Graft-versus-Host Disease: Advances in Prevention and Treatment

Graft-versus-host disease (GVHD)  is a common complication after a bone marrow or stem cell transplant using donor cells (allogeneic transplant) and can be difficult to treat. Learn about new therapies to prevent and treat GVHD.

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Graft-versus-Host Disease: Advances in Prevention and Treatment

Tuesday, May 2, 2023

Presenter: Marcello Rotta, MD, Colorado Blood Cancer Institute, part of the Sarah Cannon Cancer Institute at Presbyterian/St. Luke's Medical Center

The presentation is 37 minutes long, including 21 minutes of Q&A

Many thanks to Pharmacyclics, an AbbVie company, and Sanofi, whose support helped make this presentation possible.

Summary: Several new therapies have recently been approved to prevent and treat graft-versus-host disease (GVHD) and more are being studied.  The new therapies are more effective than the standard GVHD therapies and should result in a lower incidence of GVHD with fewer toxicities for patients, going forward.


  • A new, effective strategy to prevent GVHD after a transplant using donor cells (an allogeneic transplant) is to give patients post-transplant cyclophosphamide (Cytoxan®).
  • Three new drugs have proven more effective than traditional treatments for GVHD when it occurs: JAKAFI® (ruxolitinib). IMBRUVICA® (ibrutinib) and REZUROCK® (belumosudil).
  • Some of the newer therapies to treat GVHD work without suppressing the patient’s immune system or increasing the risk of infection.

Key Points:

(01:14): The cells provided by a donor for a patient’s stem cell transplant include the donor’s blood-forming stem cells, as well as the donor’s immune cells. The donor's immune cells can attack the recipient and are responsible for graft-versus-host disease.

(03:16): Acute GVHD generally occurs during the first three months after transplant. Chronic graft-versus-host disease typically occurs later and is the most serious long-term complication of a transplant using donor cells (allogeneic transplant).

(08:02): Post-transplant cyclophosphamide (Cytoxan®) is a new treatment that can prevent graft-versus-host disease in more patients than drugs traditionally used.

(13:55): A second to way reduce the incidence of GVHD is to remove the T-cells that cause GVHD from the donor's cells, before giving them to the patient.

(16:09): A promising strategy, called Orca-T, is being studied to reduce the incidence of GVHD while preserving the anti-leukemia effect of the donor cells..

(20:33): Once GVHD occurs, the standard treatment has been steroids, which are successful for only half of patients and can cause serious side effects.

((23:24): IMBRUVICA® (ibrutinib) is an effective treatment for some patients with chronic GVHD, particularly those with very tight or sclerotic skin.

(25:57): JAKAFI® (ruxolitinib) is effective against both acute and chronic graft-versus-host disease, and does not suppress the patient’s immune system.

(29:41): In studies of REZUROCK® (belumosudil), 77% of people with chronic GVHD showed improvement. It also does not suppress the patient’s immune system.

(33:40): Axalitimab is a new drug being studied to block macrophages that also contribute to chronic graft-versus-host disease. The drug is well tolerated, and ongoing clinical trials will determine its effectiveness.

Transcript of Presentation:

(00:00): [Michelle Kosik]:  Welcome to the workshop, Graft-versus-Host Disease:  Advances in Prevention and Treatment. My name is Michelle Kosik, and I will be your moderator for this workshop.

(00:11): Before we begin, I'd like to thank Pharmacyclics, an AbbVie company, and Sanofi, whose support helped make this workshop possible.

(00:19): Introduction of Speaker. It is my pleasure to introduce today's speaker, Dr. Marcello Rotta. Dr. Rotta is the Director of the Leukemia Service and Co-Director of the Long Term Follow Up and Chronic Graft-versus-Host Disease Program at the Colorado Blood Cancer Institute. He has worked in the field of hematologic malignancies and stem cell transplantation for nearly 20 years. His research focuses on the late effects of transplant, graft-versus-host disease, and leukemia. Please join me in welcoming Dr. Rotta.

(00:58): [Dr. Marcello Rotta]:  Hello, everybody, and thank you for having me as a speaker. I'm always honored to speak to you. My topic for today is discussing graft-versus-host disease, how we avoid it, and how we treat it right now.

(01:14): The cells provided by a donor for a patient’s stem cell transplant include the donor’s blood-forming stem cells, as well as the donor’s immune cells which can cause GVHD. I will discuss some basics about graft-versus-host disease. We will discuss how to avoid it, and we are going to discuss how we now treat it. In particular, I will focus on the new drugs we use.

(01:31): Just as a refresher, the transplant from a donor involves donating cells, called the graft. This graft from the donor includes many components and many types of cells.

The two significant components are:

  1. the blood-forming cells, the stem cells, the ones that are going to replace the recipient's stem cells
  2. the donor's immune cells

(01:57): The donor's cells can not only cause graft-versus-host disease, but they can also fight cancer cells. This is called the anti-leukemia effect. The donor's immune cells can attack the recipient, and they are the ones that are responsible for the graft-versus-host disease. But the donor's immune cells are also a therapeutic element of the transplant because they are the ones that can ultimately destroy the cancer cells and cure cancer.

 (02:21): Graft-versus-host disease is a direct consequence of transferring the immune cells from a donor into a recipient. The transplant always involves immunosuppression after the donor's cells are infused to prevent graft-versus-host disease.

(02:40): Graft-versus-host disease is always expected. We can eliminate GVHD entirely by removing the donor's immune T-cells from the cells collected for the transplant. The problem is, if you remove the T-cells, the transplant won't have a graft-versus-leukemia effect.

(03:03): Graft-versus-host disease and the graft-versus-leukemia effect are intertwined or connected. In many ways, we want the graft-versus-leukemia effect without graft-versus-host disease.

Typically, acute GVHD occurs during the first three months after transplant. Now, graft-versus-host disease can appear early post-transplant as acute GVHD. We typically think about an acute graft-versus-host disease  occurring in the first three months after transplant, but we can also see it later. The other type of GVHD we talk about is chronic graft-versus-host disease, a side effect caused by donor cells that may last for years.

(03:41): Acute graft-versus-host disease is a common problem after transplant. It occurs soon after transplant, and, in many cases, it can be challenging to treat when it shows up.

(03:58): Chronic graft-versus-host disease, which typically occurs later, is the most serious long-term complication of a transplant using donor cells (allogeneic transplant). Chronic graft-versus-host disease is a little slower, more progressive, and the most serious and common long-term complication. All patients have different experiences with chronic graft-versus-host disease. For 50% of people, it tends to involve more than three organs.. Treatment, as of now, is prolonged. When somebody has a transplant, we define whether it has been a success because, of course, we want to cure the blood cancer, and we want to avoid graft-versus-host disease.

(04:48): What is the recipe for a transplant? There is an initial phase of conditioning. Conditioning is the treatment people receive before the infusion of the cells from the donor. The purpose of conditioning is

(05:08): Chronic GVHD is usually first treated with a combination of drugs such as cyclosporine and methotrexate, tacrolimus and methotrexate, or tacrolimus and mycophenolate mofetil (MMF). We will focus on what we do post-transplant today. What is the post-transplant immunosuppression that is given to prevent graft-versus-host disease? These are just a few of those combinations of medication that are given post-transplant. These are the most classic combinations: Cyclosporine and methotrexate are one of the oldest combination  given to avoid GVHD. We also have used tacrolimus and methotrexate or tacrolimus and MMF.. Another combination uses three drugs. We call this "the old way," or the most established way of giving post-transplant immunosuppression.

(05:53): As you can see from the picture, post-transplant immunosuppression to prevent GVHD is supposed to be tapered down, and possibly end ,between six months and a year post-transplant. But as you know, GVHD may occur, so folks can need to be on immunosuppression for longer.

(06:15): A different approach to managing chronic GVHD is to manipulate the donor cells. We are thinking about reducing GVHD using different ways than the standard approach. The first thing that we have to focus on is the graft itself. We have to look at the donor cells. As I mentioned before, the cells collected from the donor contain a mix of many cells. Stem cells are only one small part. There are lots and lots and lots of immune cells as well.

(06:45): Some of those immune cells are the "players" in graft-versus-host disease. Those “Bad Guys (naive T-cells),” you don't want them. Thoseare the  immune cells from the donor that don't like the recipient. We call those cells the “Bad Guys (naive T-cells),” alloreactive. But we want many other immune cells in the bag of cells because those allow for the graft-versus-leukemia effect without causing graft-versus-host disease.

(07:21): So, looking at the donor cells that have been collected, we started developing strategies to avoid graft-versus-host disease by helping "Good Guys (regulatory T-cells)" and getting  rid of the bad ones. There are two strategies we are using right now, and they're drastically modifying how we transplant.

(07:42): The first one is  post-transplant cyclophosphamide (Cytoxan®). We give this medication post-transplant, and I'll tell you why. The second way is to modify the graft to switch the balance toward graft-versus-leukemia and no graft-versus-host disease.

(08:02): Post-transplant cyclophosphamide (Cytoxan®) is a relatively new treatment to prevent graft-versus-host disease. It was first introduced in Baltimore at Johns Hopkins and is now how we do many transplants worldwide. It infuses the donor cells into the patient on day zero, including the "Good Guys (regulatory T-cells)” (shown in red), and the “Bad Guys (naive T-cells) and (alloreactive T-cells)” (shown in orange). We leave those cells inside the recipient for two days.They start to expand; they increase in number. That's why you see more of these orange ones on day two.

(09:04): At that point, you give a form of chemotherapy called cyclophosphamide (Cytoxan®)  which is an immunosuppressive drug that targets cells that are actively dividing. So, when we give the cyclophosphamide (Cytoxan®) on day two and three, the cells that cause the GVHD get removed from the recipient's body. You start finding all these “Bad Guys (naive T-cells)” that will cause graft-versus-host disease in the years to come, and you get rid of them selectively; you snip them out. That allows all the other T-cells, the ones that don't attack the recipient, to thrive..

(09:55): We know this works because we've tried it. We have a lot of evidence that this causes much less GVHD post-transplant. We already have been using this for a while for transplants that we call haploidentical transplants - transplants for which you don't have a 10 out of 10 matched donor. Now we are looking at using this approach in virtually all transplants.

(10:25): A study comparing cyclophosphamide (Cytoxan®) to older therapies to prevent GVHD found that patients receiving cyclophosphamide (Cytoxan®) were less likely to develop either acute or chronic GVHD by one-year post-transplant.  An extensive study was published, CTN 1703, in which we compared the old way of giving post-transplant immunosuppression to post-transplant cyclophosphamide (Cytoxan®). Four hundred thirty-one patients were given a reduced-intensity transplant ,using the donors we typically use: well-matched donors, siblings, or unrelated donors. Two hundred seventeen patients were assigned to receive post-transplant immunosuppression classically -tacrolimus and methotrexate - and 214 received this new approach, cyclophosphamide (Cytoxan®).

(11:30): When we look at the characteristics of these patients, the groups of patients were very similar. The groups were very comparable.s. About two-thirds of patients in each group received their transplant from an unrelated donor, the ones we are often more concerned about GVHD. About 60% of these patients had a diagnosis of leukemia.

(12:02): Now, when we looked at the outcomes, we found that, in the long run, we saw that patients who received post-transplant “Cyclophosphamide (Cytoxan)” were much more likely not to have any graft-versus-host disease one-year post-transplant. There was an improvement of about 20%. 53% of patients who received ost-transplant cyclophosphamide (Cytoxan) had no GVHD one-year post-transplant, versus about 35% in the other arm. This was a great result.

(12:39): When we analyzed acute graft-versus-host disease and chronic graft-versus-host disease, we found that post-transplant “cyclophosphamide (Cytoxan) reduced the incidence of acute graft-versus-host disease by 70%, and the incidence of chronic graft-versus-host disease, at one year, went down from 25% to 12%, so 50% less.

(13:02): When we looked at relapse - leukemia, or lymphoma returning - we found that both regimens were equivalent. So, the post-transplant cyclophosphamide (Cytoxan®) didn't make the transplant less "anti-cancer," but it made the GVHD much less common. We also saw less transplant mortality and fewer people dying after transplant using this approach..

(13:35): This study was published in December of 2022. This is recent data. In 2023, post-transplant cyclophosphamide (Cytoxan®) will be the new standard of care. This is what we are going to use moving forward. This means that in the future, we will see less chronic graft-versus-host disease using this approach.

(13:55): A second way that’s been studied to reduce the incidence of GVHD is to remove the T-cells that cause GVHD from the donor cells given to the patient. There are other ways to manipulate the donor cells to reduce th eincidence of graft-versus-host disease.. We always try to eliminate the “Bad Guys (naive T-cells)” and nurse and help the good ones. Another way would be to remove the “Bad Guys (naive T-cells)” from the donor cells..This was done in many centers across the United States. We used technology to identify the “Bad Guys (naive T-cells),” removed them from the bag of donor cells, and only infused the good T-cells along with the stem cells.

(15:01): This approach was used in many patients across the United States at many centers. This first published study involved 138 patients. What we noted was, with this approach, that the proportion of people with acute graft-versus-host disease was much reduced; it was about 4%. It was reduced by nearly a third. And the number of people with chronic graft-versus-host disease also decreased significantly to 7%. It was reduced by more than 70%, and none of these patients had a bad form of chronic graft-versus-host disease. We also saw that patients were more likely to survive the transplant and do well. This approach still maintained their chance to fight and cure leukemia. This was one very promising way to do it.

(16:09): Orca-T is being studied to reduce the incidence of GVHD, while preserving the anti-leukemia effect. It splits the donor cells into two infusions: the first infusion contains no “Bad Guys (naive T-cells)” and is followed a few days later by a second infusion of donor cells that includes all types of T-cells..  Another way, that is more than just getting rid of the “Bad Guys (naive T-cells)”, is a new technology that has been very successful. It helps the "Good Guys (regulatory T-cells)" that protect the recipient from GVHD. This technology separates the "Good Guys (regulatory T-cells)," from all the other cells, including the T-cells that are the “Bad Guys (naive T-cells).” This approach  splits the transplant into two infusions. Infusion number one is given on day zero, and includes the stem cells and the "Good Guys (regulatory T-cells)". For two days, the "Good Guys (regulatory T-cells)" can expand. The number of cells that protect the recipient increases, making the recipient's body an environment where the rest of the incoming T-cells from the donor will behave better.

(17:41): This type of two-time infusion - on day zero, give the stem cells and regulatory cells, and then wait two days to give the rest of the T-cells- has been very successful. Here is the study that was published about this approach that included 127 patients. All 127 patients had a lot of leukemia. The outcome for these patients treated with this new type of technology was compared to a control group of patients with the same characteristics. The control groups come from CIBMTR. These two patient groups included people with the same disease, the same age, and the same proportion of men and women.

(18:37): We saw that when using this technology, called ORCA-T, the number of patients with acute graft-versus-host disease was cut by a third. The chance of having severe acute graft-versus-host disease went from 16% using the standard approach, to 5% using ORCA-T. The proportion of people with chronic graft-versus-host disease decreased from 38% to 6%. The chance to be relapse-free one-year aftertransplant jumped from 62% to 81%. This suggested this technology prevents GVHD and kept the graft-versus-leukemia effect and the advantage of the transplant itself.

(19:30): The one element that was a huge indicator of the success of this new approach was when you looked at patients one-year post-transplant, and in particular, those who were alive without disease and GVHD at one-year post-transplant. 76% of the patients in the ORCA-T group were alive, disease-free, and without GVHD. Those were successful transplants, as we define them - cure without GVHD. In the CIBMTR control, the historical control, the proportion was 34%. Currently, a multicenter study underway throughout the country will keep utilizing this new technology to see whether this is a new standard of care.

(20:33): Once GVHD occurs, the standard therapy has been steroids, which are a successful treatment for only half of patients and can cause serious side effects. So far, we have discussed extensively how to prevent GVHD. Now we're going to talk about graft-versus-host disease treatments. I will discuss three new FDA-approved medications. Now as you know, when graft-versus-host disease shows up, classically, what we have been using to knock it down are steroids, such as prednisone and Solu-Medrol®. These medications are first used to knock down acute and chronic graft-versus-host disease. But the number of patients that respond to steroids is about 50% or less.

(21:24): The problem is that steroids are toxic, and at times, folks cannot get off steroids because as soon as the steroid dose goes down, the GVHD worsens. When steroids don't work, we never have good options. Additional treatments like photopheresis or other immunosuppressive drugs are not as effective and have their own toxicity.

(21:58): No one treatment fits all patients with graft-versus-host disease, and many treatments historically have not worked. Moreover, many treatments may be toxic and may be needed lifelong, so folks end up staying on this medication for the rest of their life with a lot of impact on their quality of life.

(22:20): Now, the ideal treatment needs to work. It should not have too many adverse effects. It should not reduce immune defenses too much or damage other organs.

(22:34): Three new drugs have been approved for the treatment of GVHD: IMBRUVICA® (ibrutinib), JAKAFI® (ruxolitinib) and REZUROCK® (belumosudil). Now, the drugs I will discuss are those you already know.The the use of these drugs is recent. The FDA approval, in 2017 and 2021, were key years for approval of graft-versus-host disease drugs. Before these approvals, the agents we had been using were never truly FDA-approved. Results with those agents were very much limited, and there was a lot of toxicity.

(23:24): IMBRUVICA® (ibrutinib) is an effective treatment for some patients with chronic GVHD, particularly those with very tight or sclerotic skin. IMBRUVICA® (ibrutinib) is a medication that was first approved for treating lymphoma and leukemia. There was already a pill that people had been taking for a while. We were already using this drug in many people. We already knew the adverse effects of this drug.

Eventually, it was discovered that while using this drug to treat patients with lymphoma or leukemia, we found out that IMBRUVICA® (ibrutinib) coul block the B- and T-cells that are the “Bad Guys (naive T-cells)” responsible for GVHD. It stops the machinery of chronic graft-versus-host disease, including producing autoantibodies that target the organs. It also has an anti-inflammatory effect by reducing the substances that hurt the recipient.

(24:23): Now, the original studies included a limited number of patients, but the results were way better than what we had up to that point. These studies came out in 2017, and a more extended follow-up study was published in subsequent years. We saw that graft-versus-host disease went away completely in about a third of patients, and the results were long-lasting. And most of all, we noticed that in patients with very tight sclerotic skin, a lot of fibrosis, and tightening of the skin, we saw the tissues and the skin becoming softer.

(25:08): The adverse effects of this drug need to be watched closely. The typical adverse effect is this arrhythmia and irregular heartbeat. People can have a lot of bruising while taking IMBRUVICA® (ibrutinib). Sometimes we saw issues like pneumonia. IMBRUVICA® (ibrutinib) is a medication that has some limits. We continue to collect data on people treated with IMBRUVICA® (ibrutinib) to nail down the overall value of this drug in treating chronic graft-versus-host disease. IMBRUVICA® (ibrutinib) must be mentioned because it was the first drug approved by the FDA to treat chronic graft-versus-host disease.

(25:57): JAKAFI® (ruxolitinib) is effective against both acute and chronic graft-versus-host disease and does not suppress the patient’s immune system. JAKAFI® (ruxolitinib) was approved initially to treat myelofibrosis and polycythemia vera. We knew this drug is tolerable and could be given to people for a long period of time.

JAKAFI® (ruxolitinib) can modulate the immune system to put the “Bad Guys (naive T-cells)” to sleep and to increase the number of those regulatory cells that fight, or that switch off, the graft-versus-host disease. It's more of an immunomodulatory drug. This is very important because the key feature of these newer drugs is immunomodulation rather than immune suppression. Immunosuppression can cause a patient to get infections all the time and be on antibiotics forever. These newer drugs don't have a significant immunosuppressive effect. Still, they are smarter in the way the way that they modulate the immune system.

(27:02): The first evidence showed this drug worked in acute graft-versus-host disease. There was a large study, initially started in Europe, to which they assigned people who had bad acute graft-versus-host disease, were on steroids, and the steroids were not working. We saw an improvement in symptoms in 62% of patients on JAKAFI® (ruxolitinib)compared to 39% of those who used anything else. This was a big improvement compared to the best available treatment at the time. We also saw many people's graft-versus-host disease go away completely. This was seen in folks with acute graft-versus-host disease, generally speaking, in the first three months, sometimes six months post-transplant.

(27:58): A subsequent trial showed how well this drug can work in chronic graft-versus-host disease. This was done by comparing JAKAFI® (ruxolitinib) to the the best available treatment. We saw that the good outcomes increased from 26% for the best available treatments at the time to 50% with JAKAFI® (ruxolitinib). This was, indeed, a significant improvement.

When we say best available treatment, we refer to MMF, photopheresis, immunosuppressive drugs, steroids, et cetera. We also found that these responses lasted longer, and many folks could eventually come off JAKAFI® (ruxolitinib) without having any problems.

(28:57): The quality of life, across the board from these studies and others, was improved post-transplant. The one thing about JAKAFI® (ruxolitinib) is that it causes folks' hemoglobin to drop slightly. People can get anemic; the platelets may go down some. After a long exposure period, there's a chance for a fungal infection. Folks with a fungal infection who end up on JAKAFI® (ruxolitinib) may need to stay on the antifungal longer. We have yet to have a standard that tells us everybody needs to be on the antifungal, but this is something to watch.

(29:41): In studies of REZUROCK® (belumosudil) to treat chronic GVHD, 77% of people showed improvement. REZUROCK® (belumosudil) also does not suppress the patient’s immune system. REZUROCK® (belumosudil) was approved in 2021. This drug was not used to treat another cancer like IMBRUVICA® (ibrutinib) and JAKAFI® (ruxolitinib) had. REZUROCK® (belumosudil) was specially studied and designed to fight diseases that cause chronic inflammation and fibrosis.

(30:24): It modulates the immune system, like JAKAFI® (ruxolitinib), using a different mechanism. But the other effect it has, that we have been looking for, is an anti-fibrosis effect to treat and prevent the formation of tight skin, joint tightness, dry mouth, or eyes, which is what we see in chronic GVHD.

(30:54): When we treated patients with REZUROCK® (belumosudil), we saw improvement in about 77% of people. The patients that were treated in the studies had bad GVHD. Most of them were on photopheresis or on many other medications. What is very important is that when you put patients on this REZUROCK®, you can progressively remove other medications.

(31:29): The drug was very well tolerated. We didn't have to take patients off this drug because  it was too toxic or they got sick from it. It didn't affect their blood counts. We didn't see that they were getting an excessive number of infections. This drug is not considered to be immunosuppressive.

(31:53): REZUROCK®  worked in patients for whom JAKAFI® (ruxolitinib) and IMBRUVICA® (ibrutinib) didn't work, which is an important concept. That means that we have these three new drugs that you can use sequentially. If one doesn't work, you can move on to another because they work in different ways. As we can see here, we saw a response where the other two drugs didn't work.

(32:20): The typical adverse effect of REZUROCK® (belumosudil) that we saw was the liver numbers going up. Fatigue, edema, headache, and GI upset were reported. Still, there are not many people in whom this drug was stopped because of a toxicity.

(32:49): To prevent prolonged immunosuppression in patients, it’s important to incorporate IMBRUVICA® (ibrutinib), JAKAFI® (ruxolitinib), and REZUROCK® (belumosudil) into the GVHD treatment plan. However, they can take a while to work. During our conversation about the latest treatments for GVHD, I would like to highlight a few key points regarding IMBRUVICA® (ibrutinib), JAKAFI® (ruxolitinib), and REZUROCK® (belumosudil). These are the current medications we rely on. To prevent prolonged use of immunosuppression, it's important to start incorporating these drugs early in the treatment plan.

(33:09): An important thing to remember is that when you treat chronic graft-versus-host disease is that  all three of these three drugs take a while to work. You have to give these medications for at least three months before seeing an effect, before deciding that this is working or this is not working.

(33:40): Axalitimab is a new drug being studied to block macrophages that also contribute to chronic graft-versus-host disease.  Another new drug is called Axalitimab.. It is different. It is not a pill, like the three that we just discussed. It is not a medication given by mouth and taken every day. It is an antibody given as an IV infusion every two or three weeks.

A group of 40 patients suffering from severe graft-versus-host disease were treated with Axalitimab in a clinical trial. Prior to the treatment, the patients had undergone extensive treatment, including IMBRUVICA® (ibrutinib), JAKAFI® (ruxolitinib), and REZUROCK® (belumosudil). These newer drugs were ineffective in treating the patients, making it difficult to find a solution.

(34:37): Axalitimab was given by infusion every six weeks and there was a quick response. Within the first month, there was a response from about 50% of people, and 67% improved overall. We saw some improvement in many organs, including the mouth and liver. There was also some signal in the lungs.

(35:08): Axalitimab is an antibody that blocks macrophages. Macrophages are cells that are the final killer cells in chronic graft-versus-host disease. This drug can block those cells and switch off the inflammation caused by chronic graft-versus-host disease. In this report, the drug was very well tolerated, and we are now participating in clinical trials to continue to see how well this works.

(35:53): New treatments are to prevent and treat GVHD. I wanted to end by sharing some promising news about the future of treatments. Over the years, we have seen tremendous improvement and; even more treatments are on the horizon. One exciting development is the a method for preventing GVHD, which will likely lead to a decrease in chronic GVHD in the long term.

In 2017, newer treatments were approved, but the most effective ones were only approved two years ago and they have already made a significant impact. As a result, the less effective older treatments for chronic graft-versus-host disease will be used less frequently.

(36:39): With this, I really want to thank you for your attention. I want to thank most of all my dearest patients, nurses, and colleagues; we are all in this together. Pharmacists, transplant coordinators, case managers, social workers, and administrative staff at my site really keep supporting my work and my patients. Thank you for your attention, and I'm glad to get your questions.

Question and Answer Session

(37:12): [Michelle Kosik]:  Thank you, Dr. Rotta, for your excellent presentation. We'll now begin the question-and-answer session.  We will start with this as a first one. "Once you have graft-versus-host disease, immunosuppression is the answer. Is immunosuppression like insulin, with moderate diabetes, necessary for life, or is there an opportunity to come off immunosuppression? How do you evaluate the timing of decreasing immunosuppression?" They have used JAKAFI®, REZUROCK®, and Prednisone.

(38:17): [Dr. Marcello Rotta]: This is a great question. There are a couple of things to consider. Classic immunosuppression and steroids are indeed a little bit blind. They suppress the good and the bad. But we really want to suppress the bad, right?

(38:41):  The problem is that when we suppress the bad using standard immunosuppression, you end up knocking down the good as well. Classic immunosuppression has always had a role post-transplant in the early phase. Moving forward, we have to consider these smarter cells that are really focusing on the “Bad Guys (naive T-cells)” that help the good ones and knock down the bad ones.

(39:19): In other words, it is true that when a patient shows up and has GVHD, you give them something to make it quiet down, and that's, generally speaking, always something immunosuppressive. But your next thought is to plan to take the patient off immunosuppressive drugs by using an immunomodulatory drug. Ultimately, when you prescribe a steroid or tacrolimus, the immunosuppressive drugs, you must remember the concept of getting the patient off them. You must get them off progressively and watch the person very closely. Coming off an immunosuppressive drug may take at least a couple of months or sometimes longer.

(40:15): Sometimes, using the new drug allows that tapering to occur safely, so that when you taper down the immunosuppressive drug, you don't have any flare up of GVHD. Ultimately, the goal is for the donor and the recipient to live together in tolerance, doing fine without the need for any of these pills. Eventually, these newer immunomodulatory drugs are the most promising route to come off all medication post-transplant.

(40:51): [Michelle Kosik]:  Thank you, Dr. Rotta. The next question is, "What kind of success are people having with ECP treatments for chronic graft-versus-host disease, and what type of graft-versus-host responds the best to photopheresis?"

(41:07): [Dr. Marcello Rotta]:  Photopheresis or ECP has historically had the best results in chronic graft-versus-host disease, typically the one that makes the skin tight, and reduces the range of movement of the joints, that sclerotic form. That's typically where we saw photopheresis working well. We have also been using photopheresis for acute graft-versus-host disease, though it works less well. Generally speaking, photopheresis works best in chronic sclerotic graft-versus-host disease.

(41:46): We have observed a significant change in recent years. At my center, for instance, the new medications mentioned in the presentation have reduced the requirement for photopheresis. Michelle is aware that a few years ago, we used to conduct over 1,000 photopheresis treatments yearly, but now we only do a few hundred, maybe around 300. This is because the latest drugs have been found to be more efficient.

(42:24): [Michelle Kosik]:  Absolutely. One of our viewers said, "I love hearing your last point. However, I am disheartened sometimes when I see the mortality stats associated with lung GVHD. Do you think that these new medications are changing those mortality statistics?"

(42:44): [Dr. Marcello Rotta]:  I think so. The thing that is very, very hard about chronic graft-versus-host disease is that when it startsm,and is established, there is a lot of damage done  to the tissues and to the lungs. The lungs become tighter. Tthe airways become more restricted as well. To make people live better, live longer, and have less mortality, we need to act before the damage is established and the tissue is completely fibrotic. If we can reverse fibrosis or make it stop and maintain functionality, we will see better outcomes. I'm confident that's what we will see in the future. There are many pictures of chronic graft-versus-host disease that we hope we will not see in the future with this new treatment and how we design transplants.

(43:51): [Michelle Kosik]:  "Can REZUROCK® be used as a first-line therapy as soon as bronchiolitis obliterans is diagnosed and confirmed with PFT and lung CT?"

(44:03): [Dr. Marcello Rotta]:  Technically, REZUROCK® (belumosudil) is approved for patients with steroid-refractory disease. In other words, you cannot use it as  first line treatment if you go by the book. You need t to start on a steroid first, and when you see that the steroid works up to a certain point, you can request the drug and get it. The drug may not be used right away, but let me tell you, when I'm starting the steroid, I'm also starting to procure the REZUROCK® for the patient. Iff the picture gets better without using it, we don't use it. Otherwise, we will be ready to use it soon.

(45:11): [Michelle Kosik]:  One of our viewers has a question, "I have lung GVHD, and I have taken JAKAFI for years. I know REZUROCK® is a promising new treatment. However, I have tried it twice and gotten lung infections both times. Any data or thoughts on this? Or am I a one-off case?"

(45:32): [Dr. Marcello Rotta]:  No, you're not a one-off case. It's so hard. Lung chronic graft-versus-host disease is one of those tough situations. Now it's true that the main problem is that folks with lung GVHD have the tendency to get infections, because they were on immunosuppression for a very long time, and the structure of the lung and the immunity at the level of the lung has been messed up. It's very easy to get pneumonia, and those pneumonias can make the GVHD and life much worse. Yes, you are not a one-off, and the treatment can be frustrating. You try something, and you don't know whether something works or not.

(46:21): The other thing, that is a big part of this, is that when you start these new drugs, they need time to work. They need to be well absorbed and taken consistently. Whether the drug has been causing the infection is always a bit questionable. You don't know, but no matter what, if you try a drug, you need to stick with it for a while. The results are not 100%. Sometimes they are in the order of 50%. This is why, for example, we have to find newer drugs, such the very last one that I discussed, because we continue seeing folks who still have a problems even with the newy-approvied drugs, IMBRUVICA® (ibrutinib), JAKAFI® (ruxolitinib), REZUROCK® (belumosudil). We need more things to be done.

(47:15): [Michelle Kosik]:  "I have bronchiolitis obliterans from chronic graft-versus-host, and I've been on 10 milligrams of prednisone for 20 years. I still have frequent shortness of breath. Would you consider transitioning to REZUROCK? When do you a start steroid taper after starting REZUROCK?"

(47:38): [Dr. Marcello Rotta]: If you have been on steroids for 20 years, I would consider starting the newer drug, REZUROCK® (belumosudil). I am a big proponent of reducing steroids. Sometimes, as you know, when you taper down steroids, you may get more shortness of breath or have an exacerbation, so they bump up your steroid again. The general way that I practice is to establish an extremely slow steroid taper. Even going down from 10 to 8 once a month and plan to come off in six months or so. It also helps with the adrenal. But I would consider using REZUROCK® (belumosudil) right now.

(48:30): [Michelle Kosik]:  "I'm using my son's stem cells for transplant. Does that mean I have less or more chance to get graft-versus-host?"

(48:40): [Dr. Marcello Rotta]:  If you use your son's stem cells, ask whether the transplant is designed with post-transplant cyclophosphamide (Cytoxan®”. Chances are that you're going to use that post-transplant immunosuppression. That’s already the standard of care if you receive cells from a son or from a parent. That type of transplant is what we call haploidentical.

If you get post-transplant immunosuppression, we anticipate less chronic graft-versus-host disease. This is the data that we see. That's why we would use the post-transplant immunosuppression right now. You should see less chronic graft-versus-host disease, but you want to ask your doctor, "Am I getting post-transplant cyclophosphamide (Cytoxa®)”?"

(49:41): [Michelle Kosik]:  That's great advice. "My transplant was six years ago under the old process. I have bad graft-versus-host disease. Can I use these new medications to control my GVHD?"

(49:52): [Dr. Marcello Rotta]: If you have GVHD established, you can use these newer drugs if appropriate. If you are now still on immunosuppression and the. If you are stuck on this immunosuppression, or when you start tapering off the immunosuppression, the GVHD comes back, that's when you want to think about the newer drugs.

(50:21): [Michelle Kosik]:  "Have you seen any treatments that have helped with trunk scleroderma?"

(50:27): [Dr. Marcello Rotta]:  Yes, I've seen it in my practice. We saw some responses with photopheresis. The number of successes has been limited, but it's worked in some patients. We also saw about 30% of people with this tightening get better with IMBRUVICA® (ibrutinib). It's not a full success, but it's better. We saw improvement in folks with JAKAFI® (ruxolitinib) and also with REZUROCK® (belumosudil). Now, we have to be clear that the tightening, that sclerosis, has to be tackled soon, because when fibrosis changes the way the skin is, it's very hard to reverse it. It's like a scar. If the scar is there, making it go away is hard. The last drug I discussed, the one on a clinical trial, is looking at this specific issue of that tight skin on the trunk.

(51:57): [Michelle Kosik]:  "Of the three medications you discussed today, which one is the best for bronchiolitis obliterans?"

(52:05): [Dr. Marcello Rotta]:  The answer is that I don't know. We saw some lung results in the study with the JAKAFI®. We saw some lung results also with the REZUROCK® (belumosudil). That's still a very difficult question, and we don't have comparative studies, using one versus the other, in folks with this specific problem. The idea is to jump on one. Also, look at the adverse effects. For example, if you are very anemic, maybe JAKAFI® (ruxolitinib) may not be the drug for you because it will make you more anemic. Or, for example, if you have a lot of liver problems, that can become [inaudible 00:52:51]. I don't have an answer to know which one of the two is better.

(53:04): [Michelle Kosik]:  "I have terrible mouth sores five years after transplant; nothing has helped. This IV infusion you speak of sounds promising. When will it be approved, and will it help mouth sores?"

(53:18): [Dr. Marcello Rotta]:  It's a great question. I don't know. This larger trial, which might get approval if the drug works, is ongoing. Before having the drug approved, it's going to take a while. A while, meaning a few years. I doubt it will ever be approved. The study is ongoing, and there are very limited cases where the study drug is approved. I just need to clarify that. [Editor's note: Promising drugs are sometimes used to treat patients before receiving FDA-approval.]

(53:50): Lastly, yes, oral GVHD, at times, becomes a big issue when you lose a bunch of teeth, and the dry mouth makes it tough to eat, and you're losing weight. That’s when you need a lot of care. Having a successful drug, one of these new drugs, must be in the picture, and a lot of oral care is necessary, as you also know, for the GI issue.

(54:20): Sometimes, when GHVD is established in the mucosa of the lower GI tract, and it's very difficult to make it go away because many salivary glands are gone. There’s a need for local care of the mouth. I’ve been having a lot of discussions with dentists. Many of my patients are dentists. There are a lot of things that they recommend that could be done. For example, to change the pH inside the mouth, use a high fluoride toothpaste. The idea is to have help from a subspecialist like a dentist. Sometimes there are certain dermatologists, too, who can be helpful.

(55:13): [Michelle Kosik]:  "I'm on JAKAFI. Is that considered immunosuppression? I've had steroid-dependent mouth sores for six years. JAKAFI has been very helpful in removing my mouth sores."

(55:27): [Dr. Marcello Rotta]: We don't consider JAKAFI® (ruxolitinib) a standard immunosuppressive drug. As a matter of fact, we don't have yet any specific guidelines to tell us that people on JAKAFI® (ruxolitinib) should be on antibiotics. That said, from studies of people using JAKAFI® (ruxolitinib) for many years, there has been a signal for those folks to get some infection, like a weird fungal infection. All I'm saying is that my patients are on JAKAFI® (ruxolitinib); they are only on JAKAFI® (ruxolitinib). They come off their Bactrim®, acyclovir, and antifungal when appropriate. But indeed, if they had a history of a fungal infection, or if you did have a history of fungal infection, it may be a consideration to see whether it's worthwhile for you to take an antifungal. But per se, we think about JAKAFI® (ruxolitinib) mostly as an immunomodulatory rather than a straight immunosuppressive drug.

(56:33): [Michelle Kosik]:  This must be our last question. We're running out of time. "Which of the new drugs seems to be better for eye GVHD, JAKAFI® or REZUROCK®?"

(56:44): [Dr. Marcello Rotta]:  Wow, that's a good question. Very quickly, we don't know. That's a short answer. The other thing you need to know is that the GVHD in the eye is a very tough disease. In my experience, when eye GVHD is established, sometimes the drug you take by mouth doesn't work, no matter what drug you take. If there is a lot of damage to the parts of the eye that keepsthe eye wet or that makes oils that protect the cornea, when the damage is established, you really need a lot of eye care. The job has to be to prevent the damage. Ultimately, though, between JAKAFI® (ruxolitinib) and REZUROCK® (belumosudil), we don't have data on whether one is more beneficial for  the eyes.

(57:42): [Michelle Kosik]:  Thank you, Dr. Rotta. On behalf of BMT InfoNet and our partners, I would like to thank Dr. Rotta for his extremely helpful presentation. Thank you for our audience and your excellent questions. Please contact BMT InfoNet if we can help you in any way.

(58:03): [Dr. Marcello Rotta]:  Thank you.

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