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

Graft-versus-host disease is the most challenging side effect of a bone marrow/stem cell transplant using donor cells. Learn about new strategies to treat this disease.

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Graft-versus-Host Disease: Advanced and Challenges in Prevention and Treatment

Presenter: Iskra Pusic, MD, MSCI, Associate Professor of Medicine, Washington University School of Medicine

May 1, 2024

Presentation is 41 minutes long, followed by 19 minutes of Q&A

This presentation was made possible, in part, by a grant from Incyte and Sanofi.

Summary:  Graft-versus-host disease (GVHD) is a common complication after a bone marrow/stem cell transplant using donor cells (allogeneic transplant). This presentation will discuss current techniques to prevent GVHD,  new drugs to treat acute and chronic GVHD and clinical trials testing new GVHD therapies.

Key Points:

  • There are two types of GVHD: acute and chronic.  Both can occur any time after transplant and sometimes overlap.
  • Steroids are the first line of therapy for GVHD. However, steroids are effective in treating  chronic GVHD in only 40-50% of patients.
  • The newest strategies to prevent or treat GVJD include post-transplant cyclophosphamide (PtCy), abatacept (Orencia®), ruxolitinib (Jakafi®), ibrutinib (Imbruvica®) and belumosudil (Rezurock®).


(03:19): There are two types of GVHD: acute and chronic.  Both acute and chronic GVHD can occur any time after transplant and sometimes overlap.

(06:09): Symptoms of acute GVHD include a red rash, mouth sores, diarrhea, loss of appetite, nausea and vomiting, and elevated liver enzymes.

(08:58): GVHD could be eliminated by removing the immune cells from the donor collection. However, those same cells attack the cancer, which is called graft-versus-leukemia (GVL), which is a desired effect.. 

(10:14): Strategies to prevent GVHD include selectively removing immune cells from the donor’s stem cells or adding certain types of T-cells to minimize GVHD and maximize GVL.

(13:40): Post transplant Cyclophosphamide (Cytoxan),  or PtCy, reduces the incidence of acute and chronic GVHD but can delay immune system recovery which increases the risk of infection.

(26:32): If steroids fail to control symptoms of acute GVHD, ruxolitinib (Jakafi®) is often used as a second line therapy.

(32:49): Changes in skin, hair, and nails can be symptoms of chronic GVHD along with muscle aches and stiffness, difficulty swallowing, cough or wheezes, vaginal dryness and weight loss along with nausea and diarrhea. 

(34:06): The most effective first-line therapy for chronic GVHD is steroids, but only 50% of patients with chronic GVHD cases respond to steroids alone. 

(38:42): Clinical trials are necessary to investigate the optimal sequencing of the newer GVHD treatments and the populations in which they will have the best response.

(39:51): Success in treating chronic GVHD can be measured by arresting progression with improved function and quality of life. Chronic long-term medications may be necessary to reach this goal.

Transcript of Presentation

[Susan Stewart]: (00:01): Good morning and welcome to the workshop, Graft-versus-Host Disease: Advances in Prevention and Treatment. My name is Sue Stewart and I will be your moderator for the workshop.

(00:12): Before we begin, I'd like to thank Sanofi and Incyte, whose support helped make this workshop possible.

(00:19): Speaker Introduction. It's now my pleasure to introduce to you today's speaker, Dr. Pusic. Dr. Pusic is an associate professor in the Division of Oncology in the Department of Internal Medicine, at Washington University School of Medicine in St. Louis, Missouri. Her research focuses on long-term complications after transplant, particularly Graft-versus-Host Disease (GVHD) as well as survivorship. She's a member of the Chronic GVHD Consortium, the Clinical Trials Network and the Center for International Blood and Marrow Transplant Research committees on GVHD and late effects. Please join me in welcoming Dr. Pusic.

 (01:05): [Dr. Iskra Pusic]:  Thank you. Thank you, Sue, very much for this nice introduction. I will talk to you today about Graft-versus-Host Disease and advances and challenges in prevention and treatment.

(01:23): Overview of Lecture. As a brief overview of our learning objectives today, we are going to talk about prevention. Then, for treatment, we are going to touch on available and approved new drugs to treat acute and chronic GVHD.  We will also discuss drugs in clinical trials for side effects associated with therapies used to treat and prevent GVHD and on ancillary GVHD therapies.

(01:57): When we start talking about GVHD, and I promise I will not use abbreviations here in this talk except this one as I think that you all can stand the shortage for Graft-versus-Host Disease. So just explaining what is happening when we transplant stem cells, I want to start by saying what happens when we, for example, transplant an organ such as kidney. Our main worry is that the host, meaning the recipient, and the patient's immune system will recognize that organ as foreign and reject it, resulting in the rejection of that transplanted organ.

(02:46): GVHD is caused by an interaction between the transplanted stem cells (the graft) and the recipient/patient tissues (the host). When you transplant stem cells, those stem cells are immunologically active. Aside from having the host immune system try to reject them, you can also have these transplanted stem cells recognize the host, the patient, as different from them. That is what we call graft versus or against the host disease, as known as GVHD.

(03:19): When we talk about GVHD, it comes kind of in these two flavors, acute and chronic GVHD.

(03:28): Acute graft-versus-host disease (GVHD) can manifest at any time following a transplant and can impact the skin, liver, and gastrointestinal system. We used to think of acute GVHD as any GVHD happening between day zero, which is the day of your transplant, and day one hundred. However, we know that acute GVHD can also happen after day one hundred, and now we call it late acute, which can be either recurrent, after it had resolved previously, or persistent or new onset. This means that it starts after day hundred, even though the person didn't have it before day hundred.

(04:05): GVHD is an inflammatory process. The incidence overall is kind of, well there's a wide range, and primarily because of different prophylactic strategies we now use. It affects primarily three organs, which is skin, gastrointestinal system and liver. When we think pathophysiologically about what's going on, it is known mostly as inflammatory, which means inflammation is an underlying cause.

(04:36): Chronic GVHD occurs in 40-50% of patients. It is different from acute GCHD; it can happen early, before day one hundred post-transplant. When we talk about chronic GVHD, we used to think of chronic GVHD as any chronic GVHD that is happening after day hundred. But now, knowing that this process of chronic GVHD is a separate process from acute and has somewhat different features, we also know that classic chronic GVHD can really happen even before this mark of day hundred.

(05:07): The incidence is somewhere between 40 to 50%. It can affect essentially any part of the body. And we think of it more as a systemic disease. In many situations and instances, it resembles autoimmune diseases and eventually can lead to fibrosis and sclerosis. In some situations, people can have features of both chronic GVHD and acute GVHD. And in those situations, we call it overlap GVHD or overlap syndrome.

(05:47): Overlap syndrome is when you have both chronic and acute GVHD for a period of time. And here, I'm showing this to you in a more schematic way, where you can kind of see this flow from acute to chronic, and then a situation of overlap syndrome, if you have both of acute and chronic features.

(06:09): Acute GVHD symptoms include a red rash, mouth sores, diarrhea, loss of appetite, nausea and vomiting, and elevated liver enzymes. When you look at the organs involved, as I said in acute GVHD, you're going to have skin, gastrointestinal system and liver. For example, in skin, with acute GVHD, mostly this will be red, kind of sunburn-like rash on your skin. In the mouth, you can have mouth sores, also inflammation of your gums. Diarrhea, loss of appetite, nausea, vomiting, and elevated liver enzymes that can then lead to yellow tint of your eyes or skin.

(06:50): Chronic GVHD of the skin appears more as thick, dry, fibrotic skin. In chronic GVHD, when skin is involved, even though sometimes you can have changes that you might call rash, eventually you will have more change in the texture, where skin will appear more thicker or drier if you want, sometimes leading to poor mobility of skin, resulting in, for example, decreased range of motion in your joints that can come from skin sickness.

(07:27): Chronic GVHD can also affect your eyes, mouth, genitals, lungs, GI system and muscles and joints. It can affect your eyes, with dry or sometimes teary eyes, with pain, blurry vision. It can affect mouth, with mouth sores and ulcerations. Sometimes, again, from this thickening around the mouth and the skin, it can cause trouble opening your mouth. It can involve lungs, which will typically result in shortness of breath, cough and being more susceptible for infections. Also, one organ that is relatively often involved is joints and muscles, where people can have pain and stiffness and sometimes a lot of muscle cramps. Also, gastrointestinal system and genitals.

(08:22): When we think about Graft-versus-Host Disease, as I showed you on that initial slide, you need to have, in order to develop GVHD, to have immune cells from the donor in the graft. Those cells can attack the recipient and cause GVHD. But also, those same cells help recognize cancer cells and destroy these cancer cells. This is something that we know as Graft-versus-Leukemia (GVL) or Graft-versus-Tumor effect.

(08:58): GVHD could be eliminated by removing the immune cells from the donor collection. However, those same cells attack the cancer, which is called Graft-versus-Leukemia (GVL) which is a desired response.  So GVHD could be removed if you try to remove all the active immune cells from the donor, from the collection from the donor. But when you do that, if you completely remove donor immune cells, you potentially increase the risk of relapse. It's this balance between GVHD and this GVL on the other side. As you will see in some of my next slides, really, our efforts in prevention and treatment are to try to harness these two reactions and allow on one side Graft-versus-Leukemia effect to go on while harnessing Graft-versus-Host Disease.

(09:46): I will first touch a little bit on our methods of prevention. And prevention strategies really start before any GVHD develops, which means around the time of transplant. And when we think how to design our transplant strategies, that's the time to incorporate prophylaxis. And there are several strategies that we can use.

(10:14): Graft manipulation is a GVHD prevention strategy. One of them is to manipulate the graft. Selective removal of those immune cells that are capable of causing GVHD is one way we can do this. But also, we can try to enhance the graft with the cells that might be beneficial and try to help with this Graft-versus-Leukemia effect and minimize Graft-versus-Host Disease. We do this by adding certain types of T-cells that could have that effect.

(10:49): Depleting Naïve T-cells or alpha/beta T-cells and CD34 selection are graft manipulation strategies. Graft engineering is also being studied to reduce the risk of GVHD. These are, just for example, some of the ways we can do it. By depleting these naive T-cells that are capable of causing GVHD or alpha/beta T-cells or by selecting for CD34 cells. Here there are completely new ways of thinking and doing this, by doing complete graft engineering. These are some trials that are currently open and some of these studies have already been published with very encouraging results. You can enhance graft or even do completely new graft engineering with great results, resulting in decreased acute and chronic GVHD. These trials are available across many institutions that do stem cell transplants across the world, really.

(11:56): Immunosuppressant medications are the backbone of GVHD prevention. The other way of thinking about prevention strategies is by using medications. Use of Tacrolimus or Cyclosporine, which are known as calcineurin inhibitors, plus Methotrexate, known as Tacro-Methotrexate. It has been for years, to say really decades, the backbone of doing transplants. Sometimes we might add some additional medications, such as Mycophenolate, known as MMF or CellCept, to it. We would often add ATG, particularly in situations when we transplant using a graft from unrelated donors. Sometimes we might substitute calcineurin inhibitors with Sirolimus. These are just some of the examples of the drugs that we use as medications to prevent GVHD.

(12:54): These all very good immunosuppressive drugs. However, they have various side effects, and I listed some of them here more as an example. The other problem with them is that they ultimately do not induce immune tolerance. Really, for long-term effect and GVHD-free period, what you need to achieve is immune tolerance. This is where the host and graft kind of live together. These drugs are relatively poor in achieving immune tolerance.

(13:40): Post transplant Cyclophosphamide (Cytoxan), known as PtCy is another strategy being used for GVHD prevention. The other drug on the block, I wouldn't say it's a new drug but it's a new technique, is the use of post-transplant Cyclophosphamide (Cytoxan). Cyclophosphamide we also use as a chemotherapy drug, but it is a great immunosuppressive drug.

(14:00): This technique was initially used in haploidentical transplants. Haploidentical transplants are transplants when you have a half-matched donor, for example, a sibling who is not fully matched but is half-matched, or a parent or a child. In order for such a transplant to work and not cause horrendous GVHD in the recipient, the use of post-transplant Cyclophosphamide is designed to give it on day +3 and +4 after the infusion of stem cells. With the idea that in that time period you are going to have these alloreactive T-cells that are capable of causing GVHD, that are going to be rapidly proliferating and dividing.

(14:56): And this medication, Cyclophosphamide, has the ability to act on these rapidly dividing cells and destroy them, as you can see on this upper line. While the cells that are not in this part of the cycle, where they're rapidly dividing, such as stem cells for example, can go on and not be affected by post-transplant cyclophosphamide and continue to engraft.  Your stem cells can engraft, while those rapidly dividing alloreactive T-cells that can cause GVHD are destroyed with Cyclophosphamide. This has really enabled us to now increase our donor pools by using donors that are only half-matched.

(15:53): Post transplant Cyclophosphamide can delay immune reconstitution and increase risk for infections. A consideration when using post-transplant cyclophosphamide is that it can delay immune reconstitution. What this really means is that patients will have somewhat delayed count recovery and maybe during this time period, a somewhat increased risk of infections. Also, this drug can have some added cardiac toxicity.

(16:23): In a BMT CTN trial, PtCy was shown to have less acute and chronic GVHD while also showing an improvement in in relapse and GVHD-free survival when compared to standard care immunosuppressants. What has been done since this has been used is several studies. I'm going to underline one of the studies that was run through the network, called BMT CTN. It's a clinical trial networks running transplant trials. The number of the trial was 1703. And it was now comparing use of this drug, not anymore in haplo-identical transplants but in unrelated donor settings, when the reduce intensity conditioning was used and it was compared to that backbone I mentioned with Tacrolimus and Methotrexate on one side, and on the other side regimen with post-transplant Cyclophosphamide, together with Tacrolimus and MMF.

(17:17): What it showed was here, this was survival without GVHD or relapse. Where you can see the orange line is that post-transplant Cyclophosphamide had 52.7% of patients who had this relapse and GVHD-free survival, as opposed to 35% of patients with the use of Tacrolimus and Methotrexate. Also, if you look at acute and chronic GVHD incidence, you can see that it was lower when PtCy was used. You can see this orange arm below the blue arm. So lower incidence of both acute and chronic GVHD.

(18:06): After that study, use of post-transplant cyclophosphamide has really become a part of GVHD prophylaxis, that most centers now will use with reduced-intensity conditioning transplants when they use unrelated donors. Often, many centers will use it even when there is fully myeloablative conditioning.

(18:35): Abatacept is a T-cell co stimulation blocker that has been shown to increase survival without severe GVHD in mismatched and matched unrelated donor transplants. The other agent that is relatively new is Abatacept, which is a T-cell costimulatory blocker. It has been tested with Tacrolimus and Methotrexate. In unrelated donor transplants in the setting, when it was even, so-called mismatched unrelated donors, not fully matched but 7 out of 8 mismatched unrelated donors. You can see here Abatacept is in red. You can see that survival without severe acute GVHD was significantly higher both when it was used in 7 out of 8 mismatched or just regular unrelated donors. If you look at the grade 2 to 4 acute GVHD incidence, you can see that it was lower, the red line, when Abatacept was used compared to standard GVHD prophylaxis in blue.  The FDA approved that regimen for use in GVHD prophylaxis in 2021.

(19:54): What do we really do now in a real-world practice? We have ATG that I didn't really talk about, but that is something. It is anti-thymocyte globulin that we have often used in situations. Particularly with unrelated donor transplants or mismatched transplants. We have post-transplant Cyclophosphamide and we have Abatacept. What should you use and how you should you think about these three agents we have as new strategies for GVHD prophylaxis?

(20:33): One study that was done looking at 7 out of 8 mismatched unrelated donors, comparing Abatacept to regular prophylaxis with ATG. It showed that Abatacept was significantly better than regular prophylaxis using ATG in addition.  And this was presented as an abstract by Dr. Keen at ASH.

(21:06): Both Abatacept and PtCy have shown to be highly effective in preventing GVHD, leading to a decrease in the use of ATG for this purpose. The other study I'm showing here that looks complicated but what I just want you to concentrate on is this comparison of Abatacept without ATG and PtCy without ATG. So essentially, comparison of Abatacept and PtCy and there was no significant difference in these two approaches. Even though on these graphs Abatacept looked a little bit better, statistically, it was not significant. Meaning, that we really don't quite know whether Abatacept approach or PtCy approach is better. Really, more studies and more data are still needed and studies comparing these regimens will be coming. But what we do know, in a way, is that ATG is slowly kind of falling out of favor as opposed to these other two regimens that we now have and use.

(22:15): What I want to leave you with when we think about GVHD prevention strategies, the answer is really clinical trials. There are many new trials testing new agents, and if your institution has a clinical trial and you or your loved ones are about to go through transplant, consider participating in one of these trials.

(22:39): Treatment for GVHD depends on the severity of symptoms. When we talk about treating acute GVHD, it is determined by the severity of acute GVHD for first-line therapy. In mild skin GVHD, mostly skin, we usually continue or restart prophylactic medications. Primarily here, I mean medications like Tacrolimus, Sirolimus, or MMF (Mycophenolate), and we might use topical steroids for skin GVHD.

(23:17): For severe symptoms, steroids are standard of care along with immunosuppressants. For patients who have more severe skin GVHD or have involvement of gastrointestinal tract or liver, they will require use of systemic agents. The agents that are still considered standard of care as the first-line therapy are steroids, plus restarting your Tacrolimus or Cyclosporine. Use of ancillary therapies, such as topical steroids for skin, and other medications that we might use for gastrointestinal GVHD, such as Beclomethasone and Budesonide.

(23:57): A steroid free treatment approach is using Sirolimus. The other approach is that sometimes we will replace Tacrolimus and Cyclosporine. Particularly on somebody who was on these medications for a long time and his GVHD is getting worse, we might replace them with Sirolimus. There are other approaches without steroids, such as using only Sirolimus as a first-line agent. There was a study testing that. It showed no benefit of using only Sirolimus in GVHD, but the benefits included less steroid-induced adverse events. Again, I think the answer will be clinical trials, where new agents can be tested, either adding them to steroids or as a steroid-free approach.

(24:48): Steroids have significant side effects, which is why steroid-free options are considered for treatment of GVHD. When we talk here about steroids, I just want to take a minute to say that for acute GVHD, typical dose that we use is 1 to 2 mg per kg per day, divided usually in two doses. Then, if GVHD is improving, you can start tapering the dose. Using doses that are higher than that are not really more effective but can be more toxic. Here are some of the side effects of steroid treatment that I'm sure many of you know much better than I do. These are the reasons why we try to steer away from steroids, to taper them and think of approaches that can be steroid sparing.

(25:36): What can happen when we start first-line therapy? People can respond and that response can be sustained and GVHD can resolve. On the other side, people can have these flares where they respond initially, but then as you taper their medications, their GVHD can flare and symptoms can return or it can continue without any significant response. In those later two options, these are the patients who might need second-line therapies for acute GVHD. Typically, we think of it for people who don't respond to steroids after five to seven days or who progress after three days of treatment with high-dose steroids.

(26:32): Second-line therapy is considered when the first line fails, or GVHD symptoms flare or recur. Ruxolitinib is often used. The drug that deserves to be mentioned here is Ruxolitinib (Jakafi), which was tested in several trials and then compared to the best available therapy hand-to-hand. It showed that partial or complete response by day 28 was 62% in the Ruxolitinib arm as compared to 39% in any best available therapy that was essentially the dealer's choice. Based on that study, Ruxolitinib was FDA-approved in the United States and later on in Europe for acute GVHD.

(27:13): So how do we, in summary, approach treatment to acute GVHD? Essentially, if you have skin manifestations, yes, and then you don't have gut GVHD and your skin is mild, this is the situation where you can go to topical steroids alone. Any other combination, even if you don't have skin manifestations but have just gut or liver, or if you have both skin and gut and liver, or if you have severe skin GVHD, you will require systemic therapy, typically, with steroids. If that fails, second-line agent is Ruxolitinib. If Ruxolitinib fails, there is a variety of options that we can use. And this list here is not complete.

(28:15): Many other second-line medications are being studied in clinical trials to see what works best for steroid-refractory acute GVHD. Really, we don't know and I don't have enough information to say which one of these agents is better. I'm sure different investigators and different institutions might favor one or the other of these agents. But really, the National Comprehensive Cancer Network says there is insufficient evidence to recommend one agent over another. And that's why I think the answer to a situation where you have steroid-refractory GVHD is a clinical trial. In clinical trials, really, there are a lot of agents that are being tested and trying to target the cells that are involved in the development of GVHD, working on agents that can help with tissue repair. With all that in mind, avoiding overly broad immunosuppression and have more so-called targeted therapy as opposed to just broad immunosuppression, such as steroids is key.

(29:21): It is important to perform risk stratification early on, to identify patients at risk for GVHD in order to intervene early. This was supposed to say chapter 3, Chronic GVHD Prevention. And here, when I talk about chronic GVHD prevention, really, chronic GVHD prevention and acute GVHD prevention are not completely separable. And many agents that we use for acute GVHD prevention, really, we want them to be able to work on chronic GVHD prevention, too. And process that leads to chronic GVHD prevention, even though chronic GVHD, we all think of it kind of as something that happens later, this process begins long before clinical manifestations really develop. That is why it is important to perform risk stratification early on, to identify people who are at risk to develop chronic GVHD later on and intervene early. In a way we need to balance the risk of developing chronic GVHD on one side with the risk of graft rejection or delayed recovery of immune system, meaning infections, delayed count recovery on the other side.

(30:39): There is a need to balance the risk of developing chronic GVHD with the risk of graft rejection and delayed recovery of the immune system. And again, I keep repeating that, but really, developing targeted therapy as opposed to broad immunosuppression that can prevent chronic GVHD without really impairing immune system recovery. And it brings us back to that old figure showing this balance between GVHD on one side and Graft-versus-Leukemia on the other side, where we want to try to harness the cells that are causing GVHD, while allowing Graft-versus-Leukemia or Graft-versus-Tumor effect to go on.

(31:24): Goals of chronic GVHD treatment include controlling symptoms, preventing tissue and organ damage, maintaining the antitumor effect, and ultimately decreasing mortality. When we think about chronic GVHD treatment, what are the goals? On one side, it controls signs and symptoms of chronic GVHD but also prevents further progression and additional tissue and organ damage and maintains our antitumor effect. Eventually, to achieve tolerance between the host and the graft, and hopefully be able to stop immunosuppression down the line. To minimize treatment toxicities, because again, all of you are very well aware that those drugs that we use to prevent or treat chronic GVHD have side effects. And eventually, our goal is to decrease mortality and improve quality of life.

(32:20): When thinking about chronic GVHD, there are questions that your physician can ask you and questions that you can ask yourself. I list 10 questions here just because it is important to recognize developing chronic GVHD early on. These 10 questions are kind of going through the main organs that are involved with chronic GVHD.

(32:49): Changes in skin, hair, and nails can be symptoms of chronic GVHD along with muscle aches and stiffness, difficulty swallowing, cough or wheezes, vaginal dryness and weight loss along with nausea and diarrhea.  How does your skin feel? Is it tight? Is it hard? Is there a rash, dryness? Is it scaly? Do you have inability to sweat or keep warm? Do you have hair or nail changes? How are your joints? Do you have any limited range of motions? Muscle cramps? How about eye dryness or excessive tearing? Do you need to use artificial tears? How about oral dryness? Any change in taste, food sensitivity? Do you have any ulcers, difficulty opening your mouth? Ask about swallowing, swallowing liquids, swallowing pills, swallowing hard food. Does the food get kind of regurgitated, kind of comes back when you try to swallow it? How about shortness of breath or cough? Ask about vaginal dryness. That is something that often goes unasked in our clinics. Also inquire about any unexplained weight loss or inability to gain weight, ongoing nausea, vomiting, diarrhea or poor appetite.

(34:06): The most beneficial first-line therapy for chronic GVHD is steroids. Only 50% of chronic GVHD cases respond to steroids. When we deal with chronic GVHD, again, mild chronic GVHD can usually be handled with local therapies or topical therapies. I encourage you here to look at this paper showing and talking about ancillary therapies that might have some good suggestions on how to handle some of these adjunct issues. We use them in addition to systemic treatment of chronic GVHD. More moderate or severe chronic GVHD, involving more organs with more moderate or severe involvement will require systemic immunosuppression. Here, for a long time, again, the first agent used to be corticosteroids in little lower doses and with acute GVHD, that again, you continue and then you slowly taper. To date, many studies were testing other agents, but for first-line therapy, no other agent has been proven to be more beneficial than steroids. However, complete response is only about 50%, which is inadequate. And what we need are clinical trials.

(35:31): What you will see, if you discuss with your providers, is there are going to be and there are already ongoing clinical trials testing novel agents, now, as a first-line therapy for chronic GVHD. Agents that are already approved. I will talk about that on the next slide, for refractory GVHD, we bring them up in the front-line setting and use them as a first-line therapy. Other options are steroid-free approaches or comparing and doing randomness trials of these different drugs plus-minus steroids.

(36:10): The probability that a patient starting first-line systemic therapy for chronic GVHD will not require additional therapy is only 20%. When initial therapy doesn't work, then we will use some of the secondary therapies. This for people who progress, who develop toxicity or if there are some insurance issues. And the chance that a person who is starting the first-line therapy will never need an additional therapy is only about 20%. And many people who start the first-line therapy will require other therapies or will require therapy being restarted in next three to four months.

(36:44): Management of chronic GVHD beyond first-line therapy is not well defined and varies depending on the physician and treatment center.  Management beyond initial therapy has been very much trial and error. When we think about what we should do, should we add another agent? Should we put a patient on the study? And how do we choose? Again, NCCN guidelines list a variety of drugs, but there is no real consensus on how to use them. It will depend again on physician or center experience, on toxicity, on cost or on patient preference.

(37:21): Ruxolitinib (Jakafi), Ibrutinib (Imbruvica), and Belumosudil (Rezurock) are all FDA-approved for the treatment of chronic GVHD. Axatilimab is not yet approved but has shown very promising results.  Currently, in 2024, there are now three drugs that are FDA-approved for use in secondary therapy in chronic GVHD. All of these drugs were really tested in open-label trials, so these were not blinded studies. Only Ruxolitinib was in a comparator arm with dealer's choice. However, and if you look at these agents I listed here, they're all pills except leave the fourth column for a second. These three drugs, Ibrutinib, Ruxolitinib, and Belumosudil are all pills. Ibrutinib and Ruxolitinib have been used for other indications, and Belumosudil is a new drug that has been developed particularly for GVHD. But they all have approximately same overall response. And the third drug, Axatilimab is not yet FDA approved, but it has shown also very promising response and has been presented as a new drug potentially for treatment for chronic GVHD. It's an IV drug, intravenous, comparing to the other three agents that I talked about.

(38:42): Clinical trials are necessary to determine the best drugs to use, and in what sequence, to manage GVHD. In the last minute or two, I just want to say, how do we choose among them? I know this is a question that probably most of you will have. What is the standard of care with all these drugs that we now have available? And really, the answer is, briefly, I don't know. Much more experience is now needed after these drugs were approved and knowing whether one of them is better for certain specific manifestations of GVHD, in what order to use them and how to switch among them. For none of these questions, I really have an answer. This still varies between different investigators. But the answer to this question is that we will need more evidence and, really, clinical trials. I think we can return to this slide with question and answer, where I can discuss any one of these questions in more details.

(39:51): Success in treating chronic GVHD may be measured by arresting progression with improved function and quality of life. Chronic long-term medications may be necessary to reach this goal. For the end I just want to say, chronic GVHD is a chronic disorder and we know that often it's not possible to completely taper people off of immunosuppression. Many people need to continue at some low grade. For example, many people stay on steroids for a long time. Is stopping immunosuppression really the measure of success? Or we can develop new therapeutic approaches that will be well tolerated and might be able to be used as a maintenance long-term, where really, success will be measured as an arrested progression of chronic GVHD, with improvement in functioning and quality of life, rather than completely stopping medications. The answer here is that we need more personalized and more biologically relevant approaches using biomarkers and also testing agents at the earlier stages of chronic GVHD.

(41:01): I can probably stop here. And then as we go through question and answer, I can touch more on other questions.

Question and Answer Session

(41:16): [Susan Stewart]: All right. Well, thank you, Dr. Pusic. That was an excellent presentation. A lot of questions, very thought-provoking. We'll start the question-and-answer session now, as the operator indicated. If you have a question, type it in to the box on the left and we will try to get to as many of those questions as we can.

(41:38): Let’s start with the first question that came in, and that was, "What type of GVHD symptoms have you seen in patients with an HLA match of 7 out of 10?" And I think maybe the broader question is the greater the mismatch, the worse the GVHD, or is there no relationship between those two?

[Dr. Iskra Pusic]: (42:00): There is definitely a relationship. And we used to think always that we need to have as good match as we can. And if we had patients who were more mismatched, such as 7 out of 8 or 9 out of 10, we would be concerned that these people are at a higher risk of developing GVHD, both acute and chronic. However, this has changed now with the availability of post-transplant Cyclophosphamide and Abatacept. If you have a donor who is mismatched, your provider will probably, almost certainly use one of these agents to try to prevent development of GVHD after transplant.

(43:05): [Susan Stewart]:  This person would like to know whether you can develop joint and muscle GVHD as late as eight years after transplant.

(43:15): [Dr. Iskra Pusic]:  Well, chronic GVHD can last for a long time. And I, for sure, have had patients and have patients who have issues with some ongoing chronic GVHD for a very long time, meaning decades after the transplant. I think it would be somewhat unusual to have no signs of chronic GVHD and then all of a sudden develop muscle issues that you would then attribute to chronic GVHD, without any other signs and symptoms for seven years prior to that. Then I would consider other possible causes. But people who have had ongoing issues with chronic GVHD, for sure, can have ongoing muscle pains and cramps even seven, eight years out of transplant.

(44:18): [Susan Stewart]:  This person comments that Jakafi costs almost $20,000 per month. And is wondering at this point in 2024, are there really a lot of people that are on it? And is there anything that can be done to reduce the cost?

(44:35): [Dr. Iskra Pusic]:  Yes, I am aware that in some situations, insurance companies might not approve or there are significant co-pays involved with these medications. And this is still a significant problem and I still think that Jakafi or Ruxolitinib is a great drug and there are some patient assistance programs that we try to use and try to find a way to obtain these medications for people who have high co-pays.

(45:17): That is one slide that actually I kind of cut it down a little bit at the end, but one slide here I wanted to bring up is that we are all stakeholders in this process. With these drugs being approved by regulatory agencies, we will really need to work with payers to find optimal models, where these drugs that are now approved, the patients can have access to them. There is no question that better options are needed for patient assistance or for these drugs to be available through insurance for patients.

(46:03): [Susan Stewart]: That is absolutely true. Okay, the next question, "Is there any evidence that simple measures like exercise or diet make a difference in the development or treatment of GVHD?"

(46:16): [Dr. Iskra Pusic]:  Absolutely. This is a great question. I think that diet and exercise are definitely adjunct therapies in GVHD. I think that stretching exercises can help prevent, to certain extent, development of fibrosis and keep range of motion going. I think that there is a lot of muscle wasting in people who are on steroids. Exercising and helping build muscle mass are all really, really important in trying to maintain your physical strengths. Diet also, is very important as an adjunct method in GVHD.

(47:09): [Susan Stewart]:   All right. The next person says, "How long does it take for REZUROCK to really start to work? I began it on the first of this year and I've been on prednisone since 2017. I have adrenal insufficiency so I can't get off it. I have mouth issues, fascia issues, and..." I can't talk, "Wasting weakness and cramping."

(47:37): [Dr. Iskra Pusic]:  I didn't get from the beginning, how long was that person on REZUROCK?

(47:44): [Susan Stewart]: Started at the first of this year.

(47:47): [Dr. Iskra Pusic]:  It has been now approximately five months.  I would say when you start a new medicine for chronic GVHD, I would say it needs at least three months before you would say it doesn't work. You need to give these medications sometime to work. Sometimes it takes longer than three months to start seeing some effect.

(48:17): If by now you think that there is not any improvement, despite you being on REZUROCK, then I think you should discuss with your provider and see whether there is any possibility to get on any trials trying any of the new medications used for chronic GVHD. The medication I mentioned briefly, Axatilimab, there has been a trial and the trial is now closed. This drug might be FDA approved in the coming year for steroid-refractory chronic GVHD. There, for sure, will be other trials testing it for chronic GVHD. I would strongly encourage inquiring about that and potentially participating in one of these trials.

(49:12): [Susan Stewart]:   All right. Next question, "Do people with chronic GVHD have to be on immune suppressants for the rest of their life?"

(49:21): [Dr. Iskra Pusic]:  Not necessarily. The idea, the hope is that with time there will be immune tolerance, where there will be the balance and kind of tolerance of the host and the graft, where people will be able to discontinue their immunosuppressive medications. However, there are some people where when you start tapering immunosuppression, they will develop some worsening or a little flare of GVHD. It kind of varies from person to person, but some people might require some degree of immune suppression. But again, I'm talking broadly, because these new drugs are not that much immunosuppressive. I would call them more immunomodulatory, because they kind of modulate your immune system. Some people might need to continue them for a long time or for life, if needed. But hopefully, at lower doses. Hopefully, with these new medications, with time, we'll be able to taper people completely off the drug. However, that time might be a long process. This can take months and months, if not years, to taper somebody completely off medications for chronic GVHD.

(50:55): [Susan Stewart]:   All right. This is a rather lengthy question. Let me see if I can summarize it. This person had a transplant in May of 2020 with an unrelated donor that was a match on 10 markers. And in 2021 he developed GVHD in his eyes and saliva glands. He has been on REZUROCK and Jakafi, and since August he's been taking some new infusion treatment, he doesn't say which one. He's wondering whether these treatments should improve what he's experiencing or just prevent other symptoms from developing.

(51:35): [Dr. Iskra Pusic]:  No, I would say both. The hope is that they will improve the symptoms that that person had. I want to underline here, when I was talking about trials of Ruxolitinib, Belumosudil, and Axatilimab, improvements that were seen in these agents, for example, the last drug that was tested, Axatilimab, on that trial were patients who previously failed Ibrutinib and Ruxolitinib and Belumosudil. Similarly, on Belumosudil, people already failed both Ibrutinib and Ruxolitinib in some people. It is possible that some of these newer agents that are used, is that even though you have failed some of the prior therapies, you still have a chance to responding to some of these newer agents. And the hope is that, yes, your symptoms will improve, but it'll also stop the development of new chronic GVHD symptoms.

(52:49): [Susan Stewart]:   All right. This person wants to know whether ENBREL injections are good for gut GVHD?

(53:01): [Dr. Iskra Pusic]:  Sometimes we use it, it's a type of treatment that we might sometimes use for gut GVHD. Yes, it definitely can lead to some improvement in gut GVHD.

(53:18): [Susan Stewart]:   All right. And then this person is seven years out after transplant and has smoldering GVHD in her eyes and extensive scarring. Her eye doctor is pressing for systemic immunosuppressants even though she doesn't have GVHD symptoms elsewhere. Is there any particular drug you would suggest in this situation?

(53:40): [Dr. Iskra Pusic]:  I have had several such patients in my practice who did not have significant signs or symptoms of chronic GVHD anywhere else but in their eyes. I had success with both Jakafi, Ruxolitinib, and REZUROCK in that situation. However, it might not always work. I definitely think that this person, I think it's worth a try. I would agree that we, aside from everything that this eye doctor is doing topically for the treatment of eye GVHD, I think that this could require and I would try systemic treatment for eye GVHD. Again, I think this should be done kind of jointly through the discussion of this person's eye doctor and transplant physician.

(54:47): [Susan Stewart]:   All right. This person wants to know, "Is there a way to identify people who have a higher risk of developing chronic GVHD, like age, comorbidities, family history? Are there any factors that increase your risk of developing GVHD?"

(55:05): [Dr. Iskra Pusic]:  Well, there are risk factors that we know that can potentially lead to higher risk of GVHD, such as older age of the patient, older age of the donor. Sometimes female donor, particularly for the male recipient. The difference in HLA matching. However, many of these situations we can't really account for. If some people have several donors that are potentially an option, then we will try to choose a younger, fully matched male donor. But that's not always an option, and sometimes we have limited options and we might not have any. People might not have any unrelated donors as an option, and then we might need to use a sibling who might already be older. We know there are some potential risks, however we cannot always account for them. However, that being said, there are a lot of papers with guidelines, how to choose the best possible donor. And if you do have some options, how to kind of go among them, particularly now, when we know that with this new novel methods of GVHD prevention, we could use family members who are not fully matched.

(56:58): [Susan Stewart]:   All right. And then unfortunately, this is going to need to be our last question. We're running out of time. This person wants to know, she still needs her measles and mumps re-vaccination, but due to GVHD, she's been told not to get them. Is that going to be true forever?

 (57:17): [Dr. Iskra Pusic]:  Well, I would agree that people who have active GVHD and who are on higher doses of immunosuppression during that time should not get vaccinations right during that time period. Aside, that goes aside, usually we will vaccinate people for flu and for COVID regardless. But these vaccinations that you mentioned, that this person is inquiring about, I would postpone them until GVHD is contained and we can at least somewhat taper immune suppression. I hope it's not forever. I hope we will be able to contain this person's GVHD. And then once the GVHD kind of cools off and we lower the immune suppression, then the person will be able to be vaccinated.

(58:20): [Susan Stewart]: Great. And with that, I think we have to close. I want to thank Dr. Pusic for your very helpful presentation, particularly in the Q&A section. And I also want to thank the audience with the very excellent questions that you pose. I think we all learned a lot from the individual questions that were posed. Please contact BMT InfoNet if there's anything else we can do to support you. 

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