Donor age matters: Selecting 10/10 muds under 35 enhances survival after ptcy allo-HCT

Abstract

Abstract INTRODUCTION Allogeneic hematopoietic cell transplantation (allo-HCT) from a 10/10 HLA-matched unrelated donor (MUD) remains the preferred option for patients with acute myeloblastic leukemia (AML) or myelodysplastic syndromes (MDS) who lack a suitable 10/10 HLA-matched sibling donor. Compared with conventional GVHD prophylaxis, post-transplant cyclophosphamide (PTCy)-based prophylaxis has been shown to more effectively prevent acute and chronic GVHD in HLA-matched allo-HCTs, and its use is becoming increasingly prevalent within the transplant community. Among various donor-related factors, donor age has emerged as a relevant determinant of transplantation outcomes, with younger donors generally associated with improved survival (OS) and lower non-relapse mortality (NRM). However, the precise age threshold beyond which outcomes worsen remains undefined. In the context of PTCy-based prophylaxis and 10/10 MUD allo-HCTs, evidence on the impact of donor age remains limited. This multicenter retrospective study aims to evaluate the association between donor age and post-transplant outcomes in this specific setting. METHODS We conducted a registry-based study involving adult patients with AML and MDS who received their first peripheral blood MUD allo-HCT between 2011 and 2022 at 16 transplant centers in Spain. Donor age was analyzed as the primary variable of interest. The primary endpoints were OS and NRM. Secondary outcomes included cumulative incidence of relapse (CIR), acute and chronic GVHD, and GVHD-free/relapse-free survival (GRFS). RESULTS The analysis included 167 patients, with a median age of 55 years (range: 18–72), and 35.3% (n=59) aged >60 years. The cohort comprised 65.9% (n=110) AML and 34.1% (n=57) MDS patients, with 31.1% (n=52) classified as high-risk disease (according to the Disease Risk Index, DRI), and 59.3% (n=31.1) with an HCT-specific Comorbidity Index (HCT-CI) >2. Donor median age was 31 years (range: 18–51). Receiver operating characteristic (ROC) analysis for OS prediction identified 35 years as the optimal donor age cut-off. According to the defined donor age cut-off, 70.7% (n=118) patients received grafts from MUD younger donors (≤35 years) and 29.3% (n=49) from donors older than 35. Baseline and transplant characteristics between subgroups were compared, showing no differences between them. Median time to neutrophil and platelet engraftment was comparable between groups (p=0.471 and p=0.691, respectively). Graft failure was diagnosed in 7 (4.2%) patients, and among them 5 received grafts from older MUD (1.7% vs. 10.2%, p=0.025). Infectious complications (bacterial bloodstream infections, CMV reactivation, and disease) during the first 6 months after allo-HCT were prevalent, with no statistically significant differences between groups. Patients transplanted from younger donors experienced significantly lower rates of grade II–IV acute (a)GVHD (Day +100: 7.6% vs. 18.4%, p=0.036), with a trend toward reduced grade III–IV aGVHD (Day +100: 1.7% vs. 8.2%, p=0.099). No significant differences were found in moderate-severe chronic GVHD (2-year: 11.8% vs. 6.9%, p=0.377). Overall, with a median follow-up of 25 months, 21.0% relapsed and 29.3% died. The estimated 2-year OS, NRM, and CIR of the study cohorts were 71.1%, 19.6%, and 14.7%, respectively. Relapse incidence was similar between groups (2-year CIR: 20% vs. 19%, p=0.929). However, patients receiving grafts from younger MUD had higher OS (2-year: 76.3% vs. 58.8%, p=0.032), along with lower NRM (11.2% vs. 23.1%, p=0.032) than patients undergoing allo-HCT from MUD older than 35. Results observed in the univariate analyses were confirmed in multivariate analyses controlled for variables considered relevant for allo-HCT success (recipient age, HCT-CI, DRI, and disease type). Patients undergoing allo-HCT from MUD younger than 35 had a lower probability of death (HR 1.89, p=0.030) due to a reduced NRM risk (HR 2.25, p=0.038). In addition, recipient age exhibited a significant impact on survival (HR 1.88, p=0.028) in multivariate analysis. CONCLUSION Donor age is a relevant predictor of outcomes in MUD PB allo-HCT with PTCY-based prophylaxis. We identified 35 years as the optimal age threshold, with younger donors associated with improved survival, primarily due to lower NRM and reduced acute GVHD. These findings support prioritizing younger donors when multiple options are available to optimize transplant outcomes in AML and MDS.