Reduced Cumulative Post-Transplant Cyclophosphamide Exposure Is Associated with Increased Acute and Chronic Graft-versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation.

BACKGROUND: Post-transplant cyclophosphamide (PTCy) is conventionally administered at a cumulative dose of 100 mg/kg for graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic cell transplantation (allo-HCT). In clinical practice, cumulative PTCy exposure may be reduced because of institutional protocols, physician-directed dose modifications, or body weight-adjusted dosing strategies. However, the clinical consequences of receiving cumulative PTCy doses below the standard 100 mg/kg remain poorly defined. METHODS: We retrospectively evaluated 251 consecutive allo-HCT recipients transplanted between 2015 and 2025. Among them, 180 patients receiving PTCy-based GVHD prophylaxis were stratified according to cumulative PTCy exposure (<100 vs. ≥100 mg/kg), irrespective of the reason for dose reduction. Acute GVHD, chronic GVHD, relapse, non-relapse mortality (NRM), and overall survival (OS) were analyzed using logistic regression, Cox proportional hazards models, and competing-risk methods. RESULTS: Among the 180 PTCy recipients, 71 received <100 mg/kg and 109 received ≥100 mg/kg; the median cumulative dose in the reduced-exposure group was approximately 80 mg/kg. Reduced cumulative PTCy exposure (<100 mg/kg) was associated with a significantly increased incidence of acute GVHD compared with standard exposure (57.7% vs. 37.0%; OR 2.31, 95% CI 1.21-4.49; p=0.009). Patients receiving <100 mg/kg also experienced a higher burden of clinically significant GVHD, including grade II-IV acute GVHD (25.4% vs. 12.8%; OR 2.30, 95% CI 1.07-5.08; p=0.035), moderate-to-severe chronic GVHD (21.1% vs. 7.3%; OR 3.48, 95% CI 1.29-10.12; p=0.010), and greater use of second-line GVHD-directed therapy with ruxolitinib and/or extracorporeal photopheresis (34.4% vs. 19.8%; OR 2.12, 95% CI 1.05-4.31; p=0.036). In multivariable analyses, reduced cumulative PTCy exposure remained independently associated with acute GVHD (OR 2.29, 95% CI 1.18-4.53; p=0.016) and moderate-to-severe chronic GVHD (OR 4.07, 95% CI 1.52-11.63; p=0.005). Competing-risk analysis confirmed a higher cumulative incidence of acute GVHD (SHR 1.83, 95% CI 1.18-2.83; p=0.007). No significant differences were observed in relapse, non-relapse mortality, or overall survival. CONCLUSIONS: In this cohort, cumulative PTCy exposure below 100 mg/kg was associated with increased acute GVHD, a greater burden of clinically significant chronic GVHD, and increased use of second-line GVHD-directed therapies, without significant differences in relapse, non-relapse mortality, or overall survival. These findings suggest that effective GVHD prophylaxis with PTCy may depend on achieving adequate cumulative drug exposure and support prospective studies to define the optimal cumulative PTCy dose for GVHD prophylaxis.