Impact of Modern Strategies for Graft‐Versus‐Host Disease Prophylaxis on Relapse Risk in Matched‐Sibling or Unrelated Donor Hematopoietic Cell Transplantation: A Systematic Review and Meta‐Analysis of Randomized Trials

ABSTRACT Regimens combining calcineurin inhibitors with methotrexate or mycophenolate have been the backbone for graft‐versus‐host disease (GVHD) prophylaxis. Early studies highlighted a delicate dose–response balance. The inclusion criteria comprised randomized clinical trials of patients with hematologic malignancies undergoing sibling‐ or unrelated‐donor transplants, adding a pharmacologic immunosuppressive agent to standard GVHD prophylaxis. This meta‐analysis examined the impact of intensified GVHD prophylaxis strategies on relapse risk and included 16 randomized controlled trials among 26 eligible studies, with 1344 patients in the intervention group and 1260 in the control group. Few mismatched donors or children were included. The studies evaluated additions such as anti‐thymocyte/lymphocyte globulin (ATG, ATLG), posttransplant cyclophosphamide (PTCy), sirolimus, abatacept, and alemtuzumab. Results showed no significant effect on relapse risk or progression‐free survival overall, with HR = 1.12 ( p = 0.16) for relapse and HR = 0.92 ( p = 0.16) for progression‐free survival. Sensitivity analysis identified one outlier study using alemtuzumab that reported higher relapse and indicated a modest increased risk with ATLG. The findings suggest that adding agents like ATG, sirolimus, abatacept, or PTCy does not increase relapse risk in matched sibling or unrelated transplants. While caution is advised with ATLG and alemtuzumab, the overall evidence supports the safety of modern prophylactic strategies, potentially improving transplant outcomes without compromising relapse risk.