 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.

Joseph H. Antin, MD, Dana-Farber Cancer Institute

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