Graft Versus Host Disease: Optimizing Prophylaxis Techniques

Transcript:

Corey Cutler, MD, MPH, FRCPC: It stands to reason that if we have to deal with the risks of graft-vs-host disease [GVHD], we’re going to try to prevent it. There are several techniques that we use these days to prevent graft-vs-host disease. Yi-Bin, tell us what the standard of care is at the moment for matched donors, and then we’ll move on to issues in unrelated and mismatched and higher-risk transplants.

Yi-Bin Chen, MD: I can speak to what the predominant standard is in the United States. There may be some institutional, regional, and international differences. For a couple of decades, the backbone for a match sibling transplant for graft-vs-host disease prevention has been the use of post-transplant calcineurin inhibitors, such as tacrolimus or cyclosporine, paired with short-course methotrexate. To a lesser extent, some have paired it with mycophenolate. That’s been the standard of care for a matched sibling transplant for decades.

As we moved into the unrelated transplant world, the biggest advancement was the development of high-resolution HLA [human leukocyte antigen] typing, so we can get fully matched unrelated donors confidently. When we started, these were only allele-level matches, and really mismatches, from an immune system perspective. Fully matched unrelated donors these days have outcomes that are very close to fully matched sibling donors, even with just the use of standard calcineurin inhibitor plus methotrexate prophylaxis. In the past, some have empirically added what we call ATG [anti-thymocyte globulin] products for unrelated donors. That practice has faded in the United States with the publication of certain clinical trials that have not suggested a definitive benefit. That’s been the standard of care.

The emerging platform is built around the use of post-transplant cyclophosphamide, and that’s giving high doses of cyclophosphamide on days 3 and 4 after transplant to eliminate alloreactive T cells but also encouraging the development of regulatory T cells. That generally has been paired with tacrolimus and mycophenolate. It was first studied in haploidentical, so half-match-related transplants. Because of the success in using that platform, it’s been extrapolated to use in the mismatched unrelated donor platform and the fully matched unrelated and related settings.

It’s tough to say which platform should be the standard because ongoing prospective trials haven’t finished in terms of analysis of results and publication. Some centers have started to embrace the use of post-transplant cyclophosphamide given its ease and success. But many of us are awaiting the results of ongoing trials to figure out if there’s a single standard of care that’s superior or if we should tailor these regimens based on the patient population, underlying disease, and other characteristics.

Corey Cutler, MD, MPH, FRCPC: Linda, what’s the standard of care at your institution? What are clinicians at your center doing?

Linda Perry, PA-C: As far as the matched related donors, we’re sticking with the tacrolimus-methotrexate. We’ve shifted to post-transplant Cytoxan with our haploidentical transplants and also our mismatched unrelated. We’re still sticking with the standard of care that others have been using.

Corey Cutler, MD, MPH, FRCPC: The same holds true at our center. We’re using the calcineurin backbone of tacrolimus and methotrexate for just about all patients without a contraindication who have perfectly matched donors. We certainly use post-transplant cyclophosphamide in higher-risk scenarios. This goes back to the old days of transplants, when 3 drugs were better than 2 drugs at preventing GVHD, but there were excess toxicities when third agents like prednisone were added.

In some sense, what’s old is new again. But there are newer strategies, and we’ve alluded to the progress series of trials from the Blood and Marrow Transplant Clinical Trials Network. One study that has readout suggested that there was no tremendous advantage to cyclophosphamide-based prevention regimens. In 1 setting we’re waiting for the larger progress retrial to read out shortly, but there are other strategies. Yi-Bin, perhaps you can talk briefly about the role of abatacept, which is the most recently approved FDA drug for the prevention of acute graft-vs-host disease.

Yi-Bin Chen, MD: Abatacept is a costimulatory inhibitor. It was approved in the last few months for prevention in the setting of unrelated donor transplants. This is very exciting because it was the first approval for this setting. It gives us encouragement and motivation to continue to develop in this setting. It was combined with standard tacrolimus and methotrexate and studied in unrelated donor transplants. There’s a significant reduction in severe acute graft-vs-host disease. In looking at the study, much of that seemed to be driven by the population of single antigen mismatched unrelated donor transplants. That seemed to make up most of the difference in the benefit, though obviously the trial was studied in the entire population of unrelated donor transplants.

The issue in abatacept also is that the risk of chronic graft-vs-host disease in the long run with the addition of abatacept didn’t seem to differ from our historical experience or with standard tacrolimus and methotrexate. Given that most of us have switched to post-transplant cyclophosphamide for the use of mismatched unrelated donor transplants, we haven’t really used abatacept. There are ongoing trials. We’ll participate in 1 studying the standard course that’s approved vs a longer course of abatacept in the mismatched unrelated donor setting to see if it has a benefit in that patient population and on chronic graft-vs-host disease if we give it longer. That has the potential to move into the world that way.

Corey Cutler, MD, MPH, FRCPC: I agree. It’s the way we’ve been thinking about abatacept. There are other acute GVHD prevention strategies out there. There’s a large vedolizumab trial, which you led, which hasn’t officially read out, so we don’t have results. There are several other novel ways of preventing acute GVHD, which we’ll come back to when we get to looking ahead over the course of this session.

Transcript edited for clarity.