Outcomes after unrelated donor allogeneic hematopoietic cell transplantation in age ≥65 using post-transplant cyclophosphamide.

6560 Background: The use of allogeneic hematopoietic cell transplantation (allo-HCT) in older adults has increased with reduced-intensity conditioning and post-transplant cyclophosphamide (PTCy) based GVHD prophylaxis. While PTCy has demonstrated excellent GVHD control across multiple disease types, age-related toxicities and non-relapse mortality remain significant challenges in older patients with acute leukemia and myelodysplastic syndrome (MDS). Understanding age-associated risks in contemporary unrelated donor (URD) HCT platforms may help guide patient selection, counseling, and future refinements in transplant practice. Methods: We analyzed adults undergoing first URD allo-HCT (8/8 or 7/8 HLA-matched) with PTCy-based GVHD prophylaxis for acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome reported to CIBMTR, 2017–2021, using the P-5891 dataset. Patients were grouped into <65 and ≥65 years. Outcomes included overall survival (OS), non-relapse mortality (NRM), relapse, acute GVHD, and chronic GVHD. Univariable and multivariable Cox proportional hazards or Fine-Gray competing risks models were used as appropriate. Variables with p < 0.2 in univariable analysis and clinically relevant factors were included in multivariable models. Results: Of 2,271 patients, 849 (37%) were ≥65 years. Older patients were more frequently treated with reduced-intensity or non-myeloablative conditioning, had a Hematopoietic Cell Transplantation–Comorbidity Index (HCT-CI) ≥3, and had a Karnofsky Performance Status (KPS) <90. On multivariable analysis, age ≥65 was associated with significantly inferior OS (HR 1.20, 95% CI 1.02-1.40, p=0.029), with 3-year OS of 52.1% vs 63.4% (log-rank p<0.001). Other independent predictors of worse OS included reduced-intensity conditioning, higher disease risk index, KPS <90, and HCT-CI ≥3; graft source was not significant. Competing-risk analyses showed significantly higher NRM in ≥65 years (3-year cumulative incidence 22.7% vs 13.6%; HR 1.56, 95% CI 1.21–2.01, p<0.001), which was the primary driver of inferior survival. Importantly, relapse incidence was similar (HR 0.90, p=0.249), and no differences were found in GVHD rates: grade II–IV acute GVHD (HR 0.98, 95% CI 0.81–1.17, p=0.785), grade III-IV acute GVHD (HR 0.91, 95% CI 0.64-1.30, p=0.600), or moderate-to-severe chronic GVHD (HR 0.90, 95% CI 0.68-1.20, p=0.467). Conclusions: In patients undergoing unrelated donor HCT with PTCy-based GVHD prophylaxis for acute leukemia or MDS, those aged ≥65 years had significantly lower overall survival and higher non-relapse mortality compared to younger patients, with similar relapse and GVHD rates. These findings suggest the need to optimize the PTCy-based prophylaxis platform, such as reduced PTCy dosing with the addition of novel agents, in patients with advanced age.