 I want to touch on 2 abstracts presented at the American Society of Hematology Annual Meeting that involved graft-vs-host disease [GVHD] prevention. The first was research done by a company called Orca Bio that was working with our colleagues at Stanford University and a few other centers on the West Coast. They presented a clinical trial in myeloablative transplantation using their proprietary product Orca-T, which is a novel graft manipulation strategy. Sophie, do want to talk about that abstract a little?

 Yes. This is using regulatory T cells [Tregs]. I’m a firm believer in regulatory T cells. They’re absolutely essential to regulate GVHD after transplant. There’s basically a 1:10 ratio of regulatory T cells to effector T cells. You can transfer these Tregs, this graft, as a prophylaxis to avoid GVHD, because they’re depleted after bone marrow transplantation, and people who develop GVHD will have fewer Tregs in general. The outcomes were interesting. They were used as prophylaxis in this case. We had really good outcomes: low GVHD, low acute GVHD, low chronic GVHD, and no difference in relapse rate, which is always the risk when you add prophylaxis, that you decrease the graft-vs-leukemia. This wasn’t the case in their study. We need something to look forward. This was a combination phase 1/2 study.

 Yes, and they’re making plans to move to a phase 3 study to apply for regulatory approval, which will hopefully get started soon. The second abstract was done by our colleagues at the NIH [National Institutes of Health]. You heard Dr Nelson Chao mention the emergence of post-transplant high-dose cyclophosphamide [Cytoxan]–based regimens. This regimen was developed by colleagues at Johns Hopkins University giving cyclophosphamide at 50 mg/kg per day on days 3 and 4 after a T-cell–replete graft. This abstract asked the question, do we really need that much Cytoxan? Because high-dose Cytoxan is not without risks and toxicities.

It was a dose de-escalation study that treated patients at several dose levels, settling on 25 mg/kg per day as their ideal dosage that still engendered engraftment and protected against graft-vs-host disease. It’s interesting, although it was a small number of patients, and we’ll need to see the expansion. Hannah, do you think we need to refine high-dose cyclophosphamide after transplantation?

 I thought that was a great study for that exact reason, because some of the limitations of post-transplant cyclophosphamide are the chemotherapy toxicities related to cardiac fluid overload. By dose reducing, we can see a decrease in that, making it a more viable option for more patients. What will be interesting to see long term out of those data is if the concern for CMV [cytomegalovirus] reactivation or viral reactivation at the lower dose is also improved over time. Certainly, if we’re able to maintain great efficacy as far as acute GVHD prevention with a lower dose, and reduce toxicity, that’s absolutely the way to go. I’m very excited about those data.

 I’ve seen the data. Biologically, they seem even better than the higher dose. You have better Tregs expansion and fewer T effectors. This was in a reduced-intensity setting. I also want to mention that an Italian group has also tried days 3 and 5 recently in the full-intensity setting also with reduced toxicity, which is interesting. There will be adjustment for cyclophosphamide post-transplant.

Videos

Sophie Paczesny, MD, PhD; Yi-Bin Chen, MD; and Hannah Choe, MD, review recent advances in GVHD prophylaxis as presented at the 2021 American Society of Hematology (ASH) Annual Meeting and Symposium.

ASH 2021 Updates for GVHD Prophylaxis

 We should talk a little about the fact that not everybody gets graft-vs-host disease after transplant. The big reason is because every recipient receives some prevention or prophylactic strategy. Nelson, do you want to take us through the different ways people can be prophylaxed against graft-vs-host disease?

 Everybody gets a graft-vs-host reaction because there are allogeneic cells going into an environment that’s inflamed. But clearly, not everybody gets graft-vs-host disease. Historically, it was primarily methotrexate initially, and then cyclosporine became available in the late 1980s. The combination of cyclosporine-methotrexate, or a calcineurin inhibitor and methotrexate, has remained the standard in many practices. There have been multiple variations around it. There have been attempts in making calcineurin-free regimens. Probably the most recent is post-transplant cyclophosphamide, which has changed the field in our ability to do haploidentical transplants. That’s on the pharmacological side.

There has been lots of interest in doing graft manipulation by trying to delete T effectors, CD20-positive cells, and CD69-positive cells, using CD34 selection as a way of improving this, and there have been a lot of data on ATG [anti-thymocyte globulin] for many decades. None of these have been shown to be much better in overall survival than the standard approaches.

 It’s exciting, and I’m looking forward to seeing how this field develops. There are ongoing trials comparing calcineurin inhibitor–based to post-transplant cyclophosphamide-based regimens, and we may have a new standard of care. At the same time, other agents have shown promise added on, such as abatacept recently, and other agents and trials as well.

Nelson J. Chao, MD, MBA, reviews current GVHD prophylaxis options and factors to consider when selecting one for a given patient.

Selecting GVHD Prophylaxis

 A lot of research has gone into early detection of graft-vs-host disease [GVHD]. It’s difficult to detect graft-vs-host disease early because we’d all admit that the immune response takes weeks before we see the manifestation. Why is it difficult to detect it early?

 Hannah, do you want to take the lead on this?

 In terms of early detection of graft-vs-host disease, it’s a clinical diagnosis. There are biomarkers that Sophie can elaborate more on. We have biomarkers for both acute and chronic graft-vs-host disease that help us differentiate the risk of it. The actual diagnosis is hindered because even biopsies aren’t necessarily specific enough to help us diagnose it.

When we have the first initial presentation of acute graft-vs-host disease, we do it based on classical presentations, typically of the 3 main target organs that were mentioned: skin, which is usually the earliest manifestation of acute graft-vs-host disease, followed by the GI [gastrointestinal] tract and the liver, which would manifest as hyperbilirubinemia. There are risk scores and classifications using those 3 main target organs that allow us to determine the likelihood of response to therapy and predict nonrelapse mortality.

We have the revised Minnesota risk score to determine whether a patient has standard vs high risk at diagnosis, which will give us an idea of whether they’ll be responsive to corticosteroid therapy, vs the biomarker score with the MAGIC [Mount Sinai Acute GVHD International Consortium] score using ST2 and REG3-alpha. These can help us determine whether a patient should receive more aggressive therapy vs less aggressive therapy. The biomarkers and clinical presentations for risk assessments are able to be used in clinical trial design to help us risk stratify for eligibility purposes. It’s been used in the BMT CTN 1501 trial with sirolimus vs corticosteroids. It’s been used in an itacitinib frontline trial as a single agent studied through the MAGIC consortium. The biomarkers, at least in acute graft-vs-host disease, have become central and integrated into clinical trial design.

For chronic graft-vs-host disease, the risk assessment is similar in terms of clinical presentation. Instead of 3 target organs, we have 8 organ manifestations that we look at: skin, oral, eye, lung, liver, GI tract, genitourinary, and joints and fascia. A composite score was similarly created based off the NIH [National Institutes of Health] consensus criteria. That composite score will differentiate between mild, moderate, and severe and will help us differentiate whether the patient is more likely to have higher nonrelapse mortality. Biomarkers in that area, which Sophie will be able to expand on, are less integrated into clinical trials but are certainly a very interesting area of research right now.

Before Sophie goes on, the key point is that skin rash, GI, diarrhea, and LFTs [liver function tests] happen all the time and aren’t necessarily rare to GVHD, which makes this diagnosis difficult. Because the last time I looked, most of our patients are on 21 drugs on average. They get ablative regimens or radiation. Every one of those drugs and prep regimens can cause GI symptoms. It can cause rash. You can get an infection that causes these things. The need of biomarkers is great. Because it’s a clinical diagnosis, it’s very difficult to know for sure whether it’s real GVHD or not.

 Yes. And a good marker is able to differentiate this. ST2, for instance, has been evaluated against a type of rash, drug rash, or for colitis, including CMV [cytomegalovirus] colitis and 

 colitis. We studied markers that are specific and sensitive not only in terms of markers themselves but also specific to GVHD. The markers you talked about were mostly predictive biomarkers. That’s the biomarker that’s measured at the beginning of GVHD, and that will tell you what the outcome will be after the treatment starts.

There are even more interesting biomarkers. These are starting and are lot of ways with the same cutoff for the biomarkers at time of diagnosis early on. With a risk biomarker, where you look before the GVHD occurs, and you find the cutoff for these, ST2 is probably one of the best markers in this field…that can tell you if you will develop actual GVHD. There has been a lot of progress in GVHD. The Joseph Pidala 

 paper that was published recently on BMT CTN 1501 showed that if you look at standard risk and usable for clinical characteristics and biomarkers, you could randomize for a corticosteroid-free treatment and achieve the same outcome. That has been a pretty neat study. Biomarkers have helped in this way. The next frontier is risk biomarkers. Can we use the biomarker to say that you will develop actual GVHD?

Chronic GVHD isn’t as well developed. We don’t have biomarkers as strong. One of the limitations has been the availability of samples at the right time. Most of the patients don’t have a sample at the time of diagnosis. There are some initiated from Stephanie Lee U54 consortium. NIH also has a longitudinal study, but they’re mostly rare. And even if you look at the sample biobank did by BMT CTN [Blood and Marrow Transplant Clinical Trials Network], they stopped with sampling at day 90. At diagnosis, we don’t have a lot of samples. We have some day 100 or day 90 samples, but it’s more difficult to find a risk biomarker than a diagnosis biomarker and then see if it’s eventually interesting as a risk biomarker. That being said, we’ve looked. It’s not published. We’ve looked at 1000 samples at day 90 and we think we have some interesting markers. We’ll submit soon.

 We all look forward to being able to learn how to use these biomarkers, the ones in acute, which are already available commercially, and the ones in chronic, which we can hopefully develop.

Hannah Choe, MD; Nelson J. Chao, MD, MBA; and Sophie Paczesny, MD, PhD, comment on the importance of early detection of disease and the role of biomarker testing in GVHD.

Challenges in Early Detection of GvHD

® titled “Advances in the Management of Graft-vs-Host Disease.” I’m Dr Yi-Bin Chen, the director of the bone marrow transplant program at Massachusetts General Hospital in Boston, Massachusetts. Joining me in this discussion are my colleagues. Panelists, would you each introduce yourselves?

 Hi, I’m Hannah Choe. I’m an assistant professor at The Ohio State University in Columbus, Ohio.

I’m Nelson Chao. I’m the program director at Duke University School of Medicine in Durham, North Carolina.

 I’m Sophie Paczesny. I’m a professor at the Medical University of South Carolina in Charleston, South Carolina.

 Thank you. We’re going to discuss topics pertaining to the diagnosis and treatment of acute and chronic graft-vs-host disease. We’ll discuss the latest research and the effect of clinical trials on treatment selection and patient management. Let’s get started on our first topic. To start, we should set the table and talk about what graft-vs-host disease is. Nelson, could you give us a brief overview?

I tell my patients all the time that graft-vs-host disease is exactly what those words say. It’s the graft, which are the donor cells, vs the host, which is the patient. In that setting, the donor cells get into the recipient, the patient, and recognize antigens that are different between itself and the patient, and that starts an immunological process of the graft attacking the host.

In the acute setting, which is what happens early on, a strong cytokine-driven process by the T cells causes disease in the skin, gut, and liver. In the chronic sense, it’s much more of an autoimmune-type process. T cells are critical to start it, but afterward, there are many other cell types that probably contribute to chronic graft-vs-host disease. On the negative side, it certainly can cause morbidity and mortality. On the positive side, because of the host leukemia or lymphoma, the tumor antigens are also new to the donor. These donor cells can recognize these tumor antigens as foreign and kill tumor cells as well, giving the graft-vs-leukemia and graft-vs-tumor effect.

 Would it be fair to say that you tolerate some graft-vs-host disease in your patients, knowing that it may provide that effect?

Yes. We’d all like to have some graft-vs-host disease, which gives us this graft-vs-leukemia effect. Our problem is that we don’t have a way to fine-tune that, so when it happens, it’s grade 4, and patients can die from it.

 Let’s talk a little about how patients present. It’s interesting. When I talk with my patients before transplant, and I describe the risks and try to talk about graft-vs-host disease, they often ask, “What’s it like if I get it?” Acute and chronic graft-vs-host disease present with different symptoms. Acute graft-vs-host disease generally happens in the first 3 to 6 months, but it can happen later. It usually involves the skin with what I call an angry red skin rash. It involves the GI [gastrointestinal] tract, mainly lower GI tract disease as diarrhea. There’s upper GI involvement, which could be persistent nausea and anorexia. And there’s liver involvement, the least common of those, which presents as asymptomatic elevations in your liver function tests.

Chronic graft-vs-host disease is different. As you heard Dr Chao say, it’s more of an autoimmune disease. It can resemble classic autoimmune disease as dry eyes and dry mouth. The skin rash is less angry. It’s more like eczema. It can affect almost any organ and can have collateral autoimmune disease manifestations, like nephrotic syndrome, where your kidneys lose protein. The 2 most difficult manifestations for us in chronic graft-vs-host disease are scleroderma, where parts of the fascia, or the skin, get very thick and can limit range of motion, and pulmonary involvement, which is a syndrome called bronchiolitis obliterans. Those are the most difficult manifestations to treat.

When patients present with symptoms, they often ask, “How do I know if this is graft-vs-host disease?” That gets at, “What’s the diagnosis?” While we do often biopsy tissues, the diagnosis of graft-vs-host disease remains a clinical diagnosis. It remains taking into account the patient’s symptoms, where they are, what kind of transplant they had, and what their baseline symptoms are to try to make a diagnosis. Biopsies of tissues can help—they can have supportive findings—but the diagnosis remains clinical.

Nelson J. Chao, MD, MBA, and Yi-Bin Chen, MD, define common signs and symptoms of GVHD and share insight on approaching the diagnosis of disease.

Yi-Bin Chen, MD

Articles

ASH 2021 Updates for GVHD Prophylaxis

Selecting GVHD Prophylaxis

Challenges in Early Detection of GvHD

Overview of Graft-vs-Host Disease (GVHD)