 Acute and chronic graft-versus-host disease [GVHD] are extremely different scenarios. Acute and chronic GVHD are clinical syndromes and we diagnose them based on the clinical presentation of the patient, but they differ from a biologic point of view as well. Acute graft-versus-host disease is largely thought to be a T-cell mediated disorder and presents with involvement of 3 organs, the skin, the gastrointestinal tract, and the liver. Chronic graft-versus-host disease is a biologically heterogeneous process that involves many different cell lines, including B cells, T cells, monocytes and macrophages, and other effector cells. Chronic GVHD is also more heterogeneous in terms of its clinical presentation. It can affect any organ system, although the skin, mouth, eyes, and the myofascial tissues are the most affected. The interesting thing about chronic GVHD, is that patients tend not to develop disease in all the possible organ systems but only a select few. Two patients with chronic graft-versus-host disease might have entirely separate or different manifestations, whereas all patients with acute GVHD will have manifestations in 1 or more of 3 organs only. There’s much more overlap in terms of the clinical presentation of acute than there is of chronic GVHD.

Chronic GVHD is diagnosed largely based on clinical grounds. We tend not to use histologic or biopsy confirmation of involved organs. For the most part, chronic GVHD is recognizable by a transplant physician. Some organs require a biopsy, for example, the intestinal tract or liver. This is usually done to exclude other diagnostic possibilities, such as infection in the esophagus or in the gastrointestinal tract, or a drug toxicity in the liver. However, most of us don’t use biopsy unless there is a clinical question whether there could be something other than chronic GVHD. Many of our patients present to other physicians and other specialists who might recognize the clinical manifestations of chronic GVHD as an autoimmune condition involving that organ system. The challenge is ensuring that our patients are aware that they should be coming to us first with new signs or symptoms, rather than going to a sub-specialist like a rheumatologist who might diagnose a joint or muscle problem as something like rheumatoid arthritis. The treatments are largely similar, but we have a slightly different approach to alloimmune diseases like GVHD as compared to autoimmune diseases like rheumatoid arthritis.

Chronic GVHD is staged rather straightforwardly using the NIH [National Institutes of Health] chronic GVHD staging system. This divides patients into 3 broad categories: mild, moderate, or severe chronic GVHD. [It’s] based on the number of organs that are involved and the severity of the individual organ involvement. The staging system for chronic GVHD is simpler than the staging systems for acute graft-versus-host disease. We generally recognize that moderate and severe chronic GVHD require systemic therapy because the number of organs involved or the degree of organ involvement is too high to treat only topically. Whereas patients with mild chronic GVHD can often be managed with organ-specific topical type therapies.

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Insight on the identification of acute versus chronic graft-versus-host disease, including best diagnostic and risk stratification practices.

Acute vs Chronic GVHD: Identification and Stratification

 Graft-versus-host disease [GVHD] is a complex physiologic phenomenon that occurs when a donor is put into a new host environment. The premise of doing allogeneic transplant is to try and generate an immune milieu where the recipient’s malignancy is viewed as foreign from the point of view of the donor immune system. We want the donor’s immune system to recognize the patient’s malignancy better, whether it’s a leukemia or lymphoma, as foreign and have the graft reject that leukemia or lymphoma, this is the GVL, or graft-versus-leukemia, effect. Unfortunately, we are not fully able to direct the graft into rejection, only of tumor tissue, and sometimes it rejects healthy host tissues such as the skin, intestinal tract, and eyes, pretty much any organ system. When this occurs, this is graft-versus-host disease. It’s an unwanted side effect of allogeneic transplant and it’s the flip side of graft-versus-leukemia, and unfortunately, we don’t know how to separate the 2. You can have 1 without the other, and every now and then patients will develop graft-versus-host disease without the beneficial graft-versus-leukemia effect.

The risk group for GVHD is essentially all patients who are undergoing allogeneic transplant, with the very small exception of patients who are receiving a transplant from an identical twin, which is exceptionally rarely. Even among siblings, we only match at a few genes, the HLA [human leukocyte antigen] genes, but the immunologic reaction in graft-versus-host disease extends far beyond similarities and differences in HLA. We are very different from our siblings. There are tens of thousands of other genes and gene products that can be recognized as foreign by a donor’s immune system. For this reason, all recipients of allogeneic transplant are at risk of graft-versus-host disease. The degree of risk is often related to the degree of relatedness you are with your donor, the matching of HLA, and the methodology used to prevent graft-versus-host disease.

All patients require some form of GVHD prevention, otherwise GVHD would be universally lethal. We have a number of different ways of preventing both acute and chronic graft-versus-host disease. Most patients undergo pharmacologic prevention of graft-versus-host disease, but before getting into that, some patients undergo a mechanical form of GVHD, where the graft itself is manipulated either by selecting stem cells to transplant into the recipient, or by manipulating the graft to take the T cells away from it. There are other ways of T-cell depleting using monoclonal antibodies, such as antithymocyte globulin, but most patients undergo pharmacologic GVHD prophylaxis with one of several accepted regimens. The most common in North America is the combination of a calcineurin inhibitor, such as the drug tacrolimus, with an antimetabolite. The most common antimetabolite is methotrexate. There are many other regimens, some that include mTOR [mechanistic target of rapamycin] inhibitors, or the use of chemotherapeutic agents, such as cyclophosphamide, but every patient must have a regimen, otherwise GVHD would be universal.

Corey Cutler, MD, MPH, FRCPC, provides an overview of graft-versus-host disease, followed by insight on standard disease prevention practices.

Background on Graft-vs-Host Disease: Risk Factors and Prevention

 There’s still a lot of room for improvement in research in acute graft-vs-host disease [GVHD], specifically for steroid-refractory acute graft-vs-host disease. While ruxolitinib was approved in 2019 and does help a subset of patients, it is not a home run. There are many patients who either don’t respond at first or don’t have a durable remission after an initial response. Ruxolitinib is definitely progress, but we need more research into steroid-refractory acute graft-vs-host disease. You can come at it from several perspectives. We can develop better drugs or better agents to treat steroid-refractory acute GVHD, or we can say that we should do a better job preventing patients from even getting there. That means better initial therapy or better prevention.

There is a lot of work and investigation in novel agents. We’re moving in the right direction by getting away from cumulative immunosuppression from additional agents and focusing more on targeting specific inflammatory pathways or even organ resilience and trying to preserve the intestinal stem cells, especially for patients with acute lower GI [gastrointestinal] GVHD.

All the work that’s being done in biomarkers will hopefully help us better risk-stratify patients to do trials with a patient population that’s more homogeneous. These biomarkers can hopefully also help us complement our clinical judgment to understand how patients are really doing and better judge response. Maybe they could ultimately even serve as end points in clinical trials moving forward.

 For steroid-refractory chronic GVHD, the greatest challenge right now is understanding which drug will work in a given patient. The drugs that are approved or we are anticipating approval on work by very different mechanisms, and we have not yet determined which agent is the right one for each individual patient. We also have no great way of identifying patients who appear to have JAK-STAT–dependent GVHD or ROCK2-dependent GVHD. It is quite possible that we will not be able to determine which drug will work for which patient. We are going to need to learn how to sequence these drugs properly, as we have several drugs approved with overlapping approval and indications. We’re going to have to learn how to use these drugs rationally in combinatorial therapy and to determine whether combinatorial therapy is in fact better than single-drug therapy for chronic GVHD.

GVHD remains in the realm of the transplant center, and I would encourage community physicians to be in touch with the transplant center where the patient was initially treated. They can often provide some good advice through either telemedicine or telehealth and would like to partner in treating these patients to achieve the optimal outcome. Screening for chronic GVHD is important in the community. Finding the earliest signs of ocular, oral, and cutaneous disease is critical so that we don’t end up with long-term sequelae of chronic GVHD that might have been prevented by earlier recognition and treatment of chronic graft-vs-host disease.

 For any patient with acute GVHD, because it can be rapidly progressive, we would strongly encourage this patient to be referred back to their treating transplant physician so they can get effective treatment. It can become steroid-refractory and then they may require many specialized treatments, including clinical trials. Time can be lost if they don’t get to the clinical trials or more intensive treatment for acute GVHD.

For chronic GVHD, you can start a patient on steroids. I would definitely consider referring this patient to a transplant center because of the availability of clinical trials and multidisciplinary care. These patients are also at risk for many other problems, including steroid-induced adverse effects, opportunistic infection, and severe muscle weakness. Those can be appropriately addressed at a transplant center by a multidisciplinary team.

 The main priority for us as a community moving forward should be to continue to do well-thought out, collaborative clinical trials to make improvement. For acute graft-vs-host disease, there are ongoing efforts in prevention. Hopefully we’ll see the results of those large trials soon to understand if they will change the standard of care. For the initial treatment of acute graft-vs-host disease, the future is to better be able to risk-stratify our patients, to take the high-risk patients and treat them in clinical trials that add drugs to steroids to increase the chance of a meaningful clinical response. For the lower-risk patients, it’s actually to decrease therapy. It may be to not use steroids and use a different drug. If we do use steroids, once you achieve a response, we want to prescribe a rapid tapered steroid to spare the patient the exposure to steroids. That’s the way moving forward for acute GVHD that we’re going to make some more progress.

For chronic graft-vs-host disease, a good amount of research is ongoing. We expect approval of a couple of agents in this coming year. That’s very exciting for the field and for our patients. Akin to acute GVHD, it would be better to risk-stratify chronic graft-vs-host disease through a biomarker signal and be able to develop different treatments for biologically different patients.

For providers who are treating patients with chronic graft-vs-host disease, a lot of it is about reframing expectations. Once you develop chronic graft-vs-host disease, the statistics would say that there’s a good chance you’ll be on lifelong medication for it and will be managing it basically forever. It’s about helping patients understand that. It’s not about expecting that we should get back to normal at that point, but that we need to stop progression of the disease and then slowly make it better, while understanding that the statistics would suggest you’re going to be on chronic therapy for a long time. Once we understand and accept that, we’ll be able to better understand how to improve the lives for our patients going forward.

Challenges and unmet needs in steroid-refractory GVHD and advice to community oncologists for the optimal management of disease.

Unmet Needs in GVHD

 There are several emerging therapies in acute GVHD [graft-vs-host-disease]. We are actively testing the Equillium, Inc compound EQ001, a nondepleting anti-CD6 antibody, which prevents T-cell activation and T-cell migration. We’re testing that as initial therapy for acute GVHD. The Blood and Marrow Transplant Clinical Trials Network is actively testing alpha-1 antitrypsin, which is an anti-inflammatory acting at the level of the polymorphonuclear cell in acute GVHD. There is also a trial of a double antibody conjugate, an anti-CD3, anti-CD7, both of which are conjugated to ricin. That is also being carefully tested in acute GVHD through the Blood and Marrow Transplant Clinical Trials Network. There are lots of drugs that are being tested. I firmly believe that the proper way to deal with acute GVHD is to improve our prophylactic strategies. When we look at the results of the newest costimulatory blockade trials, such as ABA3, the Fate Therapeutics trial, which is looking at graft manipulation strategies, the vedolizumab trial, which is looking at ways of preventing T-cell trafficking to organs such as the gut, all of these strategies are likely to be more fruitful than therapy of acute GVHD. This is really when prevention becomes far better than treatment of active disease.

 There are a number of other drugs that are being actively studied for treatment of chronic GVHD. One is itacitinib, which is a selective JAK1 inhibitor. It is being used as upfront treatment for chronic GVHD. There is another drug developed by Kadmon Holdings, Inc, KD025 [belumosudil], that appears to be effective in patients who have failed multiple lines of therapy. We have a trial open for another agent called leflunomide for treatment of chronic GVHD. There are multiple combinations of various different modalities, including IL-2 [interleukin-2], ECP [extracorporeal photopheresis], and a JAK inhibitor for treatment of upfront and steroid-refractory chronic GVHD.

Novel agents in the pipeline for the treatment of acute and chronic GVHD are discussed.

Emerging Therapies for Acute and Chronic GVHD

 If we look at the patients who undergo transplant overall, probably more than 60% of patients develop some form of chronic graft-vs-host disease [GVHD]. As we talked about before, there’s a broad biological spectrum, from mild to moderate to severe, in how we classify it. We tend to not think mild disease is so significant, nor do we think mild disease requires systemic therapy for the most part. About 40% of our patients probably require some systemic therapy for chronic graft-vs-host disease at some point.

The prognosis for these patients is varied. It obviously depends on the severity of the symptoms, which organs are involved, and the severity of that organ involvement. Our classification systems don’t capture all of that. If you take a patient with scleroderma disease and you're just grading it by body surface area, they may have localized scleroderma that doesn’t look so severe on our grading systems, but if it’s on a certain part of their body, like over their anterior abdominal wall, it may make breathing very difficult as their diaphragm contracts. The quality of life in terms of what our patients experience may be different than what’s reflected in the actual classification.

The overall prognosis for these patients depends on if their disease responds to the treatments that we employ. Obviously, patients with more severe disease have a worse prognosis than those with mild disease. As we develop newer and hopefully better therapies, the prognosis will be much more dependent on how their disease responds to such therapies.

 When patients become steroid-resistant, steroid-refractory, or even steroid-intolerant, we have a number of agents that we use in the second line. Ibrutinib is the only drug that’s approved in the second line for steroid-refractory chronic GVHD. It was approved based on a 42-patient study that demonstrated a response rate of about two-thirds of subjects with steroid-resistant GVHD.

Very importantly, the REACH3 trial, which has now been presented publicly, demonstrated an improvement in steroid-refractory chronic GVHD outcomes when we compared ruxolitinib to best available therapy according to investigator choice. We expect that agent to be approved by the agency and have a label expansion later in the year. And then the ROCK2 inhibitor belumosudil has similarly demonstrated very impressive results, with approximately a 75% response rate in subjects treated with 2 to 5 prior lines of therapy. We similarly expect that belumosudil will be approved by the agency later this year. While we only have 1 agent now, by the end of 2021, we suspect that we will have 3 approved agents for the therapy of steroid-refractory chronic GVHD.

Also importantly, there are many other agents being developed in that space. We’re going to learn how to treat chronic GVHD better in the coming years, understanding which patients need which agent based on biomarkers and other clinical factors. We’re going to see a nice improvement in chronic GVHD treatment outcomes in the years to come.

 The REACH3 study compared ruxolitinib with best available therapy for steroid-refractory chronic GVHD and showed about twice as much response with ruxolitinib compared to other treatment. A number of patients actually crossed over from the best available therapy to the ruxolitinib arm, and they continued to have responses. Ruxolitinib was used even before the study for chronic GVHD. There have been multiple reports, including one that we reported from City of Hope on the 42 patients in which we showed patients were having responses on this treatment. This also confirms the finding that it is an effective and active treatment for steroid-refractory chronic GVHD.

 Based on the published work in the last few years, we had already started using ruxolitinib for steroid-refractory chronic graft-vs-host disease in our practice. We had found it quite tolerable, and a high percentage of patients had a meaningful benefit in terms of classification systems but also by subjective quality of life. REACH3 was a really important study. It was one of the only large phase 3 studies in steroid-refractory chronic graft-vs-host disease. Ruxolitinib showed a benefit in terms of overall response rate as well as multiple secondary end points compared to best available control. Even though the critique would be that the control arm was heterogeneous, there’s no other way to do the trial because there was no internationally accepted standard that could serve as a control. The results were certainly validating for our practice and reassuring that this was a standard of care that could be used.

We look forward to, hopefully, approval of this agent to allow more of our patients to gain access. Ruxolitinib for chronic graft-vs-host disease has been quite tolerable. It’s rare that you run into a toxicity where you have to stop the drug. Just like in acute graft-vs-host disease, there are cytopenias that can develop. They’re a bit less common than in the early post-transplant study. Usually with dose reductions, you’re able to get by and still continue the drug itself.

A review of treatment options for patients with chronic GVHD who don’t respond to steroid therapy and preliminary findings from the phase 3 REACH3 trial.

Treatment for Steroid-Refractory Chronic GVHD

 Steroid-refractory acute graft-vs-host disease [GVHD] has generally included 3 different patient groups. After we start initial therapy with high-dose systemic steroids, if patients are clearly getting worse after 3 days, which generally means another organ is involved or the initial organ is definitively getting worse, that is steroid-refractory. If patients receive initial steroids and haven’t gotten better after a week of that dose, that also meets the definition of steroid-refractory. The third definition is probably a more favorable group of patients. This involves patients who initially responded to steroids, either achieving a partial response or a complete response for acute graft-vs-host disease, and then upon attempts to taper steroids, their symptoms of graft-vs-host disease flared. This last group is probably more favorable. They’ve often been included in clinical trials for steroid-refractory graft-vs-host disease. Perhaps they’re more accurately referred to as steroid-dependent.

In our practice, we are fairly quick to add a second-line therapy. Your motivations to add another therapy for the treatment of acute graft-vs-host disease are 2-fold. You want to improve the response and treat the graft-vs-host disease more. You also want to spare the patient a significant exposure to high-dose steroids, because while steroids can be very helpful for certain conditions, such as graft-vs-host disease, we can all accept that long-term steroids have a bunch of toxicities, including immunosuppression, high blood pressure, osteoporosis, mood effects, and many others.

Our triggers generally follow the definition of steroid-refractory. If patients are getting worse after 3 days or not getting better after 7, we add a second agent. Also if patients experience a flare of symptoms upon tapering of steroids, somewhat dependent upon dose, we will add a second agent. There are patients who we know won’t do well with steroids. These include patients who are brittle diabetics, have horrible osteoporosis, or are already quite deconditioned and weak from other complications. In those situations, our triggers to add a second agent may be lower to spare the patient exposure to steroids.

 Patients who have failed steroids for treatment of acute GVHD, their outcome is quite poor, so they need effective treatment. Currently, the only approved treatment for these patients is ruxolitinib, which is FDA-approved for treatment of steroid-refractory acute GVHD. Some of the other options besides ruxolitinib, which I use as off-label, are various immunosuppressants, including basiliximab, infliximab, photopheresis, ATG [antithymocyte globulin], and rituximab.

 The only agent that’s approved for steroid-refractory acute GVHD is ruxolitinib. It was approved on the basis of the REACH1 and REACH2 studies. REACH2 was a randomized trial in which slightly over 300 subjects were randomized to receive either ruxolitinib or best-available care according to investigator choice. Very importantly, at day 28, the response rate in the ruxolitinib group was a little over 60%, whereas in the control arm it was just under 40%. That’s about a 50% improvement at day 28 response rates. By day 56, there was unfortunately a diminution in the response rate in both the ruxolitinib and the control arm. The ruxolitinib response rate fell from about 62% to just under 40%, so almost a third of the subjects lost their response, whereas in the control arm, about 50% of subjects lost their response, from almost 40% to just over 20%. This solidifies the role of ruxolitinib in the therapy of steroid-refractory acute GVHD. However, it does tell us that there is still room for improvement in this space. We’re actively testing other agents to see if we can find something that will be complementary to ruxolitinib or potentially even better.

 The FDA approved ruxolitinib for the treatment of acute GVHD based on the REACH1 trial, which was an open-label, single-arm trial that showed response rates up to 55% to 60% in these patients. REACH2 was another very important trial that compared a larger portion of patients to best available therapy. It gave more definitive data, and you’re comparing it with the other standard therapy, which showed that ruxolitinib was very effective in controlling steroid-refractory acute GVHD. That confirmed the findings and improved clinicians’ confidence that this is effective for treatment of acute GVHD.

Ruxolitinib was used by many clinicians even prior to the FDA approval because of the data presented by the German group that showed the response rates were close to 70% to 80%. At that time, it already had quite a buzz. People were using it because it was available and in the market. These data just increased the use of it because some of the other clinicians did not see it as approved and insurance would not approve it. With it now approved, more patients are able to get the medication.

 We have had a rather favorable experience using ruxolitinib for steroid-refractory acute graft-vs-host disease. It’s a drug that we’ve been familiar with for years because it’s been approved for other diagnoses, and it definitely has an effect and brings about a response in a certain portion of patients. It’s not a home run, meaning it certainly doesn’t work for 100% of patients. And as you’d expect, the patients who are the highest risk and most predicted to respond least well to any therapy are the same with ruxolitinib. These are people with severe lower GI [gastrointestinal] disease. In our experience, patients with skin-only disease respond extraordinarily well to ruxolitinib, while those with liver and GI disease respond a bit less well. That’s anecdotal. It’s not published, but that’s been our experience. However, we still have no hesitation using ruxolitinib for any organ involvement for steroid-refractory acute graft-vs-host disease.

From a toxicity perspective, it has been very well tolerated. The main issues are what has been described. There is a certain subset of patients who will develop cytopenias, mainly thrombocytopenia and anemia, with the use of ruxolitinib. We have found that these can usually be accommodated with dose adjustments. Rarely have we had to stop the agent itself.

 When choosing an agent for steroid-refractory, both acute and chronic GVHD, one has to look at what type of adverse effects the patient already has and what you believe the patient can tolerate based on the drug you’re going to choose. We know that agents such as ruxolitinib and the other JAK inhibitors cause some modest cytopenias, and therefore, one has to be careful when starting this agent in patients who have platelet counts below 30,000 to 50,000 per mm3. If monitored very closely, you can often overcome the shortcomings, but you do have to pay close attention, particularly to thrombocytopenia and the risk of bleeding if patients fall below 10,000 per mm3. One has to be very careful globally in both acute and chronic GVHD to prevent infection by piling on immune suppression to patients who are already suppressed with corticosteroids. It does leave patients open to further risk of infection. Therefore, prophylactic antibiotics, prophylactic antifungals, and potentially antivirals, particularly against CMV [cytomegalovirus], are very important supportive care measures to improve outcomes in acute and chronic GVHD.

Defining steroid-refractory acute GVHD, treatment options for patients who don’t respond to steroid therapy, and a review of the REACH2 trial.

Treatment for Steroid-Refractory Acute GVHD

 The goals of acute GVHD [graft-vs-host disease] treatment are rapid resolution of symptoms and abnormalities, especially the laboratory test abnormalities, and bringing it down to either very mild acute GVHD or complete remission or resolution of the GVHD.

You want resolution of the symptoms, a decrease in the complications, to decrease the use of the steroid, and resumption of organ function. The approaches and the goals are pretty much the same for both types of GVHD.

There are some patients who we may not start off with a systemic steroid, especially early grade skin acute GVHD. Most of them will resolve with a topical agent or the topical steroids. In each patient, we look at how many risk factors they have and how severe the risk factors are for the GVHD. If someone doesn’t have very high-risk factors for GVHD and they only come in with, for example, a skin rash, a topical steroid for a limited skin rash may be sufficient.

The standard of care for any patient who has high-grade, grade 2 or above, acute GVHD is treatment with systemic steroids. There are studies underway looking at alternative agents to control the GVHD, but the current standard of care is to control the GVHD with systemic steroids in these patients.

 The main regimen that we use to treat acute graft-vs-host disease is corticosteroids, generally at a dose of 2 mg/kg when there is gastrointestinal [GI] or hepatic involvement, but sometimes lower doses when there is only cutaneous involvement, as low as 1 mg/kg. There are 2 different pathways that are being studied in acute GVHD initial therapy. For patients deemed to have the lowest risk of GVHD bad outcomes, we’re working on ways of de-escalating therapy.

The CTN [Clinical Trials Network] recently published a study where patients had Minnesota standard-risk acute GVHD and biomarker-based lower-risk acute GVHD, according to the MAGIC [Mount Sinai Acute GVHD International Consortium], or Ann Arbor biomarkers. In this trial, patients were randomized to either receive corticosteroids or sirolimus. At 6 months, there was no difference in outcome in the patients who were randomized to receive sirolimus, suggesting that not all patients require corticosteroids as initial therapy for acute GVHD.

On the other hand, with higher-risk GVHD, we’re trying to understand how we can improve upon steroids alone for them. We have not yet been successful in improving outcomes with steroids alone. We’ve tried with several randomized trials. The 2 that are most important to mention are the randomized trials conducted by the Blood and Marrow Transplant Clinical Trials Network, where we looked at steroids vs steroids plus mycophenolate. Unfortunately, the arm that was randomized to receive additional mycophenolate to corticosteroids did slightly worse than the steroid-alone arm. Another very important trial was recently halted. It looked at steroids with or without itacitinib, but unfortunately it did not meet its primary end point, although there was a very nice signal in improvement in outcomes. That trial was halted early, and we do not yet have the final results from that study.

Chronic GVHD, very similar to acute GVHD, is initially treated with corticosteroids; although here we often add agents such as tacrolimus, or more recently sirolimus based on the CTN’s 0801 study, to initial therapy.

 The accepted initial therapy for a patient with acute graft-vs-host disease would be systemic steroids, usually at a dose between 1 and 2 mg/kg per day of prednisone or its equivalent. The patients with lower GI involvement will often need to receive IV [intravenous] dosing due to fears of absorption of the drugs. It’s usually that dose that has become the accepted standard. There have been trials in the past that have tried to escalate to higher doses, but they showed no benefit. There have been some retrospective studies suggesting that a lower dose of 1 mg/kg was not that different from 2 mg/kg. In our practice, if patients have visceral involvement, be it the liver or the GI tract, we tend to steer more toward 2 mg/kg. If it’s just skin involvement, we tend to give 1 mg/kg. It’s difficult to know how the dose of steroids impacts outcomes. Acute graft-vs-host disease is so biologically heterogeneous that it’s tough for me to conclude that the dose of steroids between 1 and 2 mg/kg definitively matters.

Other factors that impact the overall outcome for the patient include the severity of acute graft-vs-host disease. We know that matters in terms of organ severity. There is some evidence that there may be some acute graft-vs-host disease biomarkers that will be more mature in the years to come that better judge the biological severity than what we see clinically. We do know that patients’ other comorbidities matter because they dictate their resilience and if they’re able to make it through the various obstacles that they have to steer through to recover from graft-vs-host disease. Older patients certainly do worse, along with patients who have chronic comorbidities and organ dysfunction or preexisting infections. All of those things contribute to a patient’s resilience and the ability to eventually achieve a full recovery if we can put the acute graft-vs-host disease into remission.

Experts in hematology-oncology share insights on approaching initial treatment and the treatment goals for acute and chronic GVHD.

Initial Therapy in GVHD

 All patients undergoing transplantation require and receive some form of GVHD [graft-vs-host disease] prophylaxis. The GVHD prophylaxis in North America is for the most part pharmacologic. It’s generally based on a calcineurin inhibitor drug regimen, either tacrolimus or cyclosporine, but more commonly tacrolimus in North America. Tacrolimus is most commonly given with methotrexate or other agents, such as mycophenolate or sirolimus. There are other ways of preventing GVHD with pharmacologic prophylaxis as well. The most recently used regimen is the post-transplantation cyclophosphamide regimen, where the chemotherapeutic agent cyclophosphamide is given on the third and fourth days following transplantation, and then additional agents, such as tacrolimus, sirolimus, or mycophenolate, are administered for the next few weeks or months.

There are also nonpharmacologic ways of preventing acute graft-vs-host disease. Those involve manipulation of the graft, either with in vivo or ex vivo T-cell depletion. One can take the T cells out of the graft using bead columns to either positively select the stem cells or negatively select the T cells. You can also use drugs like ATG [antithymocyte globulin] or Campath [alemtuzumab], which are given to the recipient. Those drugs function to deplete T cells from both the host as well as the graft. Those are the ways we can prevent graft-vs-host disease. There are a number of new ways we are looking to prevent GVHD with novel pharmacologic agents and even newer graft manipulation strategies. What’s very encouraging is that these are now being tested in randomized phase 3 trials. While none are currently the standard of care, it’s hoped that in the next couple of years as we get the results of these phase 3 studies, the standard will evolve in graft-vs-host disease.

 GVHD prophylaxis is prescribed to all of the patients. However, the intensity can differ. There are different types of GVHD prophylaxis. Usually they have a backbone of one of the calcineurin inhibitors, which could be tacrolimus or cyclosporine, and it is combined with any of the other agents: either sirolimus, methotrexate, CellCept [mycophenolic acid], or post-transplant Cytoxan [cyclophosphamide]. They are decided based on the institutional preference and expertise, but there are also situations where one might be used over the other. For example, we mostly use post-transplant Cytoxan in the haploidentical donor; that’s how these studies were done, using high doses of post-transplant Cytoxan. Generally speaking, the most common ones used are tacrolimus and methotrexate, tacrolimus and sirolimus, and post-transplant Cytoxan along with a combination of cyclosporine with CellCept. They can be used interchangeably for most patients.

A discussion on the role of prophylactic therapy for patients after transplant as well as available options for GVHD prophylaxis.

Role of GVHD Prophylaxis

 Acute GVHD [graft-vs-host disease] risk depends on the type of the donor and the transplant type. The risk could be anywhere between 60% and 80%, but not all of it is serious or high-risk GVHD. The risk of chronic GVHD is about 50%. It depends on the circumstances of the transplant, the type of the donor, the conditioning regimen, and the GVHD profile. These are the average incidences of GVHD.

 Acute GVHD is a clinical diagnosis. The typical presentation involves 3 organs, and essentially only 3 organs. Those 3 organs are the skin, gastrointestinal [GI] tract, and the liver. The skin presents with an erythematous, maculopapular, and often itchy rash. The differential diagnosis includes things like drug reactions or other allergic phenomena. In the GI tract, lower GI involvement presents with copious and watery diarrhea. In the upper GI tract, it presents with persistent nausea, vomiting, and a sense of early satiety. The diagnosis of acute GVHD of the GI tract is generally made with endoscopy, either upper GI endoscopy or lower GI endoscopy, which demonstrates apoptosis in the crypt cells of the GI mucosa. The main differential diagnoses for GI GVHD are things like CMV [cytomegalovirus] or other infections, and sometimes bacterial overgrowth. The liver presents with a cholestatic jaundice. This is generally diagnosed clinically, but the main histologic findings would be a portal triaditis and loss of the biliary system. The differential diagnosis for acute GVHD of the liver is veno-occlusive disease [VOD], but these 2 syndromes present very different clinically. It’s generally not hard to differentiate the 2 on clinical grounds alone based on the pathophysiology of VOD, which presents with ascites and a hepatorenal syndrome. Those are the 3 main organs that are involved. Very occasionally, things like the eyes can be involved, but those are probably more an overlap syndrome and addressed better with chronic GVHD.

 There really isn’t a typical presentation of chronic graft-vs-host disease. It can involve almost any organ in a patient’s body and is very heterogeneous between patients. However, the most common organs involved are the eyes, mouth, and the skin to start. For the eyes, it often presents as a feeling of dry eyes or a feeling of sand constantly in one’s eyes. In the mouth, it presents as a dry mouth, often needing to drink multiple cups of water to eat a standard meal. It often presents as trouble swallowing. Frank ulcerations can occur as well. On the skin, it’s generally a rash, and the rash is different from acute graft-vs-host disease. It’s less angry. It can appear more as mimicking eczema or psoriasis. Other organs that can be involved include the underlying fascia of the skin. This is the connective tissue between the skin and the muscles. This can become quite thickened and result in a phenomenon called scleroderma, which can limit the range of motion and become very morbid and affect the quality of life. The lungs can be involved, and this leads to a phenomenon called bronchiolitis obliterans syndrome [BOS], which not only manifests as shortness of breath on exertion, but ultimately an obstructive airway disease. The lungs, BOS, and scleroderma are oftentimes the most difficult to treat.

There are other organs that can also be involved, and we see this. There are multiple joint issues, such as arthralgias or joint pains, and muscle issues, such as myositis. The GI tract can form strictures. The esophagus can fail to move correctly as it tries to do its normal peristalsis. There is pancreatic insufficiency that can cause malabsorption and chronic diarrhea. The kidneys can often show signs of what we call nephrotic syndrome or wasting protein. It’s hard to distinguish, because a lot of these manifestations mimic what we think of as classic autoimmune disease. There’s definitely some graft-vs-host disease that we view as the attack of the donor cells on the recipient’s body. And then there are some manifestations of chronic graft-vs-host disease that are clearly showing what we call immune dysregulation, where the immune system can’t regulate itself to be normal.

Chronic graft-vs-host disease remains a clinical diagnosis. There’s no 1 test, be it a blood test or biopsy, that is the gold standard for diagnosis. It’s still looking at the patient’s clinical symptoms, laboratory tests, and where they are after transplant to make a diagnosis. Biopsy of tissues can be done. Oftentimes, when you do a biopsy, there are supportive findings of fibrosis. That’s the main hallmark in many biopsies in chronic graft-vs-host disease.

We classify chronic graft-vs-host disease is by clinical severity. There have been various staging systems that have been used throughout the years, partly to help us all communicate and partly to do clinical trials. The most recent system was developed by the NIH [National Institutes of Health] consensus group. It involves 3 categories: mild, moderate, and severe. Affected organs all receive an individual number score, and these are calculated together to create an overall grade of mild, moderate, or severe.

 We classify acute GVHD to look at the severity. There are various grading systems that are being used. Most of them utilize the clinical data, like the extent of the skin rash, volume of the diarrhea, abnormalities of the liver function, especially the bilirubin. There are also some classifications based on the biomarker and these are validated. These are called Ann Arbor scoring, where it can be divided into low, intermediate, or high risk.

Hematologist-oncologists review the typical presentation and diagnosis of acute and chronic GVHD and define how severity is classified.

Diagnosis of Acute and Chronic GVHD

 GVHD [graft-vs-host disease] is an immunologic reaction that occurs after transplant when you use a foreign immune system put into a new host body. That immune system recognizes the body it is now in, the host, and determines that it’s foreign and tries to reject it. GVHD remains the most important complication after transplant. It is the most serious and important cause of decrease in overall survival after transplant, second only to relapse of the original malignancy. GVHD remains critical to the success of transplantation. One of the major goals of our research program is to try to improve GVHD outcomes.

 Allogeneic hematopoietic cell transplantation is an aggressive, potentially curative treatment for many patients with advanced hematological malignancies. The way we think transplant works is that we replace the host’s hematopoietic or blood system with the donor’s blood system. When the donor’s blood system grows up, it includes white blood cells, red blood cells, and platelets. When those white blood cells grow up, they form an immune system to help protect the recipient from infection. Ultimately, if there’s any malignancy left, we hope that the donor’s white blood cells are able to attack the malignancy, exerting what we call a graft-vs-malignancy or graft-vs-tumor effect, perhaps the earliest example of immunotherapy. That’s how we think most transplants work in terms of exerting a curative mechanism of action on patients’ malignancies.

The problem is that the patient and the donor, even though they may be either very closely matched or fully matched at the HLA [human leukocyte antigen] sites, are not identical twins. There are differences. The donor’s immune system may grow up to not only attack the patient’s underlying malignancy, but also attack the patient’s healthy body. That is the phenomenon of graft-vs-host disease, where the graft or the donor cells attack the host, which is the recipient. Graft-vs-host disease can be divided into 2 distinct phenomena. One is called acute graft-vs-host disease, which most commonly occurs within the first 6 months after transplantation. It presents as either a skin rash, a lot of watery diarrhea, or liver test abnormalities. Chronic graft-vs-host disease tends to take place after at least 3 months and can continue, ultimately for the remainder of the patient’s life.

Graft-vs-host disease presents a lot of challenges. Everyone receives some sort of prevention against graft-vs-host disease, but even with the best prevention, there is still an incidence of both acute and chronic graft-vs-host disease. Acute graft-vs-host disease is often dramatic and often results in rehospitalization, especially if the lower GI [gastrointestinal] tract is involved. It’s the leading cause of morbidity and early mortality for our patients. Chronic graft-vs-host disease tends to be more indolent, less dramatic, less life-threatening. However, it is more difficult to treat to resolution. Oftentimes, patients are on lifelong medications afterward. For long-term survivors after transplant, chronic graft-vs-host disease is the single thing that affects their quality of life the most. The medications used to treat it and the complications that ensue have a significant effect on their morbidity and even their mortality.

 We believe we understand most of the risk factors for acute and chronic graft-vs-host disease. Far and away, the most important is HLA mismatch. We know that individuals who receive perfectly matched grafts have the lowest rates of GVHD. Other risk factors include both the donor and recipient age; the drugs we use to prevent graft-vs-host disease, so the prophylaxis agents; sometimes gender, particularly in chronic GVHD; and parity. Then there are less important risk factors, like CMV [cytomegalovirus] serostatus and other very minor factors. Far and away, HLA mismatch is the most important risk factor for both acute and chronic graft-vs-host disease. Acute GVHD was once thought to be an important risk factor for chronic GVHD as well.

 Chronic GVHD happens in patients after allogeneic transplant. The common risk factors are match unrelated or mismatched unrelated donor transplant, myeloablative conditioning regimen, and gender differences between donor and recipient.

Common risk factors for chronic GVHD include the types of the donors. Unrelated donors have a high risk of chronic GVHD compared to related donors. It also depends on the type of the conditioning regimen. People getting myeloablative conditioning, including radiation-based conditioning, have a slightly high risk of chronic GVHD. One of the other factors is gender differences between a donor and the recipient. For example, a male patient getting stem cells from a female donor, especially one who has a history of pregnancy or multiple pregnancies, has a much higher risk of chronic GVHD.

Corey S. Cutler, MD, MPH, FRCPC; Yi-Bin Chen, MD; and Haris Ali, MD, provide insight on the nature of graft-vs-host disease (GVHD) and common risk factors for acute and chronic GVHD.

Haris Ali, MD, City of Hope

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