Updates in the Management of Graft-Versus-Host Disease - Episode 5
Corey S. Cutler, MD, MPH, FRCPC: Dr Antin, please share your thoughts on other special situations, such as haploidentical transplantation, cord blood transplantation, and severely mismatched donors?
Joseph H. Antin, MD: I completely agree with Zach [DeFilipp’s]’s comments. We use a similar set of regimens at Brigham [and Women’s Hospital]. When you start to get into donors who are not histocompatible, a haploidentical donor is a one who is half-matched, typically a parent to a child or a child to a parent or between 2 siblings who are matched at only half their HLA genes. You can anticipate a lot more in the way of difficulties. We’ve tried to do this since the 1980s, and it was almost uniformly catastrophic because crossing that HLA barrier was a problem. A number of regimens were developed—1 in Italy that never really caught on, 1 in China that has actually been quite effective, but it is so complex and intensive in chemotherapy that it never caught on the United States. What we have immediately and uniformly adopted is the use of PTCy or post-transplant cyclophosphamide. The notion of course is when you infuse the donor’s product, either peripheral blood or bone marrow, the immune cells of course come in contact with both HLA antigens in the case of a haploidentical transplant and minor histocompatibility antigens for which we don’t type. Zach alluded to this in terms of the man-woman disparity, and those T cells that are capable of recognizing those antigens will become activated and start to divide. The strategy here is to give them that opportunity to divide and then use the cell cycle activation, such as cyclophosphamide, to blast them when they’re in this growth phase. Typically, the post-transplant cyclophosphamide is administered on day 3 and 4 after the transplant when these cells have had the opportunity to get going, but before they’ve achieved enough of a critical mass to target organ injury. Then a large dose of cyclophosphamide is given twice, usually day 3 and 4. This is on the order of 50 mg/kg per day. Subsequently a calcineurin inhibitor or an mTOR inhibitor—so tacrolimus or sirolimus—is given often in association with mycophenolate mofetil to keep those cells down. One critical feature of this particular regimen and 1 of the tricks that makes this work is 2-fold. One is that it doesn’t kill stem cells. We’re not talking about autologous transplantation, but 1 of the ways you mobilize stem cells for autologous transplantation is by giving a dose of cyclophosphamide and then collecting the cells on the recovery phase. It’s not a stem cell toxin because it has aldehyde dehydrogenase that deactivates cyclophosphamide, whereas committed cells do not. That’s why your counts go down, but your counts ultimately recover because the stem cells are spared. Fortunately, in addition to stem cells, a subset of T cells called T regulatory cells has the same set of enzymes. T regs are ones that are counterinflammatory. In all inflammatory processes, you have to have something that generates inflammation and something that inhibits inflammation, or else we would all look like 1 giant lymph node every time we got infected. T regs slow things down. You not only kill the activated T cells that are likely to generate graft-vs-host disease but also allow the regulatory T cells to persist, and therefore both prevent graft rejection because they will inhibit any chemotherapy-resistant cells left in the host and prevent graft-vs-host disease. A number of other regimens are more investigational right now, including drugs like abatacept, which is a checkpoint blockade inhibitor that can be in graft-vs-host disease. It has not achieved widespread use, but there are a number of regimens that are currently under investigation.
Transcript Edited for Clarity