Understanding Pathophysiology and Risk of Graft Versus Host Disease

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EP: 1.Understanding Pathophysiology and Risk of Graft Versus Host Disease

EP: 2.Graft Versus Host Disease: Optimizing Prophylaxis Techniques

EP: 3.Educating Patients and Caregivers on the Impact of Graft Versus Host Disease

EP: 4.Challenges in Making a Diagnosis of Acute GVHD

EP: 5.What is the Role of Biomarker Testing in GVHD?

EP: 6.Overview of Therapy for Steroid-Refractory Acute Graft Versus Host Disease

EP: 7.Steroid-Refractory GVHD: Enrolling Patients on Clinical Trials

EP: 8.Identifying the Role of the Microbiome in HSCT and GVHD

EP: 9.Improving the Early Identification of Chronic Graft Versus Host Disease

EP: 10.Frontline Treatment Strategies for Chronic GVHD

EP: 11.Treatment Armamentarium for Steroid-Refractory Chronic GVHD

EP: 12.Steroid-Refractory Chronic GVHD: Selecting and Sequencing Therapy

EP: 13.Treatment Advances on the Horizon for Chronic GVHD

EP: 14.Treatment Advances on the Horizon for Acute GVHD

EP: 15.Using Multidisciplinary Care to Optimize Outcomes in GVHD

Transcript:

Corey Cutler, MD, MPH, FRCPC: Hello, and welcome to this OncLive® Peer Exchange®titled “The Expanding Field of GVHD.” I’m Dr Corey Cutler. I’m an associate professor of medicine at Harvard Medical School, and I’m the medical director of the stem cell transplant program at the Dana-Faber Cancer Institute [in Boston, Massachusetts]. Joining me are my colleagues Dr Yi-Bin Chen and Linda Perry. I’m going to ask them to introduce themselves. Dr Chen?

Yi-Bin Chen, MD: Hi, I’m Yi-Bin Chen. I direct the transplant and cell therapy programs at Massachusetts General Hospital in Boston. I’m happy to be here to talk about graft-vs-host disease [GVHD].

Corey Cutler, MD, MPH, FRCPC: Linda?

Linda Perry, PA-C: Hi, I’m Linda Perry. I’m a physician assistant from the allogeneic stem cell transplant program at the University of Pennsylvania [in Philadelphia]. I’m happy to be here.

Corey Cutler, MD, MPH, FRCPC: Fantastic. Let’s jump right in. We’ll be discussing acute and chronic graft-vs-host disease, and we have a fairly deep agenda to get through. We’re going to start by briefly giving an overview of the pathophysiology or pathobiology of graft-vs-host disease. I’m going to ask Dr Chen to tell us a little more about the topic.

Yi-Bin Chen, MD: To understand graft-vs-host disease, we have to take a step back and revisit why we do allogeneic transplants to begin with. For the vast majority of our patients, the indication is an underlying hematologic malignancy. For these patients, an allogeneic transplant is almost always done for potential curative intent.

We replace the recipient’s hematopoietic system or blood system with a donor’s blood system. As that donor’s white blood cells reconstitute and mature, we certainly hope the donor’s white blood cells protect the recipient from infection. More important, if there’s any sign or any evidence or any depth of malignancy left, we hope the donor’s white blood cells attack that malignancy, providing an immunologically driven graft-vs-malignancy effect. That is what most of us think is the underlying mechanism of action for how an allogeneic transplant can treat hematologic malignancies.

The flip side to that is that the donor attack can occur on not just malignant cells but also unhealthy recipient cells. This gives rise to what we call graft-vs-host disease. The underlying pathophysiology or pathobiology of graft-vs-host disease is complicated. I don’t admit to truly having the entire cascade mapped out. I don’t think any of us do.

There are 2 phases. There are acute graft-vs-host disease and chronic graft-vs-host disease, named based on the timing after transplant where they commonly take place. Acute graft-vs-host disease, which we’ll talk about, is generally thought to be a Th1 [T-helper 1]–driven T-cell effect. That’s what many of us believe to be the primary immune pathway that’s in effect. We think the events that happen around transplantation, including organ injury from the conditioning regimen, as well as perhaps effects of a dysbiotic microbiome, create a local setting in organs that’s ripe for an inflammatory or immunological process to be generated. When naïve donor T cells are infused into the body, they’re activated at these sites. They go to secondary lymphoid tissue, where they undergo more activation and traffic back to organs, where they cause damage. That’s what we believe about how acute graft-vs-host disease occurs.

Chronic graft-vs-host disease is a bit more complicated. We used to think it was all about T cells. Over the last 10 years, there was a big B-cell effect. Certainly, macrophages have entered into the conversation, and regulatory T cells have come up. Most of us believe multiple pathways get to the heterogeneous disease of chronic graft-vs-host disease. Because of these pathways, many therapeutic targets related to these pathways have been exploited. Chronic graft-vs-host disease is much more heterogeneous, probably more redundant, and it merits a lot more study in trying to figure out the exact pathways involved.

The 1 silver line in graft-vs-host disease is that large studies have repeatedly shown that patients who develop acute but much more chronic graft-vs-host disease have a much lower chance of experiencing disease relapse in the long run. I guess there’s a silver lining, though we don’t wish significant chronic graft-vs-host disease on any of our patients.

Corey Cutler, MD, MPH, FRCPC: Thanks. That’s a nice, broad overview of what we think GVHD is. I’m going to bring it back and talk about where we think the roots of GVHD lie and how that relates to risks, and that’s the HLA [human leukocyte antigen] system. The way we match donors and recipients influences, probably to the greatest extent, the occurrence of both acute and chronic graft-vs-host disease. We try to match our patients as best we can, looking at 10 or 12 HLA class 1 and 2 molecules and trying to match them at the molecular level. Certainly, a mismatch at HLA is far and away the greatest predictor of acute and chronic graft-vs-host disease.

There are other characteristics that we can sometimes modify and sometimes not that will influence the rate of graft-vs-host disease. For instance, donor and recipient, gender, and age are important. Yi-Bin touched on this in terms of how the B-cell system might be instrumental in chronic graft-vs-host disease. We know that female donors to male recipients have higher rates of graft-vs-host disease. The age of the donor and the recipient is important. Probably via several mechanisms, thymopoiesis [is important] in younger donors and recipients, and there’s a more mature and less naïve immune system among older donors. Several of these have risk factors as well.

Some older characteristics that were thought to influence graft-vs-host disease are things like CMV [cytomegalovirus] serostatus and the impact of disease activity at the time of conditioning. But most of these are a little less relevant. One thing Yi-Bin touched on was the importance of tissue injury at the time of transplantation—inflammation and how that may or may not impact graft-vs-host disease. Subjects who receive myeloablative conditioning or of greater injury to their microbiome are probably at higher risk of graft-vs-host disease. We’re definitely working on ways to modify some of these risk factors wherever possible. But sometimes, unfortunately, we’re dealt a hand where you’re given a donor, and that’s your best option for that patient in front of you.

Transcript edited for clarity.