Ruxolitinib for Steroid-Refractory GVHD: The REACH Trials - Episode 1

Acute vs Chronic GVHD, Incidence, and Risk Factors

Yi-Bin Chen, MD, delineates between acute and chronic GVHD and provides the incidence and risk factors associated with these diseases.

Yi-Bin Chen, MD: Hi, my name is Dr Yi-Bin Chen. I am the director of the hematopoietic cell transplant and cellular therapy program at Massachusetts General Hospital and Harvard Medical School [Boston, Massachusetts] welcoming you today to an investigator perspective on ruxolitnib for steroid refractory graft versus host disease, the REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals) trials.

I'd like to start by giving an overview of graft versus host disease after allogenic transplantation. Allogeneic transplantation is, as many of you know, a potential curative modality for many high-risk hematological malignancies and some nonmalignant conditions as well. We believe the therapeutic mechanism of action (MOA) of allogeneic transplant is twofold. One, there's enhanced cytotoxicity from the conditioning regimen that we give before every transplant, but once we ingraft donor hematopoiesis in the recipient, we hope those donor white blood cells can reconstitute, ultimately providing the recipient with an intact immune system. But also, we hope to cultivate a therapeutic immunological graft vs malignancy effect. And this immunological therapeutic mechanism is what we believe is the dominant mechanism of action in allogeneic transplantation. The issue with this is that transplants are done not from identical twins, so the donor and host are inherently unique allogenic individuals. When the donor immune system grows up in that recipient, there can be an attack on the recipient's healthy tissues, and this is what graft versus host disease is.

There are generally 2 types of graft versus host disease: acute and chronic. They're named that way partly because of the timelines when they commonly occur, but also because of their clinical aggressiveness and how long symptoms will remain and how long patients will remain on therapy. Acute graft versus host disease probably occurs in about 30% to 40% of individuals if we look at transplant patients as a whole. And when I give that number, it means the number of patients that we have to act upon or deliver some sort of systemic therapy for. Acute graft versus host disease commonly involves the skin, the GI [gastrointestinal] tract, and the liver, and usually occurs in the first several months after transplantation. It's important to note that these days, with all kinds of different conditioning regimens and RAF sources and transplant platforms, which have different kinetics of immuno-constitution, graft versus host disease is no longer defined by the first 100 days for acute and afterwards for chronic. It's only defined by clinical manifestations of acute vs chronic. Chronic graft versus host disease tends to occur in the first few months after transplantation, rarely occurring before the first 3 months. It is less traumatic than acute, its rash is a bit different, not as angry and erythematous, but more looking like psoriasis or eczema. Commonly involves the skin as I mentioned as well as the eyes and the mouth, which are more of a dry eyes, dry mouth syndrome, but chronic graft versus host disease can involve almost any organ in one's body. The joints can hurt, the muscles can become inflamed, and chronic graft versus host disease also is a state of significant immune dysregulation. Not only do you have the direct attack on the organs that give you the classic clinical manifestations of chronic graft versus host disease, but certain auto-immune phenomenon can arise such as nephrotic syndrome or polymyositis. And these are commonly seen autoimmune manifestations that we see in the context of graft versus host disease.

The risk factors for graft versus host disease are pretty much the same for acute and chronic. We've classically defined clinical risk factors even before transplant and they start with histocompatibility or HLA (human leukocyte antigen) matching between the donor and the recipient. Other risk factors known to associate with an increased incidence of graft versus host disease include an increased intensity of the conditioning regimen, specifically the use of total body radiation. Donor sources, in the sense that peripheral blood stem cells will give more graft versus host disease, specifically chronic when compared to bone marrow. If you're a male recipient, there is evidence that a female donor compared to a male donor will lead to an increase incidence of graft versus host disease. And age of both donor and recipient, as the older age of either will lead to a higher incidence of graft versus host disease. But interestingly, a recent risk factor identified has been the microbiome. This is the diversity of bacteria in one's GI system or colon and there's clear evidence, at least from an associative standpoint, that when the microbiome diversity is restricted, that often leads to a higher incidence of complications after transplant, such as graft versus host disease. We haven't proven a cause and effect, and it may just be a marker of illness, but much research is going on in that regard. Chronic graft versus host disease, we should mention, seems to follow acute graft versus host disease, meaning that the sequence of events is set very early on. In fact, the biggest risk factor for chronic graft versus host disease is prior acute, and that has been proven in many series throughout the years.

We generally regard acute and chronic graft versus host disease these days as separate diseases. They have distinct clinical manifestations. Acute has the angry erythematous skin, maculopapular skin rash, as well as diarrhea when the lower GI tract is involved. And chronic graft versus host disease look more like classic autoimmune phenomenon like Sjogren's syndrome and eczema and psoriasis. And that's because physiologically, we think they morph different on the immune system. Acute graft versus host disease is far more what we believe to be a direct T-cell engaged activity or a Th1 (type 1 T helper)-driven immune response. Whereas chronic graft versus host disease is much more Th2-involved. There is involvement in B-cells, the humoral immune system, and it's not uncommon to see a peripheral eosinophilia in these patients as well. There are cases of overlap syndrome; we're just humans that are trying to create categories, and there are always going to be patients who divide those categories. And there are cases where patients have manifestations of both acute and chronic, but those are quite rare. Most patients, when we talk about graft versus host disease, usually fall into one box or the other.

This transcript has been edited for clarity.