Historically, the combination of a calcineurin inhibitor and methotrexate has been the standard prevention strategy for GVHD after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This preventive strategy works best with SCT from the bone marrow of related and human leukocyte antigen–matched donors. However, peripheral blood stem cells are currently more commonly used as the source, and the donor may not be related.

In recent decades, there have been continual efforts to improve on existing GVHD prevention strategies, and recognition of the importance of cGVHD has grown. Relapse-free survival after allo-HSCT is key, but we cannot neglect GVHD, and, today, a composite end point is used in GVHD prevention trials: GVHD-free, relapse-free survival (GRFS).

When we think about GVHD prevention, we must focus on the fact that one size does not fit all. For example, pretransplant antithymocyte globulin (ATG) is one of the preventive strategies in use, and there is evidence to suggest that we should not be using a one-size-fits-all dosing approach. A concern with ATG is that it can inhibit immune reconstitution, leading to infection, undermining the benefits of GVHD prevention. A recent retrospective analysis by Butera et al suggested that lower dosing of ATG might be appropriate in some cases. Thus, more work is needed in this area, and, in my view, post-transplant ATG should be explored further, as recent studies indicate that it may have a significant effect on patient outcomes.

We are all very excited about post-transplant cyclophosphamide, which is emerging as a potentially effective GVHD prevention strategy in mismatched-related and -unrelated donor transplants. There are several clinical trials of interest in this area.

In the setting of nonmyeloablative/reduced-intensity conditioning with peripheral blood SCT, a phase 2 study from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 1203) randomized patients to the following 3 different prophylaxis regimens: tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc. Of these, tacrolimus, mycophenolate mofetil, and post-transplant cyclophosphamide was the most promising intervention and is being explored prospectively in the phase 3 randomized PROGRESS III trial from the BMT CTN (BMT CTN 1703). In the myeloablative setting, the prospective, randomized, phase 3 BMT CTN 1301 trial evaluated 2 T-cell depletion approaches (CD34-selected peripheral blood SCT without post-transplant immune suppression and post-transplant cyclophosphamide after bone marrow SCT without additional immune suppression), with tacrolimus plus methotrexate after bone marrow SCT as the control. The primary end point of this study was cGVHD-free relapse-free survival (CRFS).. Luznik et al concluded that all 3 strategies resulted in acceptable outcomes; there was no difference in CRFS across treatment arms. However, patients receiving CD34-selected grafts had lower overall survival driven by transplant-related mortality, which offset any benefit from lower cGVHD. Post-transplant cyclophosphamide alone with bone marrow SCT did not reduce the rate of acute GVHD or cGVHD compared with tacrolimus plus methotrexate with a bone marrow graft.