Factors associated with acute and chronic graft-versus-host disease after unrelated donor hematopoietic cell transplantation using posttransplant cyclophosphamide-based GVHD prophylaxis

Abstract Background: Graft-versus-host disease (GVHD) is a significant complication of allogeneic hematopoietic cell transplantation (allo-HCT), contributing to post-transplant morbidity and mortality. We aimed to evaluate clinical predictors of acute and chronic GVHD in recipients of unrelated donor HCT with posttransplant cyclophosphamide (PTCy)-based GVHD prophylaxis. Methods: This retrospective cohort study utilized data from the Center for International Blood and Marrow Transplant Research (CIBMTR) dataset P5891 (Shaffer et al.), which included adult recipients of first unrelated donor allo-HCT between 2017 and 2021. Multivariable logistic regression was used to identify independent predictors of grade II–IV acute graft-versus-host disease (aGVHD II-IV), grade III–IV aGVHD, and moderate to severe chronic GVHD (cGVHD). Results are reported as odds ratios (ORs) with 95% confidence intervals (CIs) and p-values. Analyses were conducted using Stata version 18, with p < 0.05 considered statistically significant. Results: A total of 2,132 patients were included. The median age was 61 years (IQR, 49–68), and 55.9% of the participants were male. Underlying diagnoses included acute myeloid leukemia (AML, 54.6%), myelodysplastic syndromes (MDS, 29.2%), and acute lymphoblastic leukemia (ALL, 16.2%). Peripheral blood stem cells were used in 90% of patients, and 60.7% received reduced-intensity or nonmyeloablative (RIC/NMA) conditioning. HCT-CI was ≥3 in 53.4%, and 47.3% had Karnofsky performance score <90. For grade II–IV aGVHD, use of peripheral blood grafts (OR 1.42, 95% CI: 1.02–1.96, p = 0.038) and 7/8 HLA-matched donors (OR 1.43, 95% CI: 1.11–1.83, p = 0.005) were associated with increased risk, while RIC/NMA conditioning was protective (OR 0.68, 95% CI: 0.56–0.84, p < 0.001). For grade III–IV aGVHD, increased risk was observed with PBSC grafts (OR 1.62, 95% CI: 1.01–2.60, p = 0.045) and 7/8 HLA-matched donors (OR 1.42, 95% CI: 1.02–1.97, p = 0.037). RIC/NMA conditioning remained protective (OR 0.71, 95% CI: 0.55–0.92, p = 0.010). For moderate/severe cGVHD, donor age ≥45 years (OR 1.54, 95% CI: 1.19–2.00, p = 0.001), PBSC grafts (OR 1.46, 95% CI: 1.01–2.11, p = 0.043), and 7/8 HLA-matched donors (OR 1.46, 95% CI: 1.11–1.92, p = 0.007) were significantly associated with increased risk. Compared to AML, ALL was associated with a lower risk of cGVHD (OR, 0.64; 95% CI, 0.44–0.93; p = 0.020). Recipient age, sex, race, ethnicity, GVHD prophylaxis regimen, CMV serostatus, Karnofsky score, HCT-CI, conditioning intensity (for cGVHD), and donor-recipient sex or CMV mismatch were not independently associated with the risk of acute or chronic GVHD in multivariable models.Conclusion: In unrelated donor allo-HCT recipients receiving PTCy-based GVHD prophylaxis, use of PBSC grafts, HLA mismatch, and older donor age were consistently associated with higher risk of both acute and chronic GVHD. RIC/NMA conditioning was protective against acute GVHD but not chronic GVHD. These findings support the importance of graft selection, donor matching, and individualized GVHD risk stratification.