Immunopathology and GVHD Incidence

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EP: 1.Immunopathology and GVHD Incidence

EP: 2.GVHD Prophylaxis

EP: 3.Diagnosing & Staging of GVHD

EP: 4.Management of Acute GVHD

EP: 5.Management of Chronic GVHD

EP: 6.Steroid Refractory GVHD: Scope of the Problem

EP: 7.Steroid-Refractory Acute GVHD

EP: 8.Steroid-Refractory Chronic GVHD

EP: 9.Final Thoughts: GVHD

Yi-Bin Chen, MD: Hello and welcome to this OncLive Peer Exchange®, “Current Practices and Future Directions for the Treatment of Graft-vs-Host Disease.” I am Dr Yi-Bin Chen; joining me today in this discussion are my colleagues: Dr Corey Cutler, Dr Richard Maziarz, and Dr Sophie Paczesny. Today we are going to discuss the management of graft-vs-host disease; a really challenging complication that we all see after allogeneic transplantation. Over the past 3 decades, although tremendous progress has been made in the transplantation field; expanding donor source options, the development of reduced intensity conditioning regimens, and improvements in supportive care which have all led to an increased use of allogeneic transplant and improvement in outcomes in many patients; graft-vs-host disease remains a big challenge. We have seen increased numbers of patients who develop both acute and chronic graft-vs-host disease; underscoring the need to improve prevention, recognition, and management of this serious complication. Without further ado, let us begin.

In this first section, we will discuss the basic biology of acute and chronic graft-vs-host disease. Dr Corey Cutler will lead us through a discussion of the pathophysiology, then followed by Dr Richard Maziarz illustrating modern methods of GVHD [graft-vs-host disease] prevention. Corey?

Corey Cutler, MD, PhD, FRCPC:Thank you, Yi-Bin. As you mentioned, we will start out talking about the basic biology and immunopathology of acute and chronic GVHD. Most of us tend to think of acute GVHD as a very linear process with alloantigen recognition, upregulation of an allogeneic T-cell response, and then tissue injury at the level of the target organs. However, chronic GVHD is a far more complicated process with involvement of several different T-cell subsets, some involvement of the B-cell pathway, and then variable involvement of terminal monocyte macrophages with respect to the laying down of collagen and fibrosis. I think a lot about what we know about the immune pathology of acute and chronic GVHD; it can really be derived from the biomarkers we use to measure it. I would like to ask Sophie: how we are using the biomarkers to understand the basic biology of both acute and chronic graft-vs-host disease?

Sophie Paczesny, MD, PhD: There are 3 types of biomarkers that we can access. First of all is the biopsy; we have been using biopsy for a long time, correct? Correlation between biopsy and clinical data, and response to treatment not complete, is roughly only 70%. When you have access to plasma, serum or PBMCs [peripheral blood mononuclear cell], we are preforming fewer biopsies. We have been using biomarkers in 3 different contexts. 1. response to treatment and predictive biomarkers; before you have the treatment, you can look at the re-stratification and analyze it early post-transplant. What we have found so far is that most of the biomarker inflammatory molecules such as TNF receptor alpha, elafin, ST2, which is an IL-33 receptor, ….. receptor. We can also check the PBMCs where we then see a subset of cells; the activation of T-cells, the downregulation of regulatory T-cells, the activation of B-cells…that have been established so far. We still have a way to go because not all of them have been validated. We will talk about this a little bit later; of course in chronic GVHD we do not have as strong of a biomarker as we have in acute GVHD.

Corey Cutler, MD, PhD, FRCPC: We know a little bit about what happens at the tissue level based on what you said. At the macroscopic level, many of the risk factors overlap between acute and chronic GVHD. Rich, do you want to perhaps elaborate on what the main ones are for both acute and chronic graft-vs-host disease?

Richard Maziarz, MD: The issue of risk factors is the ability to predict ahead of time who is going to have enough T-cell expansion of these 2 to have a volume of alloreactive clones to cause end-stage tissue damage. There have been a lot of studies, the CIBMTR, and the EBMT, have been critical in using large data sets to start to designate some of those risk features. Where you look first and foremast is HLA matching. We have HLA-A, -B, -C, -DR that have been critical. Recently, there has been work coming out that HLA-DP may be an important factor to designate if mismatches will be associated with increased risk. We have age issues where older donors have been now correlated with greater risk of GVHD in the recipient. Sex-mismatched grafts continue to remain controversial. There are data to suggest that sex-mismatched grafts, particularly into the female into male where you have potentially H-Y differences or other Y chromosome-corrected antigens, are correlated with GVHD. However, there are other studies that would say that in the modern era, that the sex-mismatched graft may not have that same high risk.

Cell doses have mattered; whether it’s the T-cell dosing in the graft, the CD34 dose that may be a measure. Finally, we also must talk about just the source of the graft itself; whether one uses a bone marrow product versus a peripheral blood stem cell mobilized product. I think in the latter circumstance we get a lot more T-cells, so you start with a higher number of cells that would theoretically give you the greater possibility of clonal expansion that could create the clinically significant GVHD.

Corey Cutler, MD, PhD, FRCPC: Thank you. One thing that’s come up recently is another set of risk factors; the microbiome that we all possess. You’ve just described a lot of the external risk factors that may or may not be modifiable: can we find a better match? Can we find a younger or a gender match donor? There are certain things such as the microbiome we all carry in our intestinal tract, on our skin, in our lungs even, that may influence rates of graft-vs-host disease. There was an interesting abstract at ASCO [American Society of Clinical Oncology], #7005, that looked at baseline microbiomes and how that might have impacted the incidence of acute GVHD. Yi-Bin; your group has done a fair bit of work on fecal microbiotic transplantation. I wonder how you interpret this abstract as well as the evolving field of the baseline microbiome and how that might influence GVHD.

Yi-Bin Chen, MD: The microbiome is fascinating in medicine in general, and its impact on disease and outcomes. There’s certainly been a lot of studies recently, a lot of them out of Marcel R.M. van den Brink’s lab at [Memorial] Sloan Kettering, that show associative relationships between microbiome diversity and overall outcomes after transplant; specifically acute graft-vs-host disease, as well as other end points such as relapse, bacteremia, and so forth. It’s fair to say that all of these relationships are associative right now and we haven’t proven any cause-and-effect relationship which is the next step. There was really interesting data out of Geoff Hill’s lab [at Fred Hutchinson Cancer Center] that suggested that the microbiome influences MHC expression on the GI [gastrointestinal] epithelium; that one of the leading mechanism for how microbiome diversity can influence immunological responses. One must think there is something within the GI tract, being that it is a huge lymphoid organ. At the same time, critics would say that loss of microbiome diversity is just a marker of a sick patient. I believe that’s true as well; a patient who has been in the hospital longer, a patient who suffered bacteremia, Clostridioides difficile, and other complications during, for example, acute leukemia induction therapy, all those things are true.

The next step is to figure out if there is an intervention that we can modulate microbiome diversity that can modify outcomes, and whether that is prebiotics, choice of antibiotics, probiotics, or other interventions remains to be seen. It is really great to see that we are collaborating as a community in terms of bio repositories and data to figure this out. We as a community have talked about how to do one of those trials and the challenge being what’s the primary end point to balance the ability to enroll and see a difference. Those discussions are ongoing and it remains to be seen where we end up.

Corey Cutler, MD, PhD, FRCPC: I agree; we definitely need to do something because we know that both acute and chronic GVHD have major impacts on the outcome of our patients; acute being very much linked to early morbidity and mortality, and chronic GVHD being more linked to quality of life and long-term health outcomes. What do you think we are going to see in the future; more or less GVHD? Is it going to become more impactful, less impactful? I will let anyone answer that to start.

Richard Maziarz, MD: One thing I was just going to say, is having the perspective of time. For 40 years there was a sense and there was data from animal studies showing that animals raised in pathogen-free environments had less GVHD. There was this issue of suppression, and there was a lot of focus on suppression of bacteria overgrowth during a transplant period when there were defects in the innate immune system. We are now going full circle where rather than seeking a pathogen-free experience, we are more trying to potentially liberalize diets, have outpatient allogeneic transplants, and even doing studies of prophylactic fecal microbiota.

Yi-Bin Chen, MD: I agree; it’s really fascinating where the field has gone. I think there is competing things going on, right? We’re investigating more effective ways of GVHD prevention, and I think we have at least stumbled upon certain regimens that can do that. At the same time, we’re all transplanting older and sicker patients as we go forward, and those patients inherently seem to be at a higher risk of graft-vs-host disease; it’s hard to know where that calculus ends up. I think we will still be dealing with a good burden of acute and chronic GVHD at least in the next decade.

Transcript edited for clarity.