Impact of conditioning intensity on outcomes after unrelated donor hematopoietic cell transplantation using posttransplant cyclophosphamide-based GVHD prophylaxis

Abstract Background: Reduced-intensity or non-myeloablative (RIC/NMA) conditioning is commonly used in allogeneic hematopoietic cell transplantation (allo-HCT) to reduce toxicity in older or comorbid patients. However, its impact on transplant outcomes remains uncertain in the setting of unrelated donor HCT with posttransplant cyclophosphamide (PTCy)-based GVHD prophylaxis. This study aimed to evaluate impact of conditioning intensity on unrelated donor allo-HCT recipients receiving PTCy-based GVHD prophylaxis. Methods: We conducted a retrospective cohort study of patients who underwent unrelated donor allo-HCT (2017-2021) with PTCy-based GVHD using the publicly available P-598 dataset from the Center for International Blood and Marrow Transplant Research (CIBMTR). Patients were categorized by conditioning intensity. Outcomes included overall survival (OS), disease-free survival (DFS), non-relapse mortality (NRM), relapse, grade II–IV and III–IV acute GVHD (aGVHD), moderate/severe chronic GVHD (cGVHD), and GVHD-free relapse-free survival (GRFS). Median follow-up was estimated using the reverse Kaplan-Meier method. Univariable and multivariable Cox proportional hazards models were used to assess associations between graft source and outcomes, adjusting for variables with p < 0.2 in univariable analyses or known clinical relevance. Hazard ratios (HRs) and 95% confidence intervals (CIs) were reported. Statistical significance was defined as p < 0.05. Results: A total of 2,132 adult patients underwent unrelated donor allo-HCT with PTCy-based GVHD prophylaxis. The median age was 61 years (IQR 49–68), and 55.9% were male. The underlying conditions were AML (54.6%), MDS (29.2%), and ALL (16.2%). Most patients received peripheral blood grafts (90%) and RIC/NMA conditioning (60.7%). The majority were in CR1 (52.6%) and received 8/8 HLA-matched grafts (73.8%). The median follow-up was 35.1 months. Median GRFS was 22.9 months (95% CI: 19.2–31.0) overall, 16.1 months (95% CI: 12.1–20.3) in the RIC/NMA group, and not reached in the myeloablative group. Median OS and DFS were not reached in either group. In univariable analysis, RIC/NMA conditioning was associated with higher relapse (HR 1.36; p = 0.007), worse DFS (HR 1.29; p = 0.003), NRM (HR 1.29; p = 0.039), and GRFS (HR 1.16; p = 0.045), but lower grade II–IV aGVHD (HR 0.66; p < 0.001). In multivariable analysis, RIC/NMA conditioning remained independently associated with increased relapse (HR 1.25, 95% CI 1.00–1.57; p = 0.045), worse DFS (HR 1.20, 95% CI 1.01–1.44; p = 0.043), and lower grade II–IV aGVHD (HR 0.72, 95% CI 0.59–0.88; p = 0.001). The associations with NRM (HR 1.00, 95% CI 0.75–1.32; p = 0.979), OS (HR 1.07, 95% CI 0.91–1.25; p = 0.436), and GRFS (HR 1.06, 95% CI 0.92–1.23; p = 0.413) were not statistically significant. Recipient age ≥66 was associated with higher NRM (HR, 2.86; 95% CI, 1.49–5.49; p = 0.002), worse OS (HRs, 1.57–1.85; p < 0.01), GRFS, and increased cGVHD (HR, 3.54; 95% CI, 1.45–8.63; p = 0.006). HCT-CI ≥3 predicted inferior OS (HR 1.60, 95% CI 1.36–1.88; p < 0.0001), DFS (HR 1.52, 95% CI 1.30–1.79; p < 0.0001), relapse (HR 1.34, 95% CI 1.03–1.73; p = 0.027), NRM (HR 1.84, 95% CI 1.29–2.64; p = 0.001), and GRFS (HR 1.44, 95% CI 1.25–1.66; p < 0.0001). Karnofsky <90 was associated with worse OS (HR 1.30, 95% CI 1.12–1.51; p = 0.001), NRM (HR 1.54, 95% CI 1.12–2.12; p = 0.007), and GRFS (HR 1.23, 95% CI 1.08–1.41; p = 0.003). Compared to AML, MDS was linked to higher NRM (HR 1.35, 95% CI 1.06–1.72; p = 0.014) and inferior GRFS (HR 1.16, 95% CI 1.01–1.34; p = 0.040), while ALL had lower relapse (HR 0.68, 95% CI 0.51–0.90; p = 0.010) but higher NRM (HR 1.64, 95% CI 1.20–2.25; p = 0.002). Donor age ≥45 was associated with reduced relapse (HR 0.61, 95% CI 0.40–0.94; p = 0.027) but increased cGVHD (HR 2.22, 95% CI 1.38–3.55; p = 0.001). Use of 7/8 HLA-matched donors increased grade III–IV aGVHD (HR 1.47, 95% CI 1.02–2.11; p = 0.039) and cGVHD (HR 1.57, 95% CI 1.19–2.07; p = 0.001). No significant associations were observed for graft source, GVHD prophylaxis regimen, CMV status, sex, race, or ethnicity.Conclusion: In unrelated donor allo-HCT with PTCy-based GVHD prophylaxis, RIC/NMA conditioning increased relapse and worsened DFS but reduced grade II–IV aGVHD. OS, NRM, and GRFS were unaffected. Outcomes were more influenced by age, comorbidities, performance status, and disease type, highlighting the need for individualized conditioning decisions.