Expert hematologist-oncologists provide insight on major risk factors for GVHD and associated challenges for treatment.
John DiPersio, MD, PhD: Let’s discuss some of the factors that contribute to the risk of GVHD [graft-vs-host disease], Mike. Let’s get away from the esoteric biology and tell the audience what you think the major risk factors of acute and chronic GVHD are.
Michael Bishop, MD: Our understanding of graft-vs-host disease has significantly changed in the last 20 years. A lot of that has to do with a biology that’s described. We always think about graft-vs-host disease, both acute and chronic, as a T-cell disorder. You take out the T cells, and there’s less graft-vs-host disease, both acute and even chronic.
But you emphasize B-cell biology. We didn’t have a good understanding of that, but the important role that B-cell biology plays, particularly chronic graft-vs-host disease, is very important.
Even our understanding of T-cell biology is relative to chronic graft-vs-host disease and our understanding of T-regulatory cells. The loss of T-regulatory cells plays an important role, which you were talking about with immune dysregulation. Having this further understanding about T-cell and B-cell biology has helped us define the underlying mechanisms that lead to both acute and chronic, and you couldn’t have said it any more eloquently. But it also explained a lot about what happens clinically. Why don’t we see a lot of acute lung graft-vs-host disease? Why don’t we see other forms of muscle and other organ involvement? It has to do with all this biology. That has to do how we define clinically acute and chronic graft-vs-host disease.
Unfortunately, in many ways we’re seeing more chronic graft-vs-host disease. That’s for a variety of reasons, which is good. One is patients are able to live longer from the acute phases of allogeneic stem-cell transplantation. Our supportive measures have become significantly better, so patients are living longer to develop it. Just as you described, immune suppression starts to pull off, we can see graft-vs-host disease.
We’re treating an older population, and they’re more prone to the development of graft-vs-host disease and, as you talked about, thymus involution. Their thymus gets very involuted, and there’s a difference between what we see in children, what we see in young adults, and what we see in older adults. Then our donor sources have significantly increased.
We’re using more unrelated donors. We’re using haploidentical donors. If you have an older individual, they may be using a brother and sister, or maybe a son or a daughter, as a haploidentical donor. Although we have low levels of relatively—to use the post-transplantation cyclophosphamide—these patients still can develop acute and chronic graft-vs-host disease.
Often the chronic graft-vs-host disease that evolves in these individuals can be severe and very difficult to treat. We’re seeing a lot of the factors that we already knew about in the development of acute and chronic, and probably the most important factor for development of chronic graft-vs-host disease if you did develop acute graft-vs-host disease. We’re seeing this more, and it’s becoming a challenge with us clinically, but for good reasons. The patients are living longer, and we’re able to apply transplantation to a broader audience.
John DiPersio, MD, PhD: Would you agree that some of the risk factors for at least acute GVHD have to do with mismatching of donor recipients, that the greater the mismatch between the donor and recipients, the greater the risk of acute GVHD?
Michael Bishop, MD: Absolutely, and we know that. We have it from our studies. When we’re doing sex mismatch, when we’re using female donors, when you were talking about the use of an alternative donor that’s not related, the minor histocompatibility antigens—we know that they play an important role. Those are inherited differently from how we inherited HLA [human leukocyte antigen]. Because of that, using a related donor, you have at least a 50% probability if it’s a matched sibling donor; in the haploidentical setting, it’s 25%. It might be a little less, but all the factors—prior viral exposure, prior antigen exposure during pregnancy, and age of donor, which we really hadn’t taken into consideration in the last 20 years. Maybe it’s better to use a 20-year-old volunteer donor than a 68-year-old matched sibling donor for all the reasons that we were talking about in terms of antigen exposure, etc.
John DiPersio, MD, PhD: I agree. As you mentioned, the most important predictor of chronic GVHD is the presence of some level of acute GVHD. But you can certainly get chronic GVHD if there’s no obvious acute GVHD, which means a lot of acute GVHD that occurs is physiologically happening, but we don’t clinically notice it.
One part of this acute GVHD stuff that predicts for chronic GVHD, which goes back to the pathophysiology, is that in acute GVHD or subclinical acute GVHD, the donor T cells injure these epithelial cells in the lymph nodes and thymus of the recipient. Those are the cells that can modulate this clonal deletion business. If they’re damaged, and the only thing that seems to damage them is not chemotherapy or radiation therapy but GVHD. That creates a defect in these cells. But the T cells that come out from the stem cells that go into these organs are not appropriately clonally deleted, and the T cells have some level of autoreactivity engage B cells and cause chronic GVHD. The notion of when to intervene to prevent these things is a controversial question. But I would suggest that.
Michael Bishop, MD: I want to reemphasize what we said. There’s this spectrum. They aren’t necessarily 2 distinct entities. You may not have seen clinical acute graft-vs-host disease, but there’s an immunologic process going on. Are the embers there from whatever happened before? These new T and B cells emerge from the marrow, not the passively transferred T cells or the passively transferred B cells. There’s a continuum, and that continuum is what happens in that development over time as the new immune system develops.
Transcript Edited for Clarity