The Role of Prophylaxis Regimens for GVHD
Yi-Bin Chen, MD, reviews factors affecting treatment selection among available pharmacological and ex vivo prophylaxis approaches for GVHD.
Transcript:
John F. DiPersio, MD, PhD: I wonder, Yi-Bin, if you could just briefly review some of the standard prophylaxis regimens now and how they impact both acute and chronic graft versus host disease?
Yi-Bin Chen, MD: It's a big topic. I'll try my best. There are 2 general categories of GVHD [graft versus host disease] prevention. One is far more popular than the other, and that's pharmacologically based, meaning just drugs from pharmacies. Then, 2 is ex vivo manipulation of the graft: either positive selection of certain subsets or negative selection of certain subsets like T cells and so forth. Those are the 2 main categories of prophylaxis. The vast majority of us use pharmacological prophylaxis just because it's less expensive and easier to do and requires less resources and lab expertise. In terms of pharmacological prophylaxis, the long standard has been calcineurin inhibitor-based prevention, calcineurin inhibitor being either cyclosporine or tacrolimus. That's been paired with short-course methotrexate posttransplant is the classic regimen. There have been alternatives to that involving pairing it with mycophenolate or with sirolimus or adding those with methotrexate as alternatives. As Dr DiPersio mentioned, many centers, especially in Europe, use the addition of anti–T-cell globulins on top of a calcineurin inhibitor-based backbone, specifically to prevent chronic graft versus host disease. There's a specific approval actually for anti–T-cell lymphocyte globulin in Europe, but not in the United States. With calcineurin inhibitor-based prevention, we generally think the risk of significant acute GVHD is somewhere between 25% and 40% depending on your patient population, and the risk of significant chronic graft versus host disease is probably 40% to 50%, again, depending upon certain specifics of your patient population.
The newest regimen that's emerging that has been already mentioned is post-transplant cyclophosphamide. That's the use of giving an unmanipulated graft without immunosuppression and allowing certain alloreactivity to happen and then, coming in days 3 and 4 after transplant and giving 2 daily doses of high-dose cyclophosphamide. The initial teaching was that that was very specifically cytotoxic to activated T cells that happened during that period of alloreactivity. I think more modern understanding is that it spares stem cells and regulatory T cells, and that plays a big role in being able to prevent graft versus host disease. Posttransplant cyclophosphamide is generally paired with tacrolimus and mycophenolate starting on day 5. There have been some regimens using sirolimus in place of tacrolimus as well. Those are the 2 modern backbones of pharmacological prophylaxis, be it either calcineurin inhibitor-based or posttransplant cyclophosphamide-based. These are 2 regimens that are being compared in ongoing prospective trials with interesting end points to try and figure out what should be the standard of care. I think there are pros and cons of each. It appears that posttransplant cyclophosphamide regimens do prevent chronic graft versus host disease better as Dr DiPersio mentioned, but we have yet to figure out if long-term outcomes balancing everything are more superior, and hopefully the ongoing prospective trials will be able to figure this out. I think the newer agents are all being developed to add upon these different regimens to see if we could augment prevention of either acute or chronic conditions yet preserve relatively low relapse rates and relatively low risks of nonrelapse mortality.
John F. DiPersio, MD, PhD: That's great. Hannah, I wonder if you feel comfortable discussing maybe the role of abatacept as prophylaxis?
Hannah Choe, MD: I'm not as familiar with abatacept. When we saw the FDA approval for abatacept here, like we were mentioning before, it certainly shows some improvement, but again, the long-term survival benefit, I'm not sure that we're going to see pan out. Again, we're not using it as standard here yet, but it is nice to have an FDA approval for prophylaxis as an option.
John F. DiPersio, MD, PhD: I thought the interesting thing too in that study was that as we mentioned earlier, the rates of severe acute GVHD were slightly lower. Lower grades of acute GVHD weren't that much different. The biggest change, I thought, was the early infectious-related complications and death, which I thought was kind of interesting. Obviously, the mechanism of how abatacept works as a tolerance-inducing agent is completely different than anything else, so it'll be interesting to see if it lasts and stays in our armamentarium or kind of fades away like some things do or whether we start to complement it by adding other things on top of it to see if we can actually improve the outcomes so I'm excited about that potential.
Pashna N. Munshi, MD: Additionally, as well, if you look at how it came to approval and based on the design of the trial, the GVHD-1 [clinical trial (NCT 01743131)] was using it in the 8 out of 8, if you will match to unrelated donors more in a prospective way. But the other arm looked at it using retrospective data from the CIBMTR [Center for International Blood and Marrow Transplant Research] in the mismatched setting. I don't know, it's a bit of a mixture.
John F. DiPersio, MD, PhD: My mother told me, believe nothing of what you hear and only half of what you see. I think we have to really validate this with not only maybe other studies but just in general practice to see our sense of how it works.
Transcript edited for clarity.
