trial show? The results showed that the outcomes were superior or better with this post-transplant cyclophosphamide regimen compared to the prior standard of care regimen.

(33:37): We use a term called graft-versus-host disease-free, relapse-free survival. What that means is patients who receive a stem cell transplant do not have graft-versus-host disease, and they have not relapsed with their malignancy at any given point after transplant. And if you look at this with the post-transplant cyclophosphamide regimen, that outcome was 52.7%. That means 52.7% patients after transplant were graft-versus-host disease-free without cancer and were doing well as opposed to about 34.9%, and about 35% with Tacrolimus/methotrexate.  

(34:14):  So if you look at the difference, a good 20%, 15 to 20% improvement in the outcomes, and that is pretty impressive in our transplant field. So since then, post-transplant cyclophosphamide has become a standard of care, at least in a reduced-intensity conditioning regimen. Severe acute graft versus host disease only happened in 6.3% patients. Chronic graft versus host disease in the moderate to severe form is also less than 10%, but this is all grades chronic graft-versus-host disease, which is better with post-transplant cyclophosphamide.

(35:00): Essentially, in the past five to ten years or so, remarkable improvement has been made in the field of allogeneic transplant, and now we are able to essentially prevent bad graft-versus-host disease from happening in more patients than ever before.

(35:25):  So where we are at with graft-versus-host disease prevention? We have made a lot of improvement in preventing graft-versus-host disease with this new regimen, but graft-versus-host disease still happens. Although its better, graft-versus-host disease still remains a problem. We have about 52% to 53% of patients who do well without these issues after transplant, but there are other patients who still develop graft-versus-host disease. In an ideal world we (would want the 52% to improve to 60%, 70%, 80%, or even 90%.  

(36:09): Although we have come a long way, there's a whole lot of more advancement and improvement we need to do in graft-versus-host disease prevention. Although this newer strategy or regimen is very good in preventing graft-versus-host disease and much better than what we had done before, it's not a benign treatment. Post-transplant cyclophosphamide is actually a chemotherapy that works in this particular context to prevent graft-versus-host disease, but it causes some issues.

(36:48): While reducing GVHD, post-transplant cyclophosphamide can cause its own complications.  There's a complication called cytokine release syndrome that happens in a fraction of patients. It increases the risk of infections. It may increase the risk of graft failure or rejection in some patients. It also puts patients at the risk of secondary malignancies years after transplant. So although it has improved and moved the needle quite a bit, it's not the perfect drug.

(37:25): New trials are exploring other drugs to prevent GVHD that have even fewer side effects. In that context, there are new therapies being studied to improve outcomes of graft-versus-host disease including other drugs that may have fewer issues or less toxicity. One of the agents out there, which is in clinical trials right now is called abatacept. There is a phase two trial comparing the standard-of-care tacrolimus and methotrexate with addition of abatacept, and it appears promising. The acute graft-versus-host disease incidence is way down in patients in this trial and the severe acute graft-versus-host disease in one group of patients is fairly low, 6.8%. Now there is a final trial, ABA-3 ,currently going on and we are awaiting the results to see if it's going to further improve the graft-versus-host disease endpoint and is better in terms of the side effect profile and tolerance.

(38:39): There are also many new drugs to treat GVHD if it does develop. What can we do if somebody develops graft-versus-host disease? There are many treatments available today in 2025 that we did not have five to ten years ago. So that's the good news. Now we have several drugs, some of which are FDA-approved, which we did not have few years ago. When I started practicing as a transplant physician about nine or 10 years ago, there was no drug approved for the treatment of graft-versus-host disease. But there has been much research in the past 10 years that has resulted in many drugs available to treat graft-versus-host disease.

(39:48): This table is just to show that if graft-versus-host disease happens to somebody, we have tons of drugs, tons and tons of drugs that we can use or strategies that we can use to treat both acute and chronic graft-versus-host disease. This table outlines various strategies we can use to treat acute graft-versus-host disease.

(40:21): Several newer drugs have received FDA approval to treat refractory or resistant GVHD. This slide shows some of the drugs that are approved to treat chronic graft-versus-host disease that we did not have five or ten  years ago. Steroids have always been the first line of graft-versus-host disease treatment, but now we have Jakafi, Imbruvica, Rezurock, and Niktimvo - at least four drugs that are FDA approved to treat refractory or resistant graft-versus-host disease. So these are exciting times in terms of management of graft-versus-host disease. We have an arsenal in our back pocket that we did not have before. All of these drugs are effective and are reasonably well tolerated by patients.

(41:03): This table shows other strategies that we have to treat chronic graft-versus-host disease. It includes other agents and strategies beyond those presented in the last slide for the treatment of chronic graft-versus-host disease. There has been a lot of development and a lot of good news! We have better regimens to prevent graft-versus-host disease from occurring in the first place and better, more improved, regimens to treat graft-versus-host-disease if it happens.

(41:40): But despite these newer regimens and better prevention regimens, we still see graft-versus-host-disease in some patients. Ideally we want 80%, 90% or even 100% to be well without GVHD complications years down the road. That's our goal in the field of transplant.

(42:16): With all these new treatments, it’s more essential than ever for patients to report any and all GVHD symptoms because many of them can be effectively treated. So what can we do as a healthcare team - the providers, the doctors, the nurse, as well as the patients and the caregivers? The key is monitor for symptoms of GVHD and report any of them right away.  

If you are a patient or a caregiver and you notice any new or worsening symptoms be it infections, rashes, nausea, diarrhea, appetite going down, taste alteration, a spot on your lip, on your mouth or mucosa, changes in your urinary streams, changes in your joints, any tightness, any cramps, anything at all, do not wait to speak to your provider and your transplant team and make them aware of these are the symptoms so that they can determine if any of those symptoms are related to graft-versus-host-disease or infection, and how to treat them. That's the key because in a lot of situations, we are able to manage GVHD more easily if we can pick it up early. If the patient is having a symptom and they do not let their transplant team know for weeks and months, the GVHD can progress. It can go from mild or moderate to severe and become more challenging to treat and control.

(44:16): More patient enrollment in clinical trials is also a promising way to find even more and better ways of preventing and treating GVHD. A second major aspect of improving the prevention and treatment of graft-versus-host disease is to enroll our patients in more clinical trials. I tell my patients that the best thing I can do for you at any given time is to put you in a clinical trial. The reason is that although we have made tons and tons of improvement in the past decade in preventing and treating graft-versus-host disease, still graft-versus-host disease remains a problem. What that means is that what we have is good, but it's not good enough. We need better drugs, better strategies to prevent and treat graft-versus-host disease, and we'll only be able to do that with new science and new research. And the only way to make that happen is with clinical trials. We cannot do that without the help of our patients, as well as our family members and caregivers, who participate in these clinical trials. And if any of the drugs in these clinical trials are eventually approved, that may give you a chance of a much better graft-versus-host disease outcome.

Question and Answer Period

(45:46): Jordan Sexton : Thank you very much Dr. Khimani. This was an excellent presentation. We're now going to begin the question and answer session.

So our first question is from a person who is eight years post-bone marrow transplant, and since early last year, their oncologist has been calling the chronic fatigue resulting from the bone marrow transplant that they're experiencing chronic graft-versus-host disease which manifests as chronic fatigue. They're curious if chronic fatigue is now being recognized as GVHD.

(46:25): Dr. Farhad Khimani: That's a very good question. Chronic fatigue can be related to chronic graft-versus-host disease in some patients. So I'm glad you were able to share that information and the symptom with your team. There are tons of different symptoms of graft-versus-host disease that can happen at any given patient at any given time after transplant. What we need to do is discuss the symptoms with our transplant team. I do not know if you have spoken to the transplant team or not. Often, our patients come from different states and are treated by local doctors when they return home.  

If you're having any symptoms, it would be best to discuss them with your transplant team or any transplant team that is close to you. Any symptoms including chronic graft-versus-host disease can be related to graft-versus-host disease-like chronic fatigue. But there are tons of other differentials that can also cause chronic fatigue. So if the chronic graft-versus-host disease is an issue here, the transplant team should be able to do the workup and help you manage your symptoms and treat if it's graft-versus-host disease.

(47:56): Jordan Sexton: Thank you. Our next question is how long does GVHD prophylaxis have to be taken? For example, with Jakafi, does Jakafi always have to go together with PCP prophylaxis? Is anemia a typical side effect?

(48:12): Dr. Farhad Khimani: So this is a two part question. One question is how long patients have to be on the drug we use for graft-versus-host disease prophylaxis? So in general, we try to taper off all the immunosuppression drugs in the first six months to a year after transplant, if the patient does not develop any symptoms of graft-versus-host disease.  

But if the patient were to develop any symptom of graft-versus-host disease, then some of those drugs and/or more drugs have to be continued for longer periods of time. It could be several months or even years in some patients. If you were to develop graft-versus-host disease and your team puts you on further medications like steroids or Jakafi or any other drug, that drug, that has to be continued as long as it works and as long as you tolerate it.  

If your graft-versus-host disease is controlled or goes into remission (or near remission) it is at that time your transplant doctors will attempt to taper you off the drugs as slowly and as safely as possible. And, in some patients, graft-versus-host disease symptoms may flare and you may need to go back on these drugs. Some patients may have to remain on these drugs for rest of their lives. It depends on how your body reacts and responds to the treatments.  

Now, in terms of the side effects: anemia and low blood counts are very common side effects from Jakafi, and it has to be managed in conjunction with your local doctors and your transplant team. If it's manageable, meaning you require few to no transfusions and experience minimal symptoms, then we try to continue the drug especially if it's working and you're tolerating it well.

(50:34): Jordan Sexton: Our next question is are infection risks mostly from the intestinal mucosal membrane damage?

(50:44): Dr. Farhad Khimani: So risk of infection is high after transplant in any patient who goes to allogeneic stem cell transplant for a variety of reasons. Yes, one of the reasons is the mucosal damage that happens early on with chemotherapy and radiation, but the chemotherapy and/or radiation itself suppresses your immune system, and that puts you at risk of infections.  

The damage to the mucosa can cause organisms or bacteria our body normally has to invade and cause bacteremia as an infection early on after transplant. Then the drugs that we use to prevent graft-versus-host disease – all the pills and the medication you are taking – put you at a risk of infection. The transplant itself, the chemotherapy, the drug that you are on, all of these suppress your immune system, and you remain at a risk of infection after transplant.  

But the farther out you are from transplant, the less medications you are on moving forward the risk it gets better. Six months after transplant is a higher risk of infections than two years after transplant, especially if you are off immunosuppression.

(52:06): Jordan Sexton: Our next question is, how often does diarrhea and nausea need to occur in order for it to be considered acute GVHD? This person has liquid diarrhea several times per month, every month since transplant, and also has nausea several times per month. Would you consider this classic acute GVHD or is it just normal for any person?

(52:27): Dr. Farhad Khimani: Any nausea and diarrhea that you have after stem cell transplantation and any other manifestation that we associate with graft-versus-host disease can be for a variety of different reasons. Just to give you an example, our patients after transplant, due to some of the drugs we use, lose magnesium and a lot of the patients require oral magnesium. The magnesium pills can also affect their gut and cause some diarrhea to some level. That's one of the differentials of having diarrhea because of the oral magnesium drug.  

But that does not mean that all diarrhea a month or two months after transplants is related to oral magnesium. In a fraction of patients, it can be because of infections or it can be because of graft-versus-host disease. The transplant team can do the work up and then decide what is causing diarrhea or nausea in any given patient and what's the best way to manage those symptoms.  

If you are having symptoms of nausea or diarrhea months after transplant, it may or may not be normal. If you're just having manageable, a couple of bowel movements lose a day because you're on oral magnesium, that may be related to the drug.

But if you're having a lot of nausea, that's not normal. There's some aspect of your gut that is not happy because of graft-versus-host disease or inflammation or changes in your gut, what we call microbiota. So it is best to discuss with your transplant team and they can help guide you and do some workup to figure out what's the cause of it. The workup may include checking your stool for infections, checking your stool for chronic diarrhea reasons, doing endoscopies and taking a full history and looking at your drugs and so on.

(54:34): Jordan Sexton: This person has fairly severe oral and ocular graft-versus-host disease and was also a head and neck cancer patient in 2014. They're wondering if there's anything that can help relieve the [severe oral and ocular graft-versus-host] symptoms they're experiencing. They can go with their local transplant team but would appreciate your input as to what to expect as it relates to both symptoms and therapies in the future.

(55:06): Dr. Farhad Khimani: It can be quite challenging to treat some of the symptoms of graft versus host disease. As I said, there are many drugs that are now FDA approved to treat graft-versus-host disease. So I only mentioned the systemic therapies in my presentation, because of the lack of time, the oral drugs or IV drugs to treat graft-versus-host disease.  

If you are not on any of those drugs or you have not tried them in the past, all of those drugs can be tried again to see if your symptoms improve. But in addition to systemic drugs, there are several topical therapies like mouth rinses, drops of different kinds, and other strategies like a variety of different lenses, autologous serum tears, things like that that can be used to help you with your symptoms.  

In terms of systemic therapy, immunosuppressive therapy becomes a challenge in patients who have other malignancies or solid tumors. The reason is that any immunosuppression that we use, and a lot of our drugs that we use to treat graft-versus-host disease have immunosuppressive effects, can increase the risk of other malignancies and solid tumors. So we have to be very careful about how much immunosuppression or systemic therapy we use in patients who are at risk of progression of other solid tumors. But the transplant team can decide on the type of systemic therapy.  

If you have symptoms, certainly they can pick a drug to help you with your symptoms. Also, a referral to and following up with specialized centers and specialists is recommended. For example, if you have severe eye graft-versus-host disease, there are eye doctors who focus on ocular graft-versus-host disease and they have topical therapies, as well as some procedures they can do, depending on the symptoms,  such as special scleral lenses, special drops, and autologous serum.

(57:25): And other things can be done for the mouth graft-versus-host disease. In addition to steroid rinses, there are other immunosuppressive rinses. For example, one would be azathioprine rinses and things like that can be used as a topical therapy. But if your symptoms are severe, they may have to try one of these FDA-approved drugs or other drugs or strategies like, for example, photopheresis.

(58:03): Jordan Sexton: Closing. Well, thank you very much, Dr. Khimani. I'd like to thank you on behalf of BMT InfoNet and our partners and everyone in attendance today. And thank you to all those in attendance for your excellent questions. Please contact BMT InfoNet if we can help you in any way and enjoy the rest of the symposium.