 Zach, let’s move on to chronic GVHD [graft-vs-host disease]. Can you discuss the role of recognizing chronic GVHD early and getting on top of therapy?

 As Yi-Bin [Chen] mentioned, the onset of chronic GVHD can be clinically subtle. On the other hand, it can progress quickly. We feel that early management of the disease is preferred. We see chronic GVHD, in the more involved cases, is usually managed in a multidisciplinary manner. Most large transplant centers have specialists who help see their patients who have organ-specific chronic GVHD involvement. For example, for patients with ocular GVHD, there’s usually an ophthalmologist who sees all the GVHD cases.

For patients with oral GVHD, there’s usually a dental specialist and a dermatologist, who could see skin or myofascial GVHD. One of the other things we know is that severe chronic GVHD can significantly impact the quality of life for both the patients and their family members. Oftentimes, once our patients are diagnosed with more involved chronic GVHD, they meet with our clinic social workers to make sure we are addressing their needs to the best of our abilities.

 It is tricky once the patients have been sent out closer to home after their initial transplant and 100 days are done, to have them come back to the transplant center for management of chronic GVHD. How do we deal with that? How do we talk to the referring oncologists and suggest when it’s time to refer the patient back to the transplant center for expert management of chronic graft-vs-host disease if that exists?

 That’s a very complicated issue. There are some centers that at day 100 send the patient back to the community physician and say, “Look, you know, it’s up to you. The patient doesn’t have to come to the center anymore, and we need to work together. Call us, and we’ll try and guide you.” At our center we have taken a more paternalistic approach. We have a regional transplant center. And although patients tend to have quite long drives, we have felt that it’s difficult to administer this type of complex therapy remotely. We are doing some telemedicine. We do communicate with the community doctors if a patient lives 4 hours away and has a fever, dry eyes, mouth sores, diarrhea. We do our best to try to get these things under control, and if the community oncologist or hematologist feels comfortable doing it and the patient responds to therapy, then great, but very frequently they don’t. They probably wouldn’t have responded immediately even if we had been treating them, and we do have to have a significant proportion of patients transferred to our center, so we can either enroll them on an investigational study or have more heads thinking about them who are skilled in the management of graft-vs-host disease.

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Treating Chronic Graft-vs-Host Disease

Despite this progress and research, unfortunately we still get acute graft-vs-host disease [GVHD]. What’s the initial approach to GVHD therapy [at Massachusetts General Hospital], Dr Chen?

 We believe the initial therapy for acute graft-vs-host disease is not where it should be, and there is definitely room for improvement. We believe in trying to conduct clinical trials in the treatment of acute graft-vs-host disease, and to do that appropriately involves a multidisciplinary team of providers and the research staff. Early recognition of graft-vs-host disease is how we are able to see if patients are eligible and present them with appropriate studies to see if they’d like to participate.

At Mass General, when patients present with acute graft-vs-host disease, there is a team of people who are made aware through group emails and oftentimes even before the patient shows up in our clinic, because they’ve called in with symptoms of diarrhea or a rash. By the time the patients have arrived, most of our team—including our research team—is aware that there is a potential patient with new acute graft-vs-host disease, and we’ve already had conversations about what we believe it is and what trials they might be eligible for to participate in.

The patient is to be evaluated to make sure there is a suspicion of graft-vs-host disease. They are presented with the treatment options, including potential enrollment onto a clinical trial. A lot of our clinical trials are biomarker based for risk stratification, and it’s important to get early blood samples to get the results of these biomarkers to appropriately risk stratify our patients.

 Dr Antin, do you want to talk about the actual therapy? What’s the standard of care for the management of moderate to severe acute graft-vs-host disease?

 It is a little bit of an embarrassment to the field because it’s prednisone or methylprednisolone intravenously, 1 or 2 mg/kg per day until you get it under control. There’s no question that this is an effective treatment. If prednisone were a new drug that were just coming out on the market today, we would be jumping up and down at what a wonderful drug it is because it’s so effective.

The problem with prednisone is that it’s a blunderbuss of therapies. It is not very selective. It does suppress the immune response in an adequate fashion in most patients, but it’s associated with the usual prednisone-related toxicity, hyperglycemia, hypertension, bone mineralization, Cushing syndrome, and sleeplessness. It’s something we depend on and that we use, but we have a love-hate relationship. We love its efficacy, but we hate its toxicity. The most critical aspect is that it increases susceptibility to infection because it’s nonspecific. 

Therefore, we have over the past 5-plus years been trying to change the paradigm from a global immunosuppression to either a targeted immunosuppression or a strategy that is not actually immunosuppressive but is more anti-inflammatory. This fosters regulatory T cells, which reduces the target manifestations in the organs. Concomitantly it allows the immune system to recover so that we’re not in the situation where the patient has GVHD, so you hit them with a huge dose of prednisone and you get the GVHD under control. Their disease is under control, but then they die of aspergillosis. That’s much of what we do, and it’s been only in the past decade or so that we’ve started to try to be more surgical in our approach to preventing and treating this disease. 

Shifting Paradigm in Treating Acute Graft-vs-Host Disease

 Dr Chen, can you elaborate on clinical trials these days and what we’re trying to do in graft-vs-host disease [GVHD] prevention?

 The last few years we’ve seen a resurgence in investigation into improving the prevention of graft-vs-host disease. There are 2 ways we’re embarking on this investigation. The first is trying to debunk that traditional backbone of calcineurin inhibitor with methotrexate, and the second is to add an agent to make it better. The first is currently being decided by clinical trials being done to the BMT CTN [Blood Marrow Transplant Clinical Trials Network]. There are 3 in the series of PROGRESS studies.

PROGRESS I was a phase 2 study looking at reduced-intensity transplant that randomized patients to 3 different regimens. Two of them were adding an agent onto a tacrolimus methotrexate backbone, 1 using bortezomib, 1 using maraviroc. The third was what Joe mentioned, a PTCy, or post-transplant cyclophosphamide–based regimen. This was all in conventionally matched transplants. These regimens weren’t compared with one another, but they were each compared with a control from the CIBMTR [Center for International Blood and Marrow Transplant Research] contemporaneously receiving tacrolimus methotrexate.

The only arm that appeared to have some benefit or being superior in the composite end point of graft-vs-host disease relapse-free survival was the post-transplant cyclophosphamide arm. Based on the results of that study, the PROGRESS I study has led to the PROGRESS III study, which is an ongoing phase 3 study comparing PTCy with standard tacrolimus methotrexate. Accrual is ongoing at the moment, and we await the results. In the myeloablative setting, the PROGRESS II study was conducted, and accrual has been finished. This was in myeloablative transplants in a phase 3 study comparing tacrolimus methotrexate with post-transplant Cytoxan alone with ex vivo T-cell depletion through a column.

We eagerly await those results too. Both of those studies have the potential to redefine what the prophylaxis of graft-vs-host disease is moving forward. There are also a slew of studies that I mentioned that are adding agents onto the standard tacrolimus methotrexate or calcineurin inhibitor backbone. These were led recently by adding what Zach [DeFilipp] mentioned, which was the antithymocyte globulin, or ATG, products. There have been interesting results from several phase 3 studies along those lines.

Other agents that are ongoing or have been recently done, including the monoclonal antibody vedolizumab and the protease inhibitor alpha-1 antitrypsin. Joe [Antin] mentioned the costimulatory blockade agent abatacept. There is more research going on to CCR5 blockade in addition to maraviroc. The JAK inhibitors that we’ll talk about soon are entering the prophylaxis realm as well. There are manipulations of the microbiome that many of us are interested in that are being studied for GVHD prophylaxis.

The IL-6 blocker tocilizumab has been studied. Two recent abstracts recently presented interesting targets of CD24 and CD26 that are being taken to larger studies as well. It’s a very busy field, which is good, and we all look forward to participating in these studies and seeing the results to see if we can improve on the prevention of graft-vs-host disease.

 Excellent. There’s lots of activity in the pharmacological sphere. Lots of groups are evaluating strategies that manipulate the graft itself to try to prevent graft-vs-host disease, either strategies that remove all or selectively remove T cells from the graft. There are some strategies that manipulate the graft in vitro either with pharmacological agents given in the bag or in the lab before the cells are given, and some very interesting suicide gene approaches are being done. The entire field of graph emulation, which we shouldn’t ignore, is done only at a select few centers in North America now.

Graft-vs-Host Disease Prophylaxis Clinical Trials

 Dr Antin, please share your thoughts on other special situations, such as haploidentical transplantation, cord blood transplantation, and severely mismatched donors?

 I completely agree with Zach [DeFilipp’s]’s comments. We use a similar set of regimens at Brigham [and Women’s Hospital]. When you start to get into donors who are not histocompatible, a haploidentical donor is a one who is half-matched, typically a parent to a child or a child to a parent or between 2 siblings who are matched at only half their 

 genes. You can anticipate a lot more in the way of difficulties. We’ve tried to do this since the 1980s, and it was almost uniformly catastrophic because crossing that 

 barrier was a problem. A number of regimens were developed—1 in Italy that never really caught on, 1 in China that has actually been quite effective, but it is so complex and intensive in chemotherapy that it never caught on the United States. What we have immediately and uniformly adopted is the use of PTCy or post-transplant cyclophosphamide. The notion of course is when you infuse the donor’s product, either peripheral blood or bone marrow, the immune cells of course come in contact with both 

 antigens in the case of a haploidentical transplant and minor histocompatibility antigens for which we don’t type. Zach alluded to this in terms of the man-woman disparity, and those T cells that are capable of recognizing those antigens will become activated and start to divide. The strategy here is to give them that opportunity to divide and then use the cell cycle activation, such as cyclophosphamide, to blast them when they’re in this growth phase. Typically, the post-transplant cyclophosphamide is administered on day 3 and 4 after the transplant when these cells have had the opportunity to get going, but before they’ve achieved enough of a critical mass to target organ injury. Then a large dose of cyclophosphamide is given twice, usually day 3 and 4. This is on the order of 50 mg/kg per day. Subsequently a calcineurin inhibitor or an mTOR inhibitor—so tacrolimus or sirolimus—is given often in association with mycophenolate mofetil to keep those cells down. One critical feature of this particular regimen and 1 of the tricks that makes this work is 2-fold. One is that it doesn’t kill stem cells. We’re not talking about autologous transplantation, but 1 of the ways you mobilize stem cells for autologous transplantation is by giving a dose of cyclophosphamide and then collecting the cells on the recovery phase. It’s not a stem cell toxin because it has aldehyde dehydrogenase that deactivates cyclophosphamide, whereas committed cells do not. That’s why your counts go down, but your counts ultimately recover because the stem cells are spared. Fortunately, in addition to stem cells, a subset of T cells called T regulatory cells has the same set of enzymes. T regs are ones that are counterinflammatory. In all inflammatory processes, you have to have something that generates inflammation and something that inhibits inflammation, or else we would all look like 1 giant lymph node every time we got infected. T regs slow things down. You not only kill the activated T cells that are likely to generate graft-vs-host disease but also allow the regulatory T cells to persist, and therefore both prevent graft rejection because they will inhibit any chemotherapy-resistant cells left in the host and prevent graft-vs-host disease. A number of other regimens are more investigational right now, including drugs like abatacept, which is a checkpoint blockade inhibitor that can be in graft-vs-host disease. It has not achieved widespread use, but there are a number of regimens that are currently under investigation.

Special Transplant Situations

 Zach, please share the risk factors for these 2 syndromes. Are they the same, or are they different? What are the most important things to try to modulate or change to prevent this from happening?

 There are a number of clinical risk factors that have been identified for acute and chronic graft-vs-host disease [GVHD]. For both syndromes, the most important risk factor is going to be HLA [human leukocyte antigen] matching. Patients who get transplants performed from HLA-mismatched donors have a higher risk for graft-vs-host disease. When thinking about acute graft-vs-host disease in addition to HLA matching, other clinical factors to consider are the intensity of the conditioning regimen and the use of total-body irradiation. Thinking about other factors related to the donor, transplants performed in male recipients from female donors have been shown to have a higher risk for graft-vs-host disease. With chronic graft-vs-host disease, some of the other clinical risk factors are the use of peripheral blood stem cells as a graft source, compared with bone marrow. Additionally, older patients and the development of previous acute graft-vs-host disease in their transplant course. The incidence—not necessarily the risk but the incidence—of GVHD after transplant is also influenced by the choice of GVHD prophylaxis.

 What is the standard of care for GVHD prevention, since this is a changing field?

 The standard of care at most transplant centers is to use a combination of immunosuppressive agents to help prevent the development of graft-vs-host disease. At many centers this consists of the combination of the inhibitor tacrolimus and methotrexate, which are what we use at MGH [Massachusetts General Hospital] for our fully matched transplants. Another popular combination is the combination of tacrolimus and the MTOR inhibitor sirolimus. For our HLA-mismatched transplants, there’s no agreed-upon approach to GVHD prophylaxis, but most centers consider some type of alternative regimen because of the higher risk of GVHD that we were discussing before. For some, this is through the addition of antithymocyte globulin, or ATG. Currently at MGH, we’ve been using post-transplant cyclophosphamide in this setting.

Risk Factors for Graft-vs-Host Disease

 Let’s discuss 1 of the most important sets of complications after transplantation. One of the major limitations of a successful transplantation is graft-vs-host disease. Dr Chen, would you mind giving us an overview of graft-vs-host disease and discussing the differences in acute and chronic graft-vs-host disease?

 For the vast majority of our patients who have a malignant disease, the mechanism of action behind a successful allogeneic transplant, we believe, lies in not only the conditioning therapy we give prior to the transplant but an immunological-based mechanism of action that is called graft-vs-malignancy. The donor’s immune system grows up inside the recipient. If there’s any residual malignancy left, the donor’s immune system is able to eradicate the residual malignancy immunologically.

The drawback to that therapeutic mechanism of action is that the donor cells can attack the recipient’s normal body. After all, while they may be HLA [human leukocyte antigen] matched, they’re not identical twins. This phenomenon or complication is called graft-vs-host disease. We’ve split up graft-vs-host disease into 2 types: 1 is acute and the other is chronic. Formerly, this was defined by timing after transplant. There was a 100-day timeline. With different conditioning regimens, donor types, and ability to do transplants with different platforms, the 100-day timeline no longer applies, and the different types are fully defined by clinical manifestations. Acute graft-vs-host disease still takes place within the first few months after transplant. It involves 3 organs, skin, gut, and liver. The skin is manifested by an erythematous skin rash. The gut is manifested by lower-GI [gastrointestinal] disease, causing diarrhea. There is an upper-GI variant, causing anorexia or persistent nausea. The liver is generally manifested by asymptomatic elevations in the liver function tests to start and is the rarest manifestation. Chronic graft-vs-host disease tends to occur after 3 to 6 months or later after transplantation. It’s a different disease. We believe they’re different immunological pathways that power acute and chronic graft-vs-host disease. The most common organ involved in chronic graft-vs-host disease are the skin, but the rash may be different. It’s generally not profound erythema but maybe appears eczematous. The eyes may become dry as well as the mouth, as a sort of sicca syndrome [Sjögren syndrome]. Chronic graft-vs-host disease can involve almost every organ in the body and is very heterogeneous. The 2 difficult manifestations we deal with include scleroderma, which involves the skin and the underlying fascia, or lung involvement as bronchiolitis obliterans. Chronic graft-vs-host disease tends to be less dramatic but also more long-lasting and oftentimes lifelong in terms of patients having to deal with the symptoms or us working with the patients in terms of lifelong management. Overall, they’re differentiated by the clinical manifestations, but there are certain patients who have characteristics of both and have overlap syndromes that have been well described.

Overview of Graft-Vs-Host Disease

 Dr DeFilipp, how important is it that we see these patients who might be transplant candidates early on in their disease? When should a patient be referred in?

 There are a number of important factors that play into the timing of a transplant referral. But in general, having patients meet with the transplant team early in their disease course is typically beneficial for the patients, family members, and transplant team. For the patients and their family members, the initial transplant consultation is an educational session where they can learn about what’s involved with the transplant. They can learn why they might be considered a transplant candidate and what steps need to happen to determine if transplant is going to be the right course of action. For the transplant team it allows us to review the patient’s disease in more detail and to begin the process of identifying a potential donor. When thinking about how long it typically takes from the time of the initial transplant to the actual transplant, it depends on a few main factors. The first is how urgent the transplant is from the perspective of disease treatment. For patients with acute leukemia, we’re on a shorter timeline, whereas patients with myelodysplastic syndrome or chronic leukemias may have longer courses of treatment prior to the transplant. It’s important to know what the disease status is. Is the disease in remission or at least in response and amenable to transplant at this time, or is more treatment needed before moving forward with the transplant? Finally, who is going to be the donor and what is their availability? A transplant can be arranged in as little as 4 to 6 weeks, but it often plays out over a longer period of time.

 You mentioned the element of a transplant team and the team you have working with you. Who are the members of that team? For people to understand how big a process this is.

 When patients come for their transplant consultation, in addition to meeting with the transplant physician, they also often meet with 1 of the transplant nurses where they’re provided educational information. They will meet with our transplant coordinators or at least our donor coordinators to help arrange HLA [human leukocyte antigens] typing of appropriate family members in search for a donor, and early on we have our patients meet with our social workers so that they can provide the extra support that transplant patients need in preparing and thinking about a transplant.

 Dr Antin, can you comment on the role of the nurse navigator, a very specialized position we have here at our institute and what that person generally is responsible for?

 Let me expand on 1 thing that Dr DeFilipp said earlier. Even for patients who don’t need a transplant right away, it’s helpful to have them in the system early because things happen. If you have someone who appears to have good or standard risk at AML [acute myeloid leukemia] and things are going well, there can be early relapses or changes in clinical status that may warrant transplantation sooner rather than later. It’s always useful to have everything set up and ready to go, even if you’re not using it, so if you need to move to transplant quickly, you can do it without a delay. In our program the oncology nurse navigator is the person who does virtually all the coordination of the transplant. When I see a patient and discover the underlying physiology of the disease, I discuss what transplantation is all about. I share with them why we’re doing it, how it’s accomplished, and what the adverse effects are. We talk about donor availability and the types of donors and conditioning regimens, and at that point the nurse navigator comes in and starts the process.

The patient has to acquire the names of the donors and their telephone numbers, so we can contact them and get them typed. We look into housing, housecleaning, family support at home, and who lives in the household. Do you have a spouse who is supportive? Is it a household where there is only children and no other adults? Do you live alone? All these things require special arrangements. Transplantation is a complicated, potentially dangerous procedure. It’s best to have control over the medical and social situation. The nurse navigator does the original assessment. They provide additional opportunities to social and medical history. The initial transplant consultation can be somewhat daunting for a patient. It’s complicated. Sometimes it takes awhile for things to settle in and for people to get questioned. So once I’m finished with the patient, the nurse navigator joins and may be the one who is capable of filling in the gaps and answering additional questions. Additionally, she’s the one who will coordinate with the donor center, as well as a National Marrow Donor Program, and the financial coordinators to complete insurance. She plays a critical role in tying the whole thing together.

 May I emphasize what both Joe and Zach said? We all fully agree. Seeing potential transplant recipients as early as possible makes for a successful transplant in terms of all the planning. It’s important to emphasize that you never know what a potential recipient’s donors will be. Oftentimes, if they have several siblings and you believe they’ll have a fairly straightforward search through the National Marrow Donor Program, it’s not that way until you actually do the search. It can take many months to figure out who the best donor is. If the patient is not going to get transplanted for many months or even a couple of years after you first meet them, that’s OK. It doesn’t hurt to meet us at the beginning to start the journey.

 Yes, and there are guidelines published by the National Marrow Donor Program, or Be the Match, that really speak to when is the right time for a patient to be referred in for transplantation. The NCCN [National Comprehensive Cancer Network] has come forth with guidelines in this regard. Those are easily available on the web.

For community-based oncologists, simply having that and understanding who a potential transplant candidate might be—either now or in the future—is useful in terms of making sure the referrals are done in a timely manner. So when transplantation is urgently required, we at least have some of the pieces in place to get the patient into the transplant unit quickly.

Members of the Transplant Team

 Today we are discussing the updates in the management of graft-vs-host disease. I’m Dr Corey Cutler from the Dana-Farber Cancer Institute and Harvard Medical School. Joining me today are my colleagues Dr Joseph Antin, also from the Dana-Farber Cancer Institute; and Drs Yi-Bin Chen and Zach DeFililpp, both of whom are from Massachusetts General Hospital. We’re going to discuss a number of topics pertaining to the management of graft-vs-host disease, including practical information for community oncologists. Our first topic is referrals for transplantation.

Dr Antin, can you review the main indications for transplant at our center? Then we’ll discuss the same question at Massachusetts General Hospital.

 Allogeneic transplants are principally applied in patients with acute myeloid leukemia and myelodysplastic syndrome. There are at least a dozen other diseases that are incurable with conventional therapy that transplant is amenable to, although those would be the No. 1 diagnoses.

 Dr Chen, do you want to elaborate on the rare diseases we see and the reasons a community oncologist might want to refer to a transplantation center?

 Our center sees the same subset of diseases that you see at Dana-Farber. The majority of our volume is made up of patients with AML [acute myeloid leukemia] and MDS [myelodysplastic syndrome]. We see similar diseases that you see, including acute lymphoblastic leukemia. With certain rare types of lymphomas, we still move to allogeneic transplant. There’s benign hematological nonmalignant diseases, such as aplastic anemia, that are treated with allogeneic transplant. Years ago there were diseases that took to allogeneic transplant, but because of the development of other therapies, we don’t generally see them anymore for allogeneic transplant. These include patients with CML, or chronic myeloid leukemia, except in a small subset of patients; many patients with non-Hodgkin lymphoma; and multiple myeloma. These patients we rarely take to transplant at this point in time.

Timing of Referral for Transplant

 The treatment options for patients with graft-versus-host disease [GvHD] are still limited. Therefore, future trials need to continue to investigate additional therapeutic agents. The investigation of well tolerated agents that address GvHD pathophysiology by different mechanisms is an essential need.

I also believe that the individualization of GvHD treatment is immensely important. Blood biomarkers for graft-versus-host disease, mainly ST2 and REG3 alpha, have been shown by the MAGIC consortium to be able to risk stratify graft-versus-host disease patients at the time of diagnosis and also into their treatment.

In patients with high-risk biomarkers, this may indicate that we should escalate their GvHD treatment. In patients with low-risk biomarkers, we may be able to de-escalate their therapy and still have successful outcomes.

 For future clinical trials, we need to learn how to tailor therapy to the individual patient. There are certainly some patients who we over treat with large doses of steroids, and then there are others who are destined to fail even before they receive their first dose of corticosteroids. Determining, either based on clinical or biomarker data, which patients we are going to over treat and under treat is an important research question. Minimizing toxicity from corticosteroids, either by the additive use of alternative agents with steroids or the alternative use to corticosteroids, is probably another important advancement that our field needs to take. But overall, we’ve made some tremendous strides, both in acute and chronic graft-versus-host disease in the last few years, and I suspect it’s only going to get better in the coming years.

Clinical Trial Investigation: Where to Go From Here

 In terms of research for graft-versus-host disease [GvHD] and trials moving forward, I think it helps to look back and ask ourselves why our trials of the past have failed. I think if you look at large trials in the past, we’ve always enrolled a high proportion of low-risk patients. We’ve treated grade 2, 3, and 4 the same, in the same population. And we’ve powered our large comparative studies on historical controls and watched in real time, as when we did a phase 3 trial, our contemporaneous control outperformed the historical one. We need to learn from this. We need to take lessons from that and be able to better design our trials. I think as you’ve heard me mention, developing biomarkers for graft-versus-host disease or any other system to better risk stratify patients, and this is important for trials moving forward.

For patients at diagnosis now who we deem to be high risk, either biologically or we think they’re going to be worse, the trials moving forward should probably include steroids plus an additional agent because these patients do not have satisfactory responses to initial steroids. For patients with biologically low-risk disease and those we think will respond quite well to steroids, we should think about other strategies. We should think about maybe not using steroids and just your novel drug.

Or we should start steroids at a dose and then think about doing aggressive tapers to spare patients the toxicity of steroids. Those are not novel ways to think about it, these trials are ongoing right now and are in the discussion at that level. But the ability to take what used to be 1 population of graft-versus-host disease and separate them into what we believe are biologically different populations will be very powerful and hopefully successful.

I think biologically we’ve seen that patients who do the worst with acute graft-versus-host disease are generally patients with lower GI [gastrointestinal] disease, and so targeting that subset of patients will hopefully lift the outcomes for all. And I think recent investigations in mouse models and others have suggested how important preservation of the intestinal stem cell initiative is, ultimately to helping our patients with intestinal graft-versus-host disease. Looking at that biology and the steps and learning more about intestinal stem cells may ultimately guide us into how we’re going to improve outcomes for that population.

 The field of acute graft-versus-host disease has really undergone a huge change in the last few years. Whereas, 5 to 8 years ago we had very few agents we were testing, we now have this embarrassment of riches where there are a number of agents being tested in steroid-refractory and even upfront management of acute graft-versus-host disease. We have other JAK inhibitors. We have alpha-1 antitrypsin, which is being tested broadly. There is therapy against CD6 and other targets that is being tested actively. And hopefully we’ll come up with better algorithms, both for the initial treatment of GvHD and for later on.

One thing I think that needs to be discussed is the use of biomarkers and how that might help us treat GvHD a little better. In my mind, they’re still a bit experimental, but they have become part of our clinical trial armamentarium in how to judge patients having lower- or higher-risk acute graft-versus-host disease. That’s going to make a big difference in the coming years if they’re truly validated in a number of other studies. I think the biggest push in acute graft-versus-host disease has to be prophylaxis. As we determine that the experimental agents that we have are effective for therapy of advanced disease, we’re going to move those agents into the preventive setting. Certainly, preventing acute graft-versus-host disease is a much better approach than trying to have more effective treatments for severe or steroid-resistant disease.

The REACH3 is a very large randomized trial looking at ruxolitinib versus best supportive care or best available care for steroid-resistant chronic graft-versus-host disease. This trial has completed accrual, although we do not yet have any results. Of course, the field is looking for anything that will help in this setting. There is 1 agent, that’s ibrutinib, that is approved in steroid-refractory chronic graft-versus-host disease. But there are lots of other agents that are being tested in that field, and the ROCK2 inhibitor KD025 is one of the more promising agents. But certainly, we are all anxiously awaiting the results of REACH3, and hopefully we’ll know those data soon.

The Future of GvHD: Promising Agents in Development  

 One thing that stands out to me in the treatment of patients with acute graft-versus-host [GvHD] disease, is that their treatment is truly a team effort. Therefore, establishing a team approach within the institution so that not only physicians but also NPs [nurse practitioners], nurses, social workers, dieticians, and case managers are all included is essential. This allows for good communication about the progress of patients and helps ensure that all the aspects of their complicated care are addressed.

Another take-home point from our institution is that it is essential to encourage patients to participate in clinical trials. Clinical trials remain immensely important to our field. While the FDA approval of ruxolitinib is a huge step in the treatment of patients with acute graft-versus-host disease, there’s still much to be developed and learned so that we can continue to improve the treatment landscape for our patients.

 In the management of acute graft-versus-host disease, one thing I’ve gathered over the last few years in treating patients and also participating on a national level in trials, is that it is really helpful to have a team-based approach and have an infrastructure for graft-versus-host disease. Many cases of graft-versus-host disease are not a major life-threatening event. But building an infrastructure around that to collect samples, to determine eligibility for trials, and to have a team-based approach where everyone is buying in and motivated to help the cause here will help your center participate on a national level and ultimately help us improve outcomes by developing new drugs but also figuring out how to design trials for this population.

We’ve got a long history of trials that have failed in acute graft-versus-host disease, and there are many reasons for that, and it’s on us to figure out the systems to improve that. I think that enrollment on a clinical trial still is our number 1 priority. Even with progress made with ruxolitinib being approved, I think there’s still so much more room we have to improve. There are still huge unmet needs not only in the treatment but the prevention of acute graft-versus-host disease. We want to not have to treat steroid-refractory disease, that’s our goal, because if patients have steroid-refractory disease, it means they’ve already suffered a ton to get there to begin with. And the toxicity they’re going to have along the road to recovery is definitely not trivial.

As we alluded to before, the clinical presentation of graft-versus-host disease or the symptoms of ongoing graft-versus-host disease, they’re not specific. I think we owe it to all of us to continue to think whether there are other etiologies for the patient’s symptoms because concluding that someone is steroid refractory will lead you down a pathway where they might really not be. We are still primitive in how we figure this out. Using crude clinical symptoms is not the way we need to be doing this, and so developing the ability to diagnose graft-versus-host disease by assays that are much more biologically based or accurate has to be a priority. And constant reassessment of your patient right now, including serial endoscopies to figure out if they’re improving, is certainly the right way to go for a subset of patients instead of measuring diarrhea output. Those things are, I think, important in figuring out how we go forward here.

 In terms of management of acute graft-versus-host disease, this needs to be a team approach. We are very collaborative at our center. We involve our dermatologists early on for management of skin disease. We involve our gastroenterology and nutrition teams very early on for management of GI [gastrointestinal] involvement, and similarly our hepatology colleagues when there’s an issue with hepatic GvHD. Patients need to be patient. Responses, particularly for visceral organ can take 1 to 2 weeks for us to see responses.

One of the strongest things I try to tell my colleagues is to not jump the gun and add layers upon layers of immunosuppressive therapy too early. Patients who are progressing early and who have early signs of steroid refractoriness, those patients do need escalated therapy. But for individuals with GI or hepatic involvement, I often try to wait 7 to 10 to sometimes even 14 days before escalating therapy while waiting for a response. One has to remember that if one starts with a denuded gastrointestinal epithelial layer, it does take time for these things to recover. In the absence of a real urgency, I encourage people to move a little bit slower while waiting for primary therapy such as steroids to take effect.

GvHD Management Recommendations

 The randomized data from the REACH2 study builds on the promising results of with ruxolitinib from the REACH-1 study. Ruxolitinib has already received FDA approval for the treatment of steroid-refractory graft-vs-host disease based on the results of the REACH-1 study. In that single-arm study, the overall response rate for patients with steroid-refractory graft-vs-host disease was 57%, with 31% complete response rate.

A limitation of the REACH-1 study though was that it was a single-arm study. In REACH2, 309 patients were randomized between treatment with ruxolitinib or best-available therapy. In that study, the 28-day overall response rate was 62% for ruxolitinib versus 39% for best-available therapy. The responses to ruxolitinib were durable.

With the promising results of REACH-1 and the confirmation of these results, in the randomized REACH2 study, ruxolitinib is likely to be adopted as a new standard in the treatment of steroid-refractory acute graft-vs-host disease and also sets the new bar for future studies moving forward.

 With the FDA approval of ruxolitinib, it has become a standard of care for the treatment of steroid-refractory acute graft-vs-host disease. Certainly, these findings have been validated by the REACH2 study, and it certainly is a really compelling agent to use. Our personal experience is very good with ruxolitinib. We’ve used it definitely in the setting of steroid-refractory acute graft-vs-host disease. My practical advice to people would be that it’s often helpful to have it on formulary in your inpatient hospital. The nature of steroid-refractory acute graft-vs-host disease is that many of your patients will be inpatient with lower GI [gastrointestinal] disease, and it’s difficult to make a decision to use a second-line therapy and not have access to drug while you’re waiting for outpatient approval. Having it on your inpatient formulary as a “bridge supply” before the outpatient supply can be secured is probably a really important thing to be able to use it in a timely fashion.

We’ve had very good experience with it. It works really well for cutaneous in the refractory setting. It works less well for lower GI disease, but that’s true for any therapy. Those are the sickest patients and still a population that has an unmet need. In terms of toxicity management, we’ve actually had a really good experience and haven’t encountered a lot of toxicities. I can’t remember 1 patient who we’ve had to stop drug in the steroid-refractory acute GVHD setting because of toxicity. We definitely have seen the cytopenias, both anemia and thrombocytopenia, that have been reported in not only the GVHD population but also the other settings in which ruxolitinib is used. Our experience is that these cytopenias can easily be managed either by transfusional support if you feel that dose is needed or by dose adjustments of the drug, which can lessen its impact on cytopenias.

REACH2 Trial: Practical Implications and AE Management

 In 2019, ruxolitinib became the first agent ever approved by the FDA for the treatment of acute graft-vs-host disease. It was approved for patients 12 years and older to treat steroid-refractory acute graft-vs-host disease. This was based on a pivotal trial called REACH-1, which was published by Madan Jagasia and colleagues in 2019. This was a single-arm phase 2 trial of 71 patients with steroid-refractory acute graft-vs-host disease who were treated with ruxolitinib. They were treated first at a dosage of 5 mg twice a day, and after 3 days if they tolerated such, the dosage was increased to 10 mg twice a day.

The day 28 overall response rate, which has emerged as the pivotal primary end point for such trials, was a compelling 55%. And all patients on study, if you looked at best response, was as high as 73%. The day 28 complete remission rate was 27% and best complete remission rate was all the way up to 56%. Most impressively, the 6-month overall survival was 51% which is a really great number to see for a subset of patients who traditionally had dismal outcomes.

When the FDA looked at those 71 patients in the trial, they determined that only 49 of them qualified for their strict definition of steroid refractory. But even in those 49 patients with strict eligibility for steroid refractory, the day 28 overall response was really impressive, 57%. And these really compelling outcomes laid the groundwork for the approval of ruxolitinib for steroid-refractory acute graft-vs-host disease.

 REACH2 was a very important clinical trial in our world. This was a very large randomized trial. Over 300 patients were randomized to receive either ruxolitinib or 1 of 9 alternative best-available therapies for the management of steroid-refractory acute graft-vs-host disease. The primary end point was the response at day 28, and in this trial the response in the ruxolitinib-treated patients was 62%, where it was only 39% in the patients receiving best supportive care. Patients also had a higher likelihood of having a durable response by day 56 in the ruxolitinib, so that was 40% versus only 22 in the control arm. And the rate of loss of response down to 6 months was low in the ruxolitinib group, so it was only 10% versus almost 40% in the control group. There was an improvement in median overall survival, and overall this was a very positive trial for us and really establishes ruxolitinib as a very good choice for steroid-refractory acute graft-vs-host disease. This builds on the REACH-1 results, which were very similar, but this in a randomized setting predominantly performed in European centers really adds some credence and some weight to the approval of ruxolitinib based on the REACH-1 data.

In terms of safety, the main signals in the ruxolitinib arm were related to cytopenias, which is what we would expect from this drug, knowing what the adverse-effect profile is. About a third of the patients in the ruxolitinib group had thrombocytopenia, and almost a third had some degree of anemia. There didn’t appear to be much of an infection signal, so these patients who have steroid-resistant acute graft-vs-host disease have a very high incidence of infections. Ruxolitinib did not appear to increase that rate of infections in comparison with the other best supportive care. All those types of therapies are associated with excess infections, except things like extracorporeal phototherapy, which typically is not.

Treatment for Steroid-Refractory GVHD: REACH2

 There are multiple clinical scenarios in which patients are considered to have steroid-refractory or steroid-dependent disease that would warrant second-line therapy. We often in our practice follow the criteria from clinical trials. The criteria from the REACH1 study illustrate some of the scenarios that we see clinically.

Situations in which we may start second-line therapy would include patients who progress after 3 days of at least 2 mg/kg per day, or have no improvement after seven 7 days of at least 2 mg/kilogram per day.

Additionally, we would consider adding second-line therapy in patients who develop GvHD [graft-versus-host disease] in another organ after at least 1 mg/kg per day, being treated for skin or upper GI [gastrointestinal] GvHD. And we also think about adding a second agent if the patient is unable to tolerate the steroid taper. In truth, we don’t know if it’s better to react sooner than to wait; conceptually, we tend to think so.

It would make sense that if a patient’s GvHD is not responding to systemic steroids and an additional agent is needed, adding it earlier seems like a good idea. However, at the onset, it’s sometimes hard to tell who’s going to respond to steroids or not. Also, it’s an easier proposition to begin second-line therapy more quickly when we have a well-tolerated agent with good data behind its use.

 Given the toll that steroid-refractory graft-versus-host disease takes on our patients, I think oftentimes people have asked, well should we act sooner? Should we add second-line therapy sooner, before they actually meet the definition of true steroid-refractory disease? And the answer to that is complicated. There are pros and cons, if you think about it. You’re adding further therapy, so there is the cumulative risk of toxicity and infections, and maybe the patient is going to respond to your therapy and don’t actually need it. But patients may not respond, and so perhaps treating them earlier will help them before they develop more end-organ damage or medical complications.

It’s a difficult question to answer right now. We don’t have a way of saying yes or no. I think the key to what we’re doing is being able to better evaluate patients. The key to this is not looking at someone’s rash or not measuring the volume of diarrhea, as unfortunately we still do now to evaluate patients. The key here is to have more accurate assessments for patients, and ultimately that will likely to be some sort of noninvasive blood biomarker, and this will help tell us if patients are responding or not. And it could be done much sooner than actually seeing the patient’s diarrhea decrease or skin rash vanish. And so if we’re able to validate these biomarkers after we discover them, then ultimately they’ll help us make much more informed decisions and we can act sooner.

Traditionally, the agents that have been used for steroid-refractory graft-versus-host disease have been more systemic immunosuppression, and that’s intuitive. This was based in the model that this was immunological disease and donor cells were attacking the host body, so we needed to suppress the donor cells even more. The problem with that is the more we suppressed the donor immune system, 1) it didn’t work that well and 2) the more infections recipients were left with. And so, the paradigm of using more systemic immunosuppression has not really succeeded.

I think the novel agents moving forward involve going after specific pathways, defining certain inflammatory cascades that we can target that may be GvHD specific. They may also involve using different modalities such as cellular therapy in the form of mesenchymal stem cells, or ECP [extracorporeal photopheresis] to come up with a good outcome. Ruxolitinib, which we’ll talk about, is the first approved therapy for steroid-refractory graft-versus-host disease, and we look forward to finding more drugs in this setting.

When to Initiate Second-Line Therapy

 The definition of steroid refractory for acute graft-versus-host disease [GvHD] involves several different types of patients. If you look in the literature at trials, it’s been defined in multiple ways. I’m going to list the various criteria that have been used. If patients progress or become significantly worse after 3 days of systemic steroids, that meets the definition for steroid refractory. If patients don’t respond after 1 week of systemic steroids, if patients initially respond to steroids and then as we taper the steroids they have a worsening of symptoms, that has been included as steroid refractory. And in certain patients who say, develop skin disease first, then you treat them with a certain dose of steroids and a week later they develop disease in another organ, that is steroid refractory.

The final category has been called steroid refractory. It’s also been called steroid dependent. These are patients who do respond to steroids, and as you taper and taper and taper, you figure out that they have to be maintained on a certain dose of steroids or their symptoms flare. All of these definitions have at one point or other been called steroid refractory. They’re probably all biologically different, and this is part of the reason why trials in steroid-refractory acute graft-versus-host disease have often been tough to do because of heterogeneity in these populations.

 By the numbers, acute GvHD is primarily refractory to steroids in about 25% of cases, and then there’s another 20% to 25% of cases where the disease might be steroid dependent, which is defined as the inability to wean the patient off steroids without a recurrence. The patients who are primarily refractory to corticosteroids really have the worst prognosis. What we need to do is find ways of predicting who those patients are going to be and work on escalated therapies for them initially to prevent initial steroid refractoriness. It’s associated with very poor outcomes, and so at that point, we need to move into second-line therapies quite rapidly.

Second-Line Therapy for GvHD

 For patients who initially receive topical therapy as the treatment in their graft-vs-host disease, whether it be their skin or their upper GI tract, the decision to add systemic steroids really depends on their response. For skin GVHD we use systemic steroids for lack of response, or progression with topicals. Typically, the decision to start systemic therapy is made within one to two weeks after starting the topical therapy. In patients who receive systemic steroid after topical therapy, we often will start patients at one milligram per kilogram, if the GVHD is affecting their skin or upper GI tract.

 For initial systemic therapy of GVHD, steroids unfortunately remain the primary therapy. Standard of care is 2 mg/kg of methylprednisolone or an equivalent. Every now and then we do try to get away with a lower dose of corticosteroids. In particular, when one is dealing with skin-only GVHD, be it overall grade 1 or 2, one can often get away with approximately 1 mg/kg of prednisone or the equivalent to start, and that’s our preference. Steroids are very toxic, and when one starts at 2 mg/kg, the cumulative dose of corticosteroids really becomes quite high. We try to minimize steroids when possible, and I should mention that there is at least one recent clinical trial performed by the CTN [Clinical Trials Network] that suggests for patients with very low-risk skin-only acute graft-versus-host disease, sirolimus as an alternative to steroid might actually be just as efficacious. And so, we’re starting to do that as well.

 The current standard for starting dose of steroids is anywhere from 1 to 2 mg/kg a day of prednisone equivalent. I think it might be intuitive to ask if we increase that dose, would we get better results. That’s been studied way long ago in the past when trials were done starting at much higher doses of steroids, and those outcomes show that there’s absolutely no benefit, in fact there was more harm from giving higher doses of steroids. Most of us feel the 1 to 2 mg/kg/day is a reasonable starting dose if we’re going to pick one dose, and that we’ve gotten the most bang for our buck out of steroids at that point. And to improve upon the treatment of graft-vs-host disease will have to involve sort of non-steroid approaches.

 In our practice we use steroids at a dose of 2 milligrams per kilogram per day for patients who have lower GI GVHD, or liver GVHD. We typically use one milligram per kilogram per day for patients with skin GVHD, and consider increasing or decreasing the dose based on the initial treatment response.

While there are several recommended schedules by which to follow the weaning of steroids in patients with graft-vs-host disease who are responding to treatment, we also know that there’s a lot of variation when it comes to implementation.

In our practice we do not have a specific algorithm that we follow. Due to practical considerations we tend to tapper the dose of the steroids on days when the patient comes to the clinic for evaluation, and we also tend to taper the dose according to a dose interval that is convenient. Decreasing by either 5 or 10 milligrams when making a change.

We also tend to slow our taper once patients are on a lower dose due to worries that GVHD may further flare.

 For weaning, first of all, the critical thing is to make sure that the patient has a complete response. I try to treat patients with an initial dose of corticosteroids until the time at which they had a complete response and then beyond that, for one to two weeks further. Once they hit that endpoint, I’ll start to wean initially in bigger steps. So, if the patient is using 2 mg/kg, I might go down to 1.5 mg, then 1 mg/kg, and then in general I take smaller steps, tapering 10 to 20% per week and probably not faster than that. Once you get to the very lowest doses of steroids, I tend to go down in 5 to 10 mg increments per week once the patient’s been transitioned to oral prednisone. If one tapers too quickly, unfortunately, GVHD does often come back. And so, one has to be careful and balance the risks of tapering quickly against the risks of prolonged steroid toxicity.

The Role of Steroids in GvHD Management

 As a team we really prioritize clinical trials at our center. At the Dana Farber, we have a uniform approach to clinical trials. We always have a trial available for prevention of acute GVHD, and we almost always have a trial available for the therapy of acute GVHD. Sometimes those trials are for primary therapy, sometimes they’re for organ-specific primary therapy, and sometimes they’re for steroid-resistant or steroid-refractory disease. We really try to present every patient the opportunity to participate in a clinical trial, either for prevention or the treatment of GVHD. It’s really the way we’re going to move this field forward.

 We see great variability in patients’ response to initial therapy with steroids. Some patients have steroid responsive disease which we see symptoms resolve in a short period of time with treatment. And other patients have steroid resistant or refractory disease in which their treatment course is prolonged.

In regards to supportive care, patients with severe acute graft-vs-host disease, especially those cases affecting the lower GI [gastrointestinal] tract, require extensive supportive care during their hospitalization. Patients often require parenteral nutrition, as they are on bowel rest.

Patients work with physical therapy in order to prevent deconditioning. And we know that having severe GVHD can take an emotional toll on patients and their families. So, having the support of social work is essential.

 I think expectations for treatment and supportive care for patients is really important. I think patients, despite all the counseling we try and do prior to transplant, don’t have a good idea of what graft-vs-host disease is or can do. I mean how can they? It’s such a big unknown. And so, I think at the beginning, in terms of the severity of the graft-vs-host disease, are we going to use mostly local treatments, such as skin creams, or do we have to give systemic treatments? Unfortunately, systemic treatments right now still revolve around high doses of corticosteroids, and they take a toll. Our main supportive care counseling involves the management of toxicities and preparing patients for such.

I think discussing with patients how long they’re going to be on steroids is important. Preparing them for the duration of hospitalization especially if they have lower GI [gastrointestinal] disease is important, talking to their families as well. I think talking to them about nutrition and infection. Steroids take a huge toll on proximal muscle weakness. Patients will develop swelling, as well as the appearance to their bodies and body image. Then for a lot of patients who start steroids, they develop secondary diabetes and discussing it with the patient that it may happen and the treatment that is needed for that complication is really important also.

Multidisciplinary Treatment and Supportive Care

 Caring for a transplant patient is a team sport, and we have many providers who help coordinate the care and serve different roles. These roles are not explicit, and they’re overlapping along the way from the journey of meeting the transplant through the actual transplant admission, with a very important follow-up period afterward. When a patient comes after transplant for follow-up visits, they often see 1 of our practice nurses and then 1 of our nurse practitioners or their BMT [blood and marrow transplant] physician, all of whom work together. Along the way they’ve met a social worker, a nutritionist, and a physical therapist, and they may have met our research team as well if they’re involved in our clinical trials.

When a patient develops acute graft-vs-host disease, he or she will often call our clinic because they’re home when this happens, and they will report the symptoms to their care team, generally the practice nurse, a nurse practitioner, or a physician. We’re all in open communication with one another because we all work together for the good of the patient and we’ll be on an e-mail chain, oftentimes with the patient, to figure these things out. The symptoms of acute graft-vs-host disease include rash…so we need to figure out what’s what. If there’s a rash, we’ll often ask the patient to take a picture. We have that technology these days, oftentimes with smartphones, and they’re able to send the picture in so we can do a real-time assessment without having the patient make the physical trip all the way to our center.

We often involve local providers as well, as needed, but generally if these symptoms arise and we believe it is serious enough, then we’ll have the patient come in and be assessed at our center to figure out if they have graft-vs-host disease. When they come in, they’ll meet members of their care team and may meet our research team as well, depending on if we feel a research trial is in their best interest.

 The management of patients diagnosed with graft-vs-host disease is truly a team effort, and we care for patients with GVHD in both the inpatient and the outpatient setting. In the inpatient setting there are daily rounds in which attending physicians, residents, nurse practitioners, nurses, pharmacists, dietitians, social workers, and case managers review every BMT in the hospital. Patients with GVHD usually require more extensive conversations on rounds considering their more complex care.

In the outpatient setting physicians, nurse practitioners, nurses, and social workers work together to monitor the response of patients, making sure patients and their caregivers have the appropriate level of support while receiving treatment at home.

At MGH [Massachusetts General Hospital], our research team is also heavily involved in the care of our graft-vs-host disease patients, as many are enrolled in clinical studies for their treatment.

When a patient is diagnosed with graft-vs-host disease, the first thing we need to do is assess the severity of their symptoms and which organs are involved. The initial questions we need to answer are, 1) Does this patient require systemic therapy? And 2) Should this patient be treated in the outpatient or inpatient setting?

Additionally, if patients require systemic therapy, we also assess whether the patient is eligible to participate in a clinical trial.

 At diagnosis, if someone has a skin rash, there may be utility in doing skin biopsies. Different providers have different opinions about the importance and the utility of a skin biopsy. Certainly, if patients have a lot of diarrhea or other GI [gastrointestinal] symptoms, we tend to ask for an endoscopic biopsy from our GI colleagues, whether it’s through an upper endoscopy or through a flexible sigmoidoscopy to get mucosal biopsies of their intestines. There is no gold standard pathological diagnosis of graft-vs-host disease. It remains a clinical diagnosis, but the pathology can be quite supportive. More important, it can rule out other etiologies. Oftentimes, the most important other etiologies to rule out is CMV [cytomegalovirus] enteritis for patients at risk for that complication.

Also, at diagnosis, you can make decisions about treatment, and I’m sure we’ll dive into treatment in a second. At that point, we tend to think about if a patient is eligible…and what we may have open at our site. At diagnosis we may present the opportunity to enroll in certain clinical trials at that point. At our site, we take acute graft-vs-host disease very seriously, and we’re quite involved academically in trying to improve its care and experimental efforts, both in sample collection to study biomarkers as well as in novel treatment.

Our site actually has a research infrastructure about graft-vs-host disease for any patient who presents with new grades 3 through 4 acute graft-vs-host disease. We are on a big email chain, including our research group, to let everybody know that that’s happening. There may be end points for certain trials that patients are already on. There may be samples that have to get collected, and there may be new-treatment trials the patient may be eligible for.

The Importance of Multidisciplinary Approach

 For prophylaxis of GVHD [graft-vs-host disease], which is required in all cases even with matched donors, there are a couple of accepted standards. At our institution and at most institutions in North America, the accepted combination for prevention of acute GVHD is the combination of a calcineurin inhibitor, typically tacrolimus and less frequently cyclosporine in conjunction with methotrexate. There are some alternative regimens; for example, the combination of tacrolimus with sirolimus, which we use at our institution. And some centers will use the combination of tacrolimus with mycophenolate, particularly in reduced-intensity transplantation, although that regimen is a little less effective. When one starts to go into alternative donor transplantation, regimens like post-transplantation cyclophosphamide is used predominantly in the haploidentical setting and sometimes in the mismatch setting. When we talk about umbilical cord blood transplantation, we typically don’t use methotrexate there, and that’s where regimens like tacrolimus and mycophenolate are used or tacrolimus and sirolimus.

There are a couple of other ways of preventing acute graft-vs-host disease, and some of them involve manipulation of the graft itself. One can either give in vitro or in vivo T-cell depletion where we take the T cells out of the graft or positively select the CD34-positive stem cells and simply infuse those. Most important, we have several clinical trials right now to try to advance the field of GVHD prevention, and really in all instances we do try to enroll our patients on clinical trials to try to advance the field.

 At our institution, we generally use pharmacological or drug-based graft-vs-host disease prevention, and it generally varies by the type of donor that’s being used. For a fully matched donor, related or unrelated, we still use the traditional backbone of a calcineurin inhibitor such as tacrolimus combined then with small doses of intravenous methotrexate after transplant. The general regimen is tacrolimus started a few days before the transplant orally, followed by intravenous methotrexate given on days 1, 3, 6, and possibly day 11 after transplant.

For transplants we’re using that involve mismatched donors, such as mismatched unrelated donors or haploidentical donors, we’ve adopted the use of post-transplant cyclophosphamide-based regimens. This involves giving an unmanipulated T-cell replete graft on the day of transplant and then coming in on days 3 and 4 with high doses of intravenous cyclophosphamide, usually combined with the use of tacrolimus and mycophenolate on day 5.

 At our institution we typically use the traditional combination of tacrolimus and methotrexate for our fully matched transplant. And for patients who are receiving haploidentical transplants or HLA mismatch transplants, we typically use the post-transplant cyclophosphamide approach, in combination with tacrolimus and mycophenolate mofetil.

In the BMT CTN 1203 study that was published in 2019, 3 novel approaches to GVHD prophylaxis were compared in the setting of a phase 2 study. In that study, post-transplant cyclophosphamide was found to have best overall outcomes by being able to improve the GVHD-free, relapse-free survival in patients. Based on that study, there’s an ongoing study being conducted by the BMT CTN [Blood and Marrow Transplant Clinical Trials Network], study 1703, that is going to randomize patients receiving related or unrelated donor transplants to GVHD prophylaxis with either the traditional tacrolimus methotrexate approach or with the post-transplant cyclophosphamide approach. This study is considered by many to be potentially practice changing for our field.

Frontline Agents for GvHD

 It’s important to remember that graft-vs-host disease [GVHD] is a clinical diagnosis. Sometimes we do perform biopsies that can be supportive of that diagnosis, but they’re also very important in helping to rule out other diagnoses, specifically, CMV [cytomegalovirus] infections.

For example, if a patient presents with lower GI [gastrointestinal] GVHD than is suspected, we often will perform an endoscopy and get biopsies. These biopsies may be supportive of the GVHD diagnosis if they show apoptosis along the GI tract. But more important, stains can be done to help rule out CMV, which will affect our treatment moving forward.

Biopsies can also be very helpful for patients who have suspected liver GVHD because the differential diagnosis of liver inflammation early after transplant is wide.

 Acute graft-vs-host disease is largely a clinical diagnosis. We do not necessarily need to do biopsies of the affected organs to confirm the diagnosis. Rather, we do biopsies of the affected organs to exclude other diagnoses. For example, the skin, if we do a biopsy, it’s to exclude a drug rash or another type of exanthem. If we do a biopsy of the gastrointestinal tract via colonoscopy or sigmoidoscopy, it’s to exclude things like CMV or a 

] infection. When we do a biopsy of the liver, which is done the least frequently, it’s done to exclude drug toxicity or veno-occlusive disease. That being said, more often than not, these are clinical diagnoses with no diagnostic tests that we can perform.

Classifying acute GVHD is important for us. By everyone using a common methodology, it allows us to enroll patients in clinical trials and really speak to one another about efficacy of therapies. Each organ is staged individually, so the skin is given a stage of involvement based on the degree of body surface area involved. The gastrointestinal tract is given an individual organ stage, based either on the volume of diarrhea or more recently based on the number of bowel movements per day. And the liver is given an individual organ stage based on the rise in the serum bilirubin. Once you have an individual organ stage, you can go ahead and group those individual organs into an overall grade. Traditionally, we’ve used the modified Glucksberg grading system of graft-vs-host disease. Alternatively, the CIBMTR [Center for International Blood and Marrow Transplant Research] has an organ GVHD grading system. Most recently, MaGIC [Malignant Germ Cell International Consortium] has come up with a slight reorganization, and many institutions are using the MaGIC criteria, particularly in clinical trials.

Zachariah M. DeFilipp, MD, Massachusetts General Hospital

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