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

Transcript:
Corey Cutler, MD, MPH, FRCPC: 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.

Transcript edited for clarity.