Enhancing graft-versus-host disease prophylaxis with modern strategies in matched-sibling or unrelated donor hematopoietic cell transplantation does not lead to higher relapse rates: A systematic review and meta-analysis of 15 randomized trials

Abstract

Abstract Introduction: Effective graft-versus-host disease (GVHD) prophylaxis is a crucial part of hematopoietic cell transplantation (HCT). Pession et al (PMID 9630326) have shown in a randomized trial that a higher dose of cyclosporine may be associated with increased relapse rates. However, Couriel et al (DOI 10.1182/blood.v106.11.142.142) suggested in a phase II/III trial that there may be an optimal tacrolimus level, and lower levels can lead to higher rates of acute GVHD, immunosuppression, and relapse. Broers et al (PMID 39665067) demonstrated that time-restricted versus standard-duration immunosuppression does not reduce relapses. Since the introduction of newer and more effective GVHD prophylactic regimens, this issue has not been revisited. Methods: This meta-analysis of randomized controlled trials published from 2013 to 2025 was registered at PROSPERO under CRD42024560191. The review question was: Does more effective GVHD prophylaxis with immunosuppressive agents lead to a higher relapse rate compared with conventional GVHD prophylaxis in patients who underwent HCT from matched sibling donors or unrelated donors? Inclusion criteria were randomized clinical trials in hematologic malignancies with allogeneic sibling or unrelated donor HCT that added an immunosuppressive agent to a conventional GVHD prophylaxis backbone and had positive results for GVHD prophylaxis. We excluded studies comparing two widely different strategies. Gray literature was not included. Screening, full-text selection, and data extraction were performed independently by 2 reviewers. We searched PubMed and CENTRAL. We used fixed-effect models. Primary outcomes were the hazard ratio (HR) and risk difference (RD) for relapse; secondary, progression-free survival (PFS). If not reported, HR and SE were estimated by the cumulative incidence curves. Leave-one-out method, funnel plots, and risk of bias tool were the main assessments of bias. All analyses were conducted in R, v4.3.2. Results: A total of 2,841 were screened, 49 were selected for full-text review, and 15 were included in the final analysis. Ten studies reported HR and 95%CI, while in five studies, the HR was estimated. All studies provided relapse incidence rates and 95%CI. Five studies tested the addition of ATG; three, ATLG; three, PTCy; two, sirolimus; one each, abatacept or alemtuzumab. A total of 1,380 and 1,283 patients were included in the intervention and control arms, respectively. HR for relapse was 1.11 (95%CI 0.95-1.31, p=0.20, I2 =19%). RD for relapse showed a non-significant +3% risk in relapse (95%CI -0.19 to +6.27, p=0.07, I2 =34%). Results for PFS were not different. The funnel plots for HR and RD indicated that the only study that tested high-dose alemtuzumab had divergent results. The leave-one-out methods showed that omitting this study from the analyses reduced the I2 to nearly 0% (given the low weight, only minor changes in the results were observed). A meta-regression found no effect of graft source, conditioning, or donor type on the results. Discussion: This meta-analysis of randomized trials involving matched-sibling and unrelated donors demonstrates that modern, more effective GVHD prophylaxis does not increase the relapse rate. Although almost every study followed an expected distribution, the only study that tested alemtuzumab diverged (HR=2.60, RD +31%). We don't feel comfortable extrapolating our results to alemtuzumab. Future studies should focus on estimating the relapse risk with alemtuzumab and on strategies to prevent relapse. Our study has several limitations. We excluded gray literature because it is unlikely that a positive randomized study would go unpublished in peer-reviewed journals. Also, some studies from the gray literature were later published under different titles, authors, and author orders. Including only positive results for GVHD prevention was a methodological choice. Our alternative hypothesis was that there would be a trade-off between better GVHD prevention and higher relapse rates, and including negative studies could mask this association. In summary, we have shown that modern and more effective GVHD prophylaxis, using ATG, ATLG, sirolimus, abatacept, or PTCy, does not lead to higher relapse rates. Modern GVHD prophylaxis should not be withheld from patients undergoing matched-sibling or unrelated transplants. Acknowledgements: The authors declare no conflict of interest. This study received no external funding.