Younger donors, better outcomes: The impact of donor age in haploidentical transplantation for acute myeloid leukemia. study conducted on behalf of geth-TC

Abstract INTRODUCTION Haploidentical hematopoietic cell transplantation (haplo-HCT) using post-transplant cyclophosphamide (PTCy)-based prophylaxis has emerged as a safe and effective alternative for patients with acute myeloid leukemia (AML) who lack a suitable HLA-matched related or unrelated donor, and significantly expanded patient's access to transplantation. Donor age has consistently demonstrated a strong association with transplant outcomes. Younger donors have been linked to lower rates of graft-versus-host disease (GVHD) and improved overall survival (OS), making age a key consideration during donor selection. Since patients may have multiple haploidentical donor options with varying chronological ages, understanding the role of donor age in this context, and when PTCY-based prophylaxis is administered, is essential to optimizing outcomes. This multicenter retrospective study evaluates the impact of donor age on outcomes in AML patients undergoing haplo-HCT with PTCy-based prophylaxis. METHODS This registry-based analysis included 274 consecutive AML patients who underwent their first peripheral blood haplo-HCT between 2014 and 2022 at 16 Spanish transplant centers. Donor age was the primary explanatory variable. The main outcomes variables were OS, non-relapse mortality (NRM), cumulative incidence of relapse (CIR) and GVHD incidence. RESULTS Among the 274 patients included, the median age was 53 years (range: 17–74), with 62 (22.6%) aged over 64, 123 (45%) female patients, and 99 (36.8%) adults with a HCT-CI >2. According to the ELN classification, 116 (42.6%) patients had a high-risk AML, and 11 (4.0%) underwent transplantation with active disease. Myeloablative conditioning (MAC) was used in 145 (53%) cases, and all transplants were done with PB. The median donor age was 38 years (range, 13–75). Overall, 49 (17.9%) donors were female, and in 46 (16.4%) cases, female donors provided grafts to male recipients. In univariate analysis, increasing donor age (continuous variable) was associated with worse OS (HR 1.01, p=0.041) and higher NRM (HR 1.02, p=0.009). Receiver operating characteristic analysis identified an optimal donor age cut-off of 30 years for predicting OS. Based on this, the study cohort was divided according to donor age: <30 years (n=85, 31%) and ≥30 years (n=189, 69%). Baseline characteristics were comparable between groups, except for a higher proportion of recipients aged >65 years in the older donor group (27.5% vs. 11.8%; p=0.004). Neutrophil and platelet engraftment kinetics were similar between groups p=0.416 and p=0.948, respectively. Infection rates in the first 180 days post-transplant did not differ significantly: bloodstream infections (50.6% vs. 42.2%, p=0.237), CMV reactivation (60.3% vs. 64.8%, p=1), and CMV disease (10.3% vs. 8.2%, p=0.523). Importantly, patients with younger donors (<30 years) had significantly lower rates of acute GVHD: grade II–IV (Day +100: 3.0% vs. 19.9%, p<0.001) and grade III–IV (1.5% vs. 10.2%, p=0.034). However, moderate-severe chronic GVHD incidence was similar between groups (2-year: 11.7% vs. 11.4%, p=0.49). Relapse rates were comparable (2-year CIR: 18.6% vs. 20.6%; p=0.599), but mortality was lower in recipients of younger donor grafts (28.2% vs. 42.0%; p=0.032), primarily due to reduced NRM (12.9% vs. 24.3%; p=0.016). Consequently, OS was significantly better in the younger donor group (2-year 80.6% vs. 64.3%; p=0.011), with lower NRM (2-year: 11.1% vs. 23.2%; p=0.031). Multivariate analysis (MVA), adjusting for clinically relevant variables [recipient age older than 59 years (vs. younger), high-risk ELN (vs. low and intermediate), HCT-CI >2 (vs. 0-2) and the use of reduced intensity conditioning regimens (vs. MAC)] confirmed that donor age ≥30 years was associated with inferior OS (HR 1.88; p=0.019) and increased NRM risk (HR 2.06; p=0.049). Additional independent predictors of worse OS included patient age >59 years (HR 1.02; p=0.016), high-risk AML (HR 1.60; p=0.029), and comorbidity burden (HCT-CI >2) (HR 2.01; p<0.001). CONCLUSION Donor age is a relevant factor in PB haplo-HCT outcomes for AML. Transplants from donors under 30 years are associated with significantly better OS, primarily due to reduced NRM and lower incidence of grade 2-4 aGVHD incidence. These findings suggest that when multiple haploidentical donors are available, selecting the youngest donor (<30 years) may enhance the probability of haplo-HCT success.