New Treatments to Prevent or Treat Graft-versus-Host Disease

Transcript of Presentation:  

(00:02): Becky Dame: Introduction. Welcome to the workshop, New Treatments to Prevent and Treat Graft-versus-Host Disease. My name is Becky Dame, and I will be your moderator for this workshop.

(00:13): Before we begin, I'd like to thank Incyte Corporation, whose support helped make this workshop possible.

(00:20): It is my pleasure to introduce today's speaker, Dr. Trent Wang. Dr. Wang is an Associate Professor of Clinical Medicine in the Division of Transplantation and Cellular Therapy at the University of Miami Sylvester Comprehensive Cancer Center. Dr. Wang's research focuses on complications of allogeneic hematopoietic stem cell transplantation. He conducts interventional, behavioral, and retrospective studies of graft-versus-host disease, infectious transplant complications, and transplant survivorship. He also studies the outcome of immune-effector cell therapies, such as CAR-T cells for various oncologic indications. Please join me now in welcoming Dr. Wang for this session.

(01:15): Dr. Trent Wang: Overview of Talk. Thank you so much. I'm super happy to be here, and glad you could all join us today. As mentioned, the title of our talk today is Treatments on the Horizon to Prevent or Treat Graft-Versus-Host Disease. Our learning objectives today are to describe graft-versus-host disease (GVHD), to review how many patients develop acute or chronic GVHD and the changes in the trends, and to talk about new developments in GVHD treatment and prevention. A lot of these therapies are being investigated or recently had new data published. Not all of these are ‘ready for prime-time’ treatments; however, we'll still touch on these topics, and we'll talk about clinical trials in general.

(02:17): Allogeneic transplant (using donor cells) is a potentially curative treatment for relapsed or refractory blood cancers. What is hematopoietic stem cell transplant, also called bone marrow transplant or stem cell transplant? Allogeneic transplantation relies on an immunotherapy effect to cure advanced blood cancers or bone marrow failure disorders. In fact, it is often the only treatment that is considered curative for relapsed or refractory blood cancers, such as leukemias or lymphomas, that have failed other therapies.

(02:42): A donor's new bone marrow or stem cells produce blood and immune system cells, which are ultimately able to recognize cancer cells in the patient as foreign and bad and thus eliminate them. This is a good graft-versus-leukemia or lymphoma effect. But this new immune system may also cause graft-versus-host disease, which is an off-target injury that we'll talk more about later.

(03:10): This graphic on the right shows in purple the number of allogeneic transplants over the years. Despite a slight decrease during the COVID years, the numbers continue to rise. And despite advances and new FDA approvals of other treatments for lymphoma, myeloma, you name it, the number of allogeneic transplants continues to be at a very high level, so it is still relevant in this day and age.

(03:45): Most of you here today probably already understand a lot about bone marrow transplant or stem cell transplant, but I do want to review what happens through this treatment journey, as each part of the treatment has an impact on what happens next and the eventual outcomes.

(04:02): I use a dating and marriage analogy for stem cell transplants. Transplant is obviously just as big of a commitment and certainly life changing. The pre-transplant period is like dating, where we learn about each other, including the patient's background and the transplant program, and determine whether transplant is the right decision, balancing risk and benefit. In the pre-transplant period, our bodies are already impacted by prior treatments from chemotherapy, biologic agents, or radiotherapy. The depth of remission, i.e., how good a remission one achieves, is a very important indicator, as it predicts how well people do after transplant. Less disease is obviously better.

(04:59): Many factors can impact the likelihood of a successful transplant. The transplant itself is the marriage, with the commitment being the conditioning and cell infusion. During transplant, a lot of the important variables that come into play include the level of HLA, or human leukocyte antigen, matching between the donor and the patient, the conditioning chemotherapy or radiation therapy chosen, as well as the strength of it, and the immunosuppressive regimens or the bone marrow transplant protocols that are selected by the transplant program.

(05:34): After transplant patients need to be monitored for graft-versus-host-disease (GVHD) and infections. Finally, the post-transplant period is the hard work that's involved in making the relationship between the new immune system and our body harmonize, including working out kinks such as graft-versus-host disease and oftentimes infection. The development of graft-versus-host disease, the use of medications that have both good and bad side effects, health maintenance, and surveillance, all play important roles in the outcome of transplant.

(06:02): There are a lot of variables that can impact what happens, many of which we can control, but just as many that we can't. There's certainly a bit of luck involved in this whole process.

(06:17): A new posttransplant treatment has reduced the incidence of GVHD in patients. How can we improve this transplant process? One of the most notable advancements recently in transplant has been the increasing adoption of something called post-transplant cyclophosphamide, or PTCy, in short. This is a special chemotherapy agent that's given on days three and four after the transplant, as shown here on the diagram, where day zero is a day of infusion with that little bag of stem cells.

(06:47): Chemotherapy being given after stem cell infusion always sounds bad and a little bit risky, but it works in a really neat way. The PTCy targets more of the reactive T-cells that cause bad GVHD or rejection, and it targets selectively fewer good cells that promote tolerance. It also doesn't injure the stem cells much.

(07:12): This new treatment has also reduced complications and rejection rates. PTCy has been used in many different transplant platforms with different donors. Initially, it was developed with half-identical or half-match family donors, but now we're increasingly using it in mismatched, which are seven out of eight or below, and matched donors as well, as eight out of eight, because we've seen such promising results. It has reduced a lot of complications, reduced rejection rates, reduced GVHD, especially the chronic form, and has been adopted throughout the country.

(07:48): New drugs are also reducing rates of GVHD and overall survival rates. Other ways of improving transplant outcomes include bettering the current transplant platform. One of the most logical ways is to add promising new drugs to established transplant procedures or protocols. The addition of Ruxolitinib (Jakafi), a JAK inhibitor and effective anti-inflammatory drug which is used currently in the treatment of acute and chronic GVHD. It was originally developed for myelofibrosis and is being evaluated in a large study to see if Ruxolitinib plus our usual transplant protocol can reduce rates of GVHD and improve survival. All the while we focus on safety in terms of stem cell engraftment, growth and the blood counts. Preliminary evidence has shown promising rates of engraftment and GVHD, and this is currently being studied in a large Phase III multicenter study.

(08:49): Vedolizumab (Entyvio) is a drug that blocks immune system cells from attacking the intestines and was FDA approved for the treatment of inflammatory bowel disorders, such as Crohn's and ulcerative colitis. There's anecdotal evidence that show it seems to work reasonably well in treatment of gut graft-versus-host disease. The current trial is a large Phase III study involving hundreds of patients, combining Vedolizumab with a standard transplant protocol to determine if it can reduce the rates of lower GI GVHD. And lower GI GVHD is always a target, because this type of GVHD is one of the most dangerous types. The study does show a significant reduction in the rates of lower GI GVHD with the addition of Vedolizumab.

(09:42): Graft engineering may also reduce GVHD, promote engraftment, and fight leukemia more effectively. And thirdly on this slide, graft engineering is being investigated as an avenue to improve outcomes. Graft engineering is the manipulation of the stem cells that we get from the donor to modify and rebalance the specific cell subpopulations to try to reduce graft-versus-host disease, possibly to improve the graft-versus-leukemia effect, and to promote engraftment. In one recent clinical trial, patients who received the engineered graft called Orca-T were more likely to be without moderate to severe chronic GVHD and had very low toxicity rates when compared to a traditional regimen. There are also several other graft-engineered constructs being investigated.

(10:29): So, what is GVHD? The purpose of this transplant is basically to get a graft-versus-cancer effect. GVHD, however, is a friendly-fire side effect from the same cells that are trying to kill the leukemia or lymphoma. When we do see GVHD, we usually do see some degree of the graft-versus-cancer effect as well and, currently, we don't have a great way of separating these effects.

(10:58): This picture is of a confused lymphocyte character that I created with Microsoft paint, patent pending obviously, and that's how I liken the GVHD picture. The transplant process, as alluded to earlier, is a marriage, and with all marriages one of the inevitable steps involves meeting your in-laws, GVHD here being the in-laws. It becomes a necessary part of your life, oftentimes, with some good effects, i.e., less relapse, but also some bad effects that we can manage effectively but with effort.

(11:39): There are two main types of GVHD. Acute GVHD is classically defined as that diagnosed before day 100. It most commonly involves the skin, GI tract, or liver, and is generally considered something caused by T-cells from the donor, which affects how we treat it.

(12:00): Chronic GVHD usually develops after the three-month mark, sometimes well after, and manifests in many more organs, including eyes, mouth, joints, and more. And chronic GVHD is believed to be caused by more than just T-cells, but also B-cells and other immune system components as well.

(12:19): As a result of these differences, acute and chronic GVHD are viewed as different entities, and they're diagnosed differently as well as treated differently, although there certainly are overlaps. In the middle of these two circles there is an overlap area as well, and sometimes we see features of chronic GVHD and features of acute, GVHD as well.

(12:48): Acute GVHD is pictured here. We see a patient with a macular rash. That means it's red, it's itchy, it's often on the chest, the neck, the upper back. It usually presents in the first one or two months after transplant and can cause many symptoms like we talked about.

(13:05): One of the most important features of GVHD is that we have to make sure it is GVHD, and that's always harder than it sounds. While patients are in this acute GVHD window, they're also on many other medications that can cause rash or these other side effects. We have to do our best to navigate and figure out, beyond a reasonable doubt, that it's not other causes like infection or medications that are leading to similar presentations, because the treatments can be very different.

(13:41): The treatment for acute GVHD involves immune suppression, which aims to dampen an overly active immune system. A well-known example is prednisone or a corticosteroid, typically administered at high doses initially and then reduced or tapered as improvement is observed.

(14:03): Sometimes we don't need to give prednisone in the form of pills, because the GI tract absorbs the pills, and it goes everywhere in the body and potentially has more side effects. In these cases, where the symptoms are milder or localized, we might be able to use lotions, creams, or topical therapies that control these symptoms. An example would be the rash that we saw on the previous slide; we could treat that with a corticosteroid cream instead of a pill, which would certainly have fewer side effects, because side effects can be very substantial when we're on immune suppressants and corticosteroids.

(14:42): Steroids work by weakening the immune system, and the biggest threat from that is an infection. Infection in someone after transplant is not the same as an infection in someone who didn't have a transplant. The immune system is generally much weaker, and even a simple infection can become more serious, so we take them very seriously.

(15:05): Other side effects from steroids can include many things, such as fatigue, high blood sugars, muscle weakness, bruising, appetite changes, sleep problems, anxiety, depression, you name it, it can happen. In fact, patients have so many complaints about steroids generally that we decided to start developing a digital health app to help with the side effects and the adherence to this. We also have to remember that as we lower steroids, sometimes we see different symptoms, whether it's from withdrawal of steroids, or perhaps the GVHD symptoms may worsen again. There's always a lot to monitor while we're on steroids.

(15:52): Steroids are usually the first treatment when we have GVHD that requires systemic treatment. If there is improvement, we reduce the doses to reduce these toxicities. However, if there is no improvement or symptoms worsen after we reduce the doses, we usually need to consider adding more immune suppressants, as well as working out other causes that might be contributing to the worsening symptoms, of course.

(16:24): One of the best drugs for this worsened acute GVHD that's not responding well or is very dependent on steroids is Ruxolitinib, which we talked about using for prevention, but which is also one of the most effective therapies for acute GVHD. There are countless other immune suppression agents that work, although Ruxolitinib has the best data so far. The other drugs are less standardly used, and centers tend to have very different practice patterns. It depends on who you see and what day you see them. Even at the same center, you might get different recommendations outside of Ruxolitinib. It's very much a work-in-progress on our end, but we also try to supplement these systemic immune suppressants with our supportive topical therapies, such as anti-diarrheals, creams, non-absorbed steroids, you name it. We will try anything to improve the symptoms, as well as reduce the symptom burden.

(17:39): An exciting area that's being developed now is biomarkers for acute GVHD, specifically whether a biomarker drawn early in the transplant course can identify patients who are more at risk of developing acute GVHD or have an adverse outcome. Essentially, a biomarker may be able to demonstrate GVHD before clinical manifestations are apparent.

(18:03): In this case, a blood biomarker IL1RL1, or ST1, was found to be elevated in patients who are at increased risk of GVHD. Just because we know who's at increased risk doesn't necessarily mean we know yet how to fix it, but it's certainly a start. Similar biomarkers are used at the onset of GVHD diagnosis to see who is more likely to respond to steroids, and those have also been developed and are in some clinical practice. We're developing more technology to help guide us in the treatment of graft-versus-host disease.

(18:51): New treatments for newly diagnosed, i.e., first-line acute GVHD, are also being investigated and reported. Alpha-1-Antitrypsin is a liver-produced protein that reduces inflammation and GVHD severity without much added side effects. Due to the nature of GVHD and the treatments for GVHD, which cause immune system weakening, there's a lot of emphasis on looking for drugs like this that don't weaken the immune system but might help to regenerate and heal and to control the immune system in different ways.

(19:29): The addition of Alpha-1-Antitrypsin into a standard high-dose steroid regimen for the treatment of GVHD was shown to reduce the likelihood of the GVHD therapy failing, meaning needing additional immune suppression, which is a big deal.

(19:45): Ruxolitinib is also combined with urinary human chorionic gonadotropin (HCG). HCG is a protein that stimulates intestinal stem cell growth and was previously shown in a smaller study to reduce GVHD severity. So Ruxolitinib with urinary HCG is being tested with lower doses of prednisone to see if this combination can effectively treat GI GVHD, specifically lower GI GVHD. The goal here is to reduce the steroid toxicities and get better outcomes if possible.

(20:29): Some of the most ill patients that we see in GVHD are those who have failed prior acute GVHD therapies, or have not responded, or have gotten worse. This is an area that has a lot of focus because the population is at risk for infection and uncontrolled GVHD symptoms.

(20:47): Apraglutide (not yet FDA approved and therefore not yet branded) is a medicine that's been studied to improve tissue regeneration and GI function. When added to Ruxolitinib, as well as steroids in patients who have this very advanced GVHD, apraglutide seems to improve the likelihood of response in these patients, without much in terms of added toxicity.

(21:10): I want to mention fecal microbiota transplantation, which is essentially a poop transplant, in which donors with healthy gut microbiota donate their stool to those in need. The healthy stool is usually administered as an enema or as a pill. In GVHD, there's been a lot of talk about this, and some small series or cases have shown this improving very refractory cases, but it's not yet standard or mainstream. I hope that it will be one day.

(21:47): We see chronic GVHD as a long-term complication of transplant that affects about 30 to 50% of patients, although this percentage is decreasing. Newer ways of doing the transplant, such as with the post-transplant cyclophosphamide, have made a big dent in that percentage. It's a major cause of problems in cancer survivors, including many years out of transplant, and having significant chronic GVHD is a risk factor for a bad outcome, even years and years after transplant.

(22:20): The image here shows skin lichen sclerosis, areas of dyspigmentation. Often patients may have areas of skin that are thickened, with restricted joint mobility as well.

(22:36): Treating GVHD requires balancing risk and benefit to control symptoms but minimize side effects and infections. The approach to chronic GVHD is similar to acute GVHD but also different. It's a little bit tricky and requires more balancing of risk and benefit. Given enough time, we think all GVHD patients will eventually have their symptoms diminish and clinical tolerance will develop, but this can take years and years, so we walk that fine line of giving enough therapy to control symptoms and prevent organ damage, but not too much therapy where we predispose someone to infection and significant side effects of the drugs that we're using.

(23:13): When we see a patient with chronic GVHD, we always have a few options, and one option may be to do nothing and just observe. There are many times where this is reasonable. It can be distressing to the patient, because they see these symptoms which are not too bad but they're there. However, doing nothing is a possibility.

(23:34): If we decide to do something, then we have to decide whether that something is a minimally toxic topical therapy, such as a cream, eye drop or mouth rinse, or is instead a systemic agent, given orally or intravenously. All of this needs that benefit/risk discussion.

(23:57): Fortunately, treatment has made a lot of progress for chronic GVHD. You can see that since the birth of transplantation in 1957, there have been a lot of 'nothing burgers' until 2017, when a boom occurred. Since 2017, we have seen FDA approvals of four chronic GVHD therapies, indicating significant interest from investigators and pharmaceutical companies.

(24:26): Three medications have recently been approved for chronic GVHD: Ibrutinib (Imbruvica), Belumosudil (Rezurock), Ruxolitinib (Jakafi). and  The three approved pills for chronic GVHD are listed here. Ibrutinib (Imbruvica) was the first pill approved by the FDA, after a rather small trial showed efficacy in skin and mouth chronic GVHD. Ibrutinib originated as a chronic lymphocytic leukemia (CLL) therapy that targets B-cell pathways and chronic GVHD. It has somewhat limited efficacy and more toxicity than we generally like to see, so it's often skipped over in favor of one of the other pills as initial therapy.

(24:59): Belumosudil (Rezurock) targets scar pathways and rebalances the immune system subpopulations. This drug is used a lot. It's very effective and very well-tolerated. There are minimal noticeable side effects for most patients.

(25:14): Ruxolitinib (Jakafi) makes another appearance here. It's a JAK inhibitor that reduces inflammation. It works very well in chronic GVHD, with a manageable side effect profile. It has the strongest phase III data because it compared ruxolitinib to other therapies that were available at that time and showed a lot of promise.

(25:38): These oral therapies provide excellent options for patients who need treatment. However, they all still require varying degrees of clinical or lab monitoring. You can't just take it and forget about it and come back in six months. There's potential for side effects that we need to watch for.

(25:58): The newcomer to the scene, the FDA scene at least, is Axatilimab (Niktimvo), which was approved late last year. This drug targets inflammatory immune cells, namely monocytes and macrophages. The difference here is that this is an intravenous therapy that's given every two weeks.

(26:19): Response rates are similar, meaning it's still very effective, the difference mostly being that since this study drug was approved, more patients had been treated with the oral agents, whereas the previous trials had less of those heavily pretreated patients. We know that it works in people who have already tried the pills, and the side effects also are very reasonable. It's very well-tolerated.

(26:50): A very good treatment for chronic GVHD that has been around for a long time is extracorporeal photopheresis, or ECP, which is a blood exchange therapy. We like this therapy a lot here because it does a good job of treating severe GVHD manifestations without much increased infection risk. This is used in higher-risk GVHD cases, such as severe skin, joint, and liver involvement.

(27:17): This use of ECP is not FDA-approved. It's CMS (Centers for Medicare & Medicaid Services) approved since 2006. That means insurance will generally still cover this therapy. The negatives for ECP are a) the need for an IV catheter or port, because it accesses the blood, and b) the major time commitments that are necessary for the therapy. The treatment sessions usually start off around two or three times a week for two to three hours per session, and the treatment course is at least three to six months. It really is a commitment.

(28:00): Despite these new drug approvals, we don't quite know the best sequence or combination of therapies. Most of these therapies were studied alone or after two prior lines of failed therapies. But with new drugs, physicians and cancer centers across the country are combining therapies and sequencing them in very different fashions compared to one another. This raises the question of how best to use them and how best to combine them, which is being studied.

(28:30): Additionally, we're looking at how to treat GVHD with the use of less or no steroids than we conventionally have given. First-line treatment, so newly diagnosed treatment for chronic GVHD, studies are now looking at either entirely skipping steroids or giving low doses of steroids to see if we can get equivalent effects with safer therapy.

(28:56): Finally, there is an initiative looking at organ-specific clinical trials. For example, an early directed therapy for a lung graft-versus-host disease trial was recently reported using belumosudil. In this case, lung GVHD, known as bronchiolitis obliterans syndrome, can be very debilitating by the time it is usually diagnosed. If you treat someone, who has possible changes, early and with aggressive therapy, perhaps we can ward off the development of the severe manifestations later on.

(29:34): Accessing GVHD care can be challenging but digital healthcare is an alternative for some patients. I want to talk a little bit about how patients can access specialized GVHD care, since this is still a rare disease with limited expertise across the country. The map on the right shows what percentage of the US population needs to travel more than three hours to get to their nearest transplant center, at least as of 2015. And we can see that there are plenty of areas shaded in color that fall into this category.

(29:59): Digital healthcare can bridge this gap, as we can increase patient and caregiver access using the internet. Through various interventions, including new applications and Zoom, we can guide patients and caregivers through this kind of complex survivorship care, and this would allow us to provide patient-centered approach to receiving information remotely and at the right pace.

(30:26): Digital health interventions are being developed that focus on many topics. For example, telehealth-based group interventions are being designed to reach out to a broader patient population with chronic GVHD for a group session, group management, that covers coping, education of GVHD, and involves several patients with GVHD as well as a transplant clinician and a psychosocial provider.

(30:51): Another app is working on improving sexual health education and awareness, which is highly under-recognized, and transplant clinicians as a whole are under-trained to do this.

(31:05): Additionally, as previously mentioned, a high-risk medication education adherence app is being developed for corticosteroids and other high-risk medications to help patients learn and better use and navigate these medications, these drugs.

(31:22): On the topic of clinical trials, there are always varying opinions about them. Many patients are excited about clinical trials and getting one of the new, promising agents, whereas many others say they don't want to be considered a guinea pig. Clinical trials are the way for us to advance the field with these new and promising investigational therapies.

(31:44): There are different degrees of experimentation with which patients may find they do or do not have comfort. Phase I studies are usually the least studied in humans, so we have the least data, whereas phase III studies have accumulated a fair amount of human safety data, now usually looking at efficacy, so if one type of clinical trial doesn't suit your fancy, perhaps a different phase will.

(32:11): As academic physicians, and based on the recommendations of the National Comprehensive Cancer Network, our priority is always to look for available clinical trials for our patients, and usually we at the cancer centers bring in trials that we believe in. We're not going to bring in trials that don't make sense or seem to have higher than acceptable safety, or lower than what we want our patients to experience, in terms of safety or efficacy.

(32:41): Clinicaltrials.gov is the mothership of clinical trial searching. It's what I usually use, but the interface is challenging to navigate. There are a lot of boxes of active versus not accruing versus completed. So fortunately, there are several other patient resources.

(32:59): The Jason Carter clinical trial search at ctsearchsupport.org can help you find a clinical trial. Another great resource is the Leukemia Lymphoma Society's Clinical Trial Support Center. They can provide you with a live person clinical trial navigator to help identify relevant trials.

(33:22): Onto the summary of what we talked about today.  

We discussed some of the improvements to transplant methodology for all types of donors, including new GVHD treatment and rejection prevention regimens.  

We reviewed several of these new trials, but not all are ready for primetime, as I mentioned, however, many are being increasingly adopted.

We discussed the potential role of diagnosing GVHD earlier to allow earlier intervention to help us find out who has essentially preclinical GVHD.

We discussed the updates of new treatments and combinations of treatments for acute GVHD, which has clinically already occurred. This is important, because patients with acute GVHD that have not responded well to therapy are the ones who become very sick.

We also discussed the ways that we can improve treatment in chronic GVHD with new drugs and combinations and steroid-sparing regimens to improve toxicity, and we talked about improving access to specialized GVHD care through Digital health interventions.

(34:38): I always want patients and caregivers to be vigilant and to maintain close communication with their providers. Always look for new or worsening symptoms, both physical and psychological, and report these quickly, since any minor symptoms can be a big deal in an immunocompromised patient.

(35:02): We always look for the possibility of infection. The presence of GVHD, even without much immune suppression, implies a dysregulated immune system, so infections are more prone to occur and are more prone to be serious as well.

(35:17): Don't forget to do your health maintenance and cancer screenings. Although your transplant physician may do a lot of these, there's also a lot of stuff that they probably can't cover, given the time constraints, so make sure to see your primary care provider to ensure nothing is missed for your health maintenance. For example, we don't want you to have a heart attack due to high cholesterol or blood pressure.

(35:38): We are actively trying to improve our treatments for acute and chronic GVHD overall, and reduce side effects, find new and better combinations and ways to target specific organs earlier than we traditionally have. And we're also focusing on the behavioral health and survivorship aspects, implementing more care through the technology that we have, and remote access through the internet.

(36:06): And again, thank you for giving me your time this afternoon, and I will open up for questions.

Question and Answer Session

(36:19): Becky Dame: When you discuss the importance of checking in with your medical team when using Rezurock, Jakafi, or Ibrutinib, is that to watch the levels of WBCs? Are there known symptoms that would indicate medication toxicity?

(37:05): Dr. Trent Wang: Usually, when we're on therapies that can weaken the immune system and impact blood counts or other organs, what we're looking for is number one, infection. Number two, we want to make sure that the drug is not lowering the blood counts. Some drugs lower platelets more than others, for example, or the neutrophils. A lot of these drugs can elevate the liver enzymes, so we also watch those. But I would say first and foremost, we just want to make sure that there's no infection going on.

(37:40): Infection doesn't necessarily just mean that you have a cough. It could also be something that we're checking for in the blood and, especially if you're on steroids as well, viruses become relevant here. The classic viruses that we are concerned about include cytomegalovirus, which is CMV, but we have great medications to prevent that these days, as well.

(38:02): Becky Dame: With so many patients needing to use Jakafi, why is the cost still so expensive? It has come down in price, but not as much compared to its cost. Is there any insight here?

(38:19): Dr. Trent Wang: That's a difficult question for me to answer specifically. There's always a component of this that has to do with the development cost from the pharmaceutical companies. But we know that the monthly cost of these drugs is still astronomical, and the pharmaceutical companies are aware of this as well, so they generally have patient assistance programs that are able to help lower the copay to something very low or to zero altogether, although sometimes it's income-based.

(38:52): I would also reach out to your local social workers to see if they have grants available for medication assistance and the sort. But in general, it is not just a Ruxolitinib or Jakafi issue, it is the healthcare system that's the issue.

(39:14): Becky Dame: What kind of success are you seeing with the new infusion Axatilimab? Are people able to taper off Jakafi once the Axatilimab has kicked in?

(39:25): Dr. Trent Wang: Yeah, Axatilimab, we were part of the clinical trial when the drug was being developed, and we've treated a couple of patients since it's been available. It provides the same general response rates, meaning one organ improving based on a scoring sheet that we use for GVHD assessment.

(39:45): The usual response rates for these therapies is between 50 and 70%. I would think that's fairly accurate. Now, the important thing is whether or not that 50 to 70% maintains, meaning no organs worsen during your treatment on it.

(40:03): In terms of the combination, you mentioned you're also on Jakafi as well as the infusion, that is a more complicated answer, because there's very limited data. We don't really know how to combine these medications as mentioned. Depending on what organs are the most severe and how dangerous the chronic GVHD might be, you might benefit from combining them, because we want to get maximum effect, or you might not need both, and the risk of infection is just not worth it. So that's a question that I can't answer without more information, but that's why the clinical team and you will discuss whether both are needed or if one can potentially replace the other.

(40:53): Becky Dame: Many patients have chronic graft-versus-host disease manifesting as chronic fatigue. Are there any studies or research being done on how to treat chronic fatigue? Stimulants such as Vyvanse work, although it doesn't resolve it, but it does improve their quality of life. Just curious what might be on the horizon.

(41:30): Dr. Trent Wang: With chronic GVHD, from the clinical side, usually we are grading eight major organs, like the skin, the eyes, the mouth, et cetera. Fatigue is certainly a possibility, just like muscle aches and cramps, as a chronic GVHD symptom, but it's very difficult to correlate that with the GVHD itself. It's almost the diagnosis of exclusion. Because almost anything can contribute to chronic fatigue, it is hard to prove whether or not it's GVHD, and it's hard to prove how well therapies work for this specific chronic GVHD manifestation when it is diagnosed by your clinical team.

(42:16): I don't have much insight to add here, other than making sure the important things are ruled out, such as depression, anxiety, thyroid or endocrine metabolic issues, and just continuing the support that you've been given.

(42:35): Steroids will make anyone feel great for a matter of days, but then fatigue may worsen. It could be steroid withdrawal if you've been on steroids for a long time. There are just too many things that cause fatigue for me to be able to say. But it is certainly a very frustrating symptom, and we do see it all the time in our patient population, but oftentimes not as the only symptom.

(43:00): Becky Dame: In chronic graft-versus-host disease, what is considered ‘low-dose’ prednisone?

(43:08): Dr. Trent Wang: If you ask me and you ask the next guy over, you'll get two different answers. To me, low-dose prednisone is usually half a milligram per kilogram of your body weight. If you weigh 60 kilograms and you're on 30 milligrams of prednisone, I would consider that low-dose, and anything under that low-dose. But it is a subjective answer. Low-dose means within an area that I feel we're not at overwhelming risk of infection or endocrine problems or all of those side effects that we mentioned.

(43:43): Becky Dame: What does it mean if your cancer is in remission, but you still have GVHD in your stomach?

(43:53): Dr. Trent Wang: Yeah, so that's actually a fairly common presentation, depending on how long after transplant we're talking about. I would say most patients after transplant are in remission, and when they get GVHD, the GVHD helps us estimate that they're more likely to stay in remission. It just means that the new donor immune system is active, it's doing its job, and that although there's a little bit of GVHD in there – hopefully a little bit in the stomach and not too much – it can still be managed with either steroids or non-absorbable steroids, such as Beclomethasone (Qvar RediHaler, Beclovent, Vanceril, Vanceril DS) or Budesonide (Entocort, Uceris, Rhinocort Allergy, Pulmicort Flexhaler, and Pulmicort), and appetite stimulants, that kind of thing.

(44:42): Becky Dame: With steroid use, do you see a significant percentage of diabetes as a result from the steroid use for chronic GVHD?

(44:54): Dr. Trent Wang: We certainly do. High blood sugars and the development of diabetes are very common from any steroid use, not just in chronic GVHD. It seems like there's a genetic component of this, of who is just more sensitive to the steroids, that their body just does not like it. They have more side effects when it begins. It's very common.

(45:15): Most times when we have the patient start steroids, we put them on a monitoring program to see how their sugars are at home in addition to the ones we're drawing at the clinic. It's very common, to the point where we're looking for it in every patient.

(45:32): Becky Dame: This patient just recently had their BMT in May of 2024. They soon developed acute graft-versus-host disease, which then became chronic graft-versus-host disease. They are currently on Jakafi, Bactrim, and voriconazole (Vfend). Their red counts are not responding, and they are severely anemic, below normal on the white cell and platelets. Their weight is down about 20%. Any additional advice to give to their healthcare providers at Stanford?

(46:33): Dr. Trent Wang: Sure. I would start off by saying that weight loss and general well-being is a marker for chronic GVHD activity. So sometimes when we see these manifestations where weight is just not going up and we're feeling ill overall, we have to make sure that the GVHD overall is controlled, whether Jakafi alone is enough, or the steroid dose, if any, is enough. Maybe there needs to be an addition or a change of GVHD therapy. That's the first thing that comes into mind: how well have we controlled the GVHD?

(47:07): Regarding the blood counts, that part depends on many factors. After transplant, about a year later, usually we don't have the donor incompatibility as a major cause of anemia. Anemia can be due to the immune system breaking the blood in a hemolysis process. But there's a blood test that can be drawn, a hemolysis workup, which I'm sure they've done.

(47:37): If that's not showing signs that the immune system is causing the anemia, they're looking for vitamins, B-12, iron, all of those things that are the fuel for the bone marrow. Additionally, anemia can occur as a result of medication such as the Jakafi.

(47:58): And finally, there's the anemia of chronic disease, which is from overall inflammation. If the GVHD overall is not well controlled, you can also have anemia that requires transfusions here and there, or other injections for management. There are a lot of workups that can be done for it. I hope your team has already done it, but you can bring up the hemolysis, the vitamin levels, and whether the GVHD as a whole is controlled.

(48:35): Becky Dame: What are some indications that chronic GVHD has resolved?

(48:46): Dr. Trent Wang: The indications would be that your quality of life is good and that you don't have many complaints. Sometimes even years later, the eyes may remain dry, but that's because of the loss of some of the tear glands, and that doesn't necessarily reverse itself. It might just be managed supportively with eye drops. But if there are no red rashes or areas of worsening and the mouth is feeling well, chronic GVHD might be inactive or gone.

(49:16): People with long-standing chronic GVHD are also at the highest risk for developing a second kind of cancer, so cancer screening is critical. For skin cancers, make sure you see your dermatologist once or twice a year. Oral cancers, if there were significant oral GVHD. Colonoscopies. The gynecologic screenings, as well as mammograms. All of those are very important, especially if you've had chronic GVHD before.

(49:45): Becky Dame: When chronic GVHD is in multiple organs, is it less likely that the GVHD will burn out or resolve?

(49:59): Dr. Trent Wang: Not necessarily, but it's certainly worse when it's in more organs. We like it better when it's in fewer organs. But we've also seen cases of both. In general, the less GVHD you have, the more likely it is to resolve, but it can resolve even when there are many organs involved, too.

(50:22): Becky Dame: Is it possible to taper and reduce Rezurock once you've been taking it regularly for two to three years?

(50:33): Dr. Trent Wang: It is possible. Rezurock is a medication that serves a purpose. If the purpose has been achieved, such as resolution of the symptoms associated with chronic GVHD, taper discontinuation is certainly on the table. That depends on how we believe the control of the symptoms is, whether the provider thinks that all the active issues are addressed, and whether the risks of being on it are not warranted at that point.

(51:10): Becky Dame: Can you develop joint and muscle chronic GVHD as late as eight years after transplant?

(51:21): Dr. Trent Wang: You can. I wouldn't say it is common, but I've seen cases just like that. The joint and muscle discomforts, aches, pains, need to make sure that they're not associated with any inflammatory muscle process like myositis. This is usually one of the first tests the doctors will check. But it is a known GVHD-related immune phenomenon that sometimes comes on late. It's again not one of the classic eight organs that we assess. It goes under ‘chronic GVHD other’, but it's a frequently seen diagnosis. Yes.

(52:06): Becky Dame: Do you know people with chronic GVHD who must be on immune suppressants for the rest of their lives?

(52:15): Dr. Trent Wang: Yes, we do have such a population. These are patients with very advanced symptoms. They just don't do well when we remove immune suppressants or lower them, their symptoms flare. So yeah, we do see that.

(52:35): Becky Dame: Is there any evidence that simple measures like exercise or diet may make a difference in the development or treatment of GVHD?

(52:46): Dr. Trent Wang: Exercise and diet are important for everything overall, in terms of having good fiber intake, having adequate vitamin D levels, good muscle strength is protective against falls. But in terms of data, I'm not aware of any, so I'd have to look into that. I'm not aware of any published series saying that this is something definitively associated with less GVHD. But overall, in terms of the transplant big picture, those are very important indicators of fitness.

(53:27): Becky Dame: What are your thoughts on the use of Abatacept (Orencia) for chronic GVHD?

(53:35): Dr. Trent Wang: There's been a lot of new data, small data, but new data coming from several cancer centers that Abatacept works in chronic GVHD. I don't have experience using it personally, but if insurance were to provide it in the appropriate patient, I think it is very reasonable.

(53:57): Becky Dame: How long does it take for Rezurock to really start to work?

(54:13): Dr. Trent Wang: For Rezurock, as well as most of the immune suppressants, the amount of time it takes to work is based on how the clinical trials were developed, because we usually start the therapy and then we assess them every 28 days, so the median time to seeing some kind of response is four or five weeks, for Rezurock and for most of the drugs. However, the range is really broad. We see patients respond even months later.

(54:43): I think, for Rezurock, in the trial it was as far as a year before one patient responded and had improvement. You have to give these therapies time. In chronic GVHD, a lot of the manifestations are chronic, and it takes weeks and weeks and weeks for them to improve.

(55:04): Becky Dame: Closing. Absolutely. Thank you. Thank you so much. On behalf of the BMT InfoNet and our partners, I'd like to thank you, Dr. Wang, for a very helpful presentation, and thank you to the audience and for all of the questions that I'm sure will help other patients who wanted to ask as well. Please contact BMT InfoNet if we can help you in any way.