Low-Dose Post-Transplant Cyclophosphamide in Haploidentical Stem Cell Transplantation: A Systematic Review

Haploidentical allogeneic stem cell transplants (ASCT) has transformed the treatment landscape for patients with life-threating hematologic disorders who lack matched donors. Post-transplant cyclophosphamide (PTCy) at 50 mg/kg at days +3 and +4 is established as one of the standard regimens for graft-versus-host disease (GvHD) prophylaxis. Studies on whether reducing the dose of PTCy can reduce toxicity while maintaining efficacy suffer from significant heterogeneity and lack a robust synthesis of available data. We conducted a systematic review to investigate the hypothesis that low-dose PTCy in haploidentical ASCT can offer comparable or superior outcomes than the standard, 100 mg/kg dose with regards to acute and chronic GvHD incidence, survival, and toxicity. This review had a preregistered protocol on PROSPERO (CRD420250650291) and followed PRISMA guidelines. Relevant literature across multiple databases was searched from inception until 2025. We included retrospective and prospective observational studies and clinical trials of patients receiving haploidentical ASCT and low-dose PTCy that reported acute/chronic GvHD incidence, overall survival (OS), relapse-free survival (RFS), hemorrhagic cystitis, infections, or immune reconstitution. ROBINS-I was used to assess risk-of-bias for observational studies and Cochrane RoB 2.0 for randomized studies. Study heterogeneity and a paucity of randomized studies precluded a meta-analysis of treatment efficacy. RESULTS: After screening 4065 studies, 33 studies published encompassing over 2500 patients were included. There were 31 observational and two randomized controlled trials (RCTs). The lower dose of PTCy ranged from 29 to 80 mg/kg and was often combined with antithymocyte globulin (ATG). Most studies showed lower or comparable rates of acute GvHD with low-dose PTCy compared to controls. Differences in rates of chronic GvHD between different doses of PTCy were not statistically significant in most studies. One RCT showed significant reductions in rates of acute and chronic GvHD, treatment toxicity, OS and RFS, while the other showed no significant differences in these outcomes and was halted prematurely for futility. Most observational studies (87%) had either serious or critical risk of bias, mainly due to residual confounding. Both randomized studies had low concerns of bias. Lower doses of PTCy may be comparable or superior for acute GvHD prevention than the standard 100 mg/kg dose. Protection against chronic GvHD is more variable. Trials report conflicting outcomes on toxicity reductions. Heterogeneity, bias, and a paucity of RCTs limit definitive conclusions. A consensus on what defines a low dose of PTCy is needed. Studies identifying patient subgroups that benefit from PTCy dose de-escalation may optimize GvHD prophylaxis.