Post-transplant cyclophosphamide (PTCy) is a key strategy to prevent graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). By targeting proliferating alloreactive T cells while preserving immune reconstitution, it enables safer use of haploidentical, unrelated, and mismatched related donors. Its growing use warrants updated evidence on efficacy, safety, and applicability.

To synthesize evidence on PTCy in allo-HSCT, assessing its effects on acute and chronic GVHD, survival, relapse, infection, graft failure, and its performance versus alternative prophylaxis across donor types, conditioning regimens, graft sources, and special populations.

A systematic review was performed following PRISMA guidelines, searching PubMed (2015–2025) with terms on cyclophosphamide, GVHD, allo-HSCT, and systematic reviews/meta-analyses. Inclusion: studies assessing PTCy as GVHD prophylaxis in allo-HSCT and reporting outcomes (GVHD incidence, survival, relapse, infections, graft failure). Eighteen articles met criteria.

Post-transplant cyclophosphamide (PTCy) is a key GVHD prophylaxis in allogeneic HSCT, effective across haploidentical, unrelated, and matched donor settings. In unrelated donor HSCT, PTCy reduced grade II–IV aGVHD (RR = 0.68; HR = 0.63) and grade III–IV aGVHD (RR = 0.32; HR = 0.35) versus ATG, with no significant difference in cGVHD. OS was higher (RR = 1.29; HR = 0.62), PFS improved (HR = 0.76), and NRM lower (RR = 0.67; HR = 0.59) without relapse increase (RR = 0.95). In haploidentical HSCT, PTCy achieved similar aGVHD to ATG but improved OS (HR = 0.70), LFS (HR = 0.66), GRFS (HR = 0.79), and reduced relapse (HR = 0.69). ATG+PTCy further lowered aGVHD (RR ≈ 0.52) and improved OS/GRFS over either alone. Compared to methotrexate, PTCy regimens had lower severe oral mucositis (55.4% vs 83.4%). In aplastic anemia, engraftment reached 97.3%, with reduced aGVHD (12.8% vs ≥ 27.8%), CMV viremia (10.4% vs ≥ 38.6%), and CMV disease (0% vs up to 33%). In pediatric thalassemia, haplo-HSCT achieved OS 92.4%, TFS 84.5%, graft failure 8.1%, TRM 7.4%, with no PTCy vs non-PTCy difference. Haplo-HSCT with PTCy lowered cGVHD risk by ∼50% vs matched sibling donors but had higher NRM; versus unrelated donors, OS was similar but GVHD rates lower. Graft source analysis in haplo-HSCT showed PBSCs lowered relapse (HR = 0.84) and improved engraftment but increased acute/chronic GVHD; bone marrow had lower GVHD rates. Myeloablative conditioning reduced relapse (HR = 0.70) and improved PFS but increased NRM versus RIC, with no OS difference. Overall, PTCy provides robust GVHD control, improved survival, reduced infection rates, and broad applicability, especially in haploidentical HSCT.

This review confirms PTCy as a versatile and effective GVHD prophylaxis in allo-HSCT, improving survival, reducing NRM, and maintaining relapse control across donor types. Outcomes vary with graft source and conditioning, underscoring the need for individualized approaches. Post-transplant cyclophosphamide (PTCy) is an effective and versatile GVHD prophylaxis across donor types in allogeneic HSCT. It consistently reduces acute and chronic GVHD, lowers non-relapse mortality, and improves overall survival without increasing relapse rates. Benefits extend to special populations, such as aplastic anemia and pediatric thalassemia, and can be enhanced when combined with ATG. Graft source and conditioning intensity influence outcomes, allowing tailored approaches.