Graft-Versus-Host Disease Prevention: Corticosteroids Revisited

The morbidity caused by graft-versus-host disease (GVHD) limits the success of allogeneic stem-cell transplantation. For the past two decades, the regimen that was pioneered by the Seattle group that combined a calcineurin inhibitor with methotrexate has been the most widely adopted for the prevention of GVHD. Over the years, numerous trials have been performed to explore alternative regimens in an attempt to improve GVHD control and reduce toxicity related to the agents used to prevent GVHD. Several randomized trials have addressed the addition of corticosteroids to the standard regimen or whether to replace methotrexate with corticosteroids. 1,2 ; however, the results of these trials have been mixed, and the addition of corticosteroids has not been routinely adopted in GVHD prevention regimens. In the article that accompanies this editorial, Chang et al 3 demonstrate a reduction in the incidence of acute and chronic GVHD with the addition of corticosteroids to their GVHD prevention regimen in patients undergoing haploidentical transplantation. This trial provides an opportunity to consider both the opportunities and challenges of this type of trial design to identify new regimens to prevent GVHD and the applicability of these results to other transplantation settings. The clinical trial reported by Chang et al 3 included 228 patients who underwent haploidentical transplantation and that wereaccruedover a17-monthperiodatasingle institution—thisis a remarkable accomplishment in and of itself. The investigators used a previously identified biomarker to stratify patients at a low risk or a high risk of developing GVHD. Patients with either . 1.9 3 10 6 /kg CD56bright natural-killer cells or a high CD4:CD8 ratio of . 1.16 in bone marrow grafts were allocated to the highrisk group. By using these criteria, the this study compared three groups: those at a low risk of developing GVHD who received the standard GVHD prevention regimen, and those at a high risk who were randomly assigned to receive either the standard GVHD prevention regimen or corticosteroids in addition to the standard regimen. The incidence of acute and chronic GVHD was compared among the three groups. Additional comparisons include treatmentrelated mortality, risk of relapse, and overall survival. The identification of a validated biomarker for the prediction of risk of developing acute GVHD or for the prediction of GVHD severity would be advantageous in several respects. 4 If the biomarker used peri-transplant data to identify patients who are at an increased risk of developing GVHD, as in the trial by Chang et al 3 in which the biomarker was based on the infused cellular product, this would allow the GVHD prevention regimen to be altered to help reduce the risk of GVHD. Chang et al used his is the approach by adding corticosteroids to the treatment regimen of patients at a high risk of developing GVHD. One advantage of this approach is that it spares those patients with a low risk of developing GVHD from being exposed to additional immunosuppressive agents. Stratification by using a biomarker allows a clinical trial to be more efficient by targeting the high-risk group, thereby reducing the total number of patients who need to be accrued to a trial. Alternatively, a biomarker used in the analysis of posttransplant parameters, such as elevated cytokines, inflammatory markers, or specific immunologic T-cell profiles, would allow for the identification of patients who may benefit from pre-emptive treatment with GVHD therapy. It may also help to direct the intensity of therapy that is used to treat patients with GVHD when it is predicted to be severe. A recently published study that used this approach validated three biomarkers (TNFR1, ST2, and Reg3a). Patients with a high Ann Arbor GVHD score are candidates for intensive therapy, whereas those with lower scores are candidates for less-intensive therapy. 5