A Network Meta-Analysis of Randomized Trials to Determine Optimal GVHD Prophylaxis in Matched Sibling Donor...

Post-transplant cyclophosphamide (PTCy), originally developed for haploidentical transplantation, has recently demonstrated efficacy in matched donor transplantation in randomized trials. Anti-thymocyte globulin (ATG) is also an established graft-versus-host disease (GVHD) prophylaxis strategy in matched donor transplantation. However, no prospective randomized trial has directly compared PTCy- and ATG-based approaches in the matched sibling donor (MSD) setting. To evaluate the comparative effectiveness of PTCy-based, ATG-based, and conventional calcineurin inhibitor (CNI)-based GVHD prophylaxis strategies in MSD transplantation, including an indirect comparison between PTCy- and ATG-based approaches. We performed a prospectively registered systematic review and network meta-analysis (PROSPERO registration 1290948) of prospective randomized trials evaluating GVHD prophylaxis in MSD transplantation. Six trials including 860 MSD transplant recipients were identified, with three studies evaluating PTCy-based prophylaxis and three evaluating ATG-based prophylaxis, each against conventional CNI-based regimens. Direct pooled comparisons and Bucher-adjusted indirect comparisons were performed. In an exploratory sensitivity analysis, reconstructed individual patient data from published survival and cumulative incidence curves were pooled to assess longer-term time-to-event outcomes. In pooled direct comparisons versus conventional prophylaxis, both strategies improved GVHD-related outcomes, although with distinct clinical profiles. PTCy was associated with a greater reduction in grade III-IV acute GVHD (risk ratio [RR], 0.36; 95% confidence interval [CI], 0.16-0.81; P = .014) and improved GVHD-free, relapse-free survival (GRFS) (RR, 0.68; 95% CI, 0.56-0.82; P = .001). ATG was associated with greater reductions in chronic GVHD of any severity (RR, 0.48; 95% CI, 0.39-0.59; P < .001) and moderate-to-severe chronic GVHD (RR, 0.28; 95% CI, 0.17-0.44; P < .001). In indirect comparison, no significant differences were observed between PTCy and ATG for GRFS (RR, 0.88; 95% CI, 0.70-1.11; P = .29), overall survival (RR, 0.65; 95% CI, 0.40-1.05; P = .077), disease-free survival, relapse, or nonrelapse mortality. Reconstructed pooled time-to-event analyses confirmed broadly comparable outcomes, with similar 24-month GRFS, overall survival, relapse, and nonrelapse mortality across the two strategies. Neutrophil engraftment was 100% with ATG but lower with PTCy (91.4%; 95% CI, 87.6-94.2%). Based on currently available prospective randomized evidence, both PTCy- and ATG-based prophylaxis represent effective alternatives to conventional CNI-based prophylaxis in MSD transplantation. Although their overall clinical benefit appears broadly comparable, they show complementary profiles in GVHD prevention, with PTCy favoring reduction of severe acute GVHD and ATG favoring reduction of chronic GVHD.