Older donor age is not associated with inferior survival in contemporary haploidentical transplantation

Abstract Background: Data regarding the association of donor age with haploidentical hematopoietic stem cell transplant (HCT) outcomes has been inconsistent, particularly concerning a specific age cutoff. Most published studies on donor age in the haploidentical setting predated the advancement in cytomegalovirus (CMV) prophylaxis, improved graft-versus-host disease (GVHD) treatments, maintenance therapy post-HCT. We aimed to examine the role of donor age in a recent cohort of patients, from January 2018 to November 2024. Methods: We included consecutive adult patients with hematologic malignancies who underwent their first HCT with a haploidentical donor (n=364) at MD Anderson Cancer Center. All patients received post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis. To determine the optimal donor age cutoff associated with overall survival (OS) and progression-free survival (PFS), we explored a series of donor age dichotomizations as well as categorization by 5-year intervals. Results: Our analysis, using dichotomization of donor age, did not reveal a clear donor age cut-off to be associated with either OS or PFS. In the absence of a statistically significant age cutoff for OS or PFS, we categorized donor age into three groups (≤30 years [range: 11-30]; 31-44 years [range: 31-44]; ≥ 45 years [range: 45-69]) for all subsequent analyses based on cohort distribution and clinical relevance. Compared to donor age ≤30 years, the hazards of overall mortality were 0.92 (95% CI 0.62, 1.37, p=0.69) for donor age 31-44 years, and 1.19 (95% CI 0.78, 1.81, p=0.43) for donor ≥45 years. Similar patterns emerged for PFS. Older donor age was associated with increased hazards of non-relapse mortality (NRM): (31-44 years: HR 1.44, 95% CI 0.84-2.45, P=0.18) and (≥45 years: HR 1.52, 95% CI 0.87-2.66, P= 0.14). Consequently, relapse rates were lower in these groups (31-44 years: HR: 0.55, 95% CI 0.33-0.93, P=0.025) and (≥45 years: HR 0.70, 95% CI 0.36-1.36, P=0.29) compared to donors ≤30 years. Older donors were associated with a significantly increased risk of grade III-IV acute GVHD: for donors aged 31-44 years, HR was 3.77 (95% CI 1.69-8.39, P=0.001), and for those aged ≥45 years, the HR was 3.83 (95% CI 1.64-8.98, P=0.002) compared to donors ≤30 years. The risk of chronic GVHD was also higher with older donors (31-44 years: HR 1.44, 95% CI 0.84-2.45, P=0.18; ≥45 years: HR 1.52, 95% CI 0.87-2.66, P=0.14) compared to younger donors. We noted patient and disease-related factors to significantly influence mortality risk; older patient age (≥ 65 years) was associated with an HR of 1.90 (95% CI 1.22-2.98, P=0.005), and a high/ very high disease risk index (DRI) and HR of 1.89 (95% CI 1.38-2.60, P<0.001). DRI also influenced relapse rates with a 2.5-fold increased risk observed in patients with high/ very high DRI (95% CI 1.63-3.90, P<0.001). Conclusion: Our study suggested that dichotomization of donor age did not identify it to be a major selection factor for survival. However, older donor age remained a significant predictor of severe acute GVHD risk. It remains to be assessed whether HLA factors play a more dominant role, if improved post-HCT strategies have altered the adverse effect of donor age, or if categorization of age may present a limited methodology of modeling donor age and novel approaches need to be adopted in this contemporary era.