Impact of Donor Age and Donor-Recipient Sex Mismatch on HLA-Matched Related and Unrelated Donor Hematopoietic Cell Transplantation Outcomes
Authors: Aljawai Yosra M. , Chen George , Oran Betul , Fingrut Warren B. , Alousi Amin M. , Bashir Qaiser , Hosing Chitra , Kebriaei Partow , Marin David , Popat Uday , Qazilbash Muzaffar H. , Ramdial Jeremy , Smallbone Portia , Rezvani Katayoun , Champlin Richard E. , Shpall Elizabeth J. , Mehta Rohtesh S. 
Published: December 2024

Background:
Among donor-related factors, younger age is consistently associated with improved outcomes in patients undergoing hematopoietic cell transplantation (HCT). While a female donor for a male recipient (F-to-M) may pose an increased risk of graft-versus-host disease (GVHD), it may offer a potential benefit through mismatched minor histocompatibility antigens (H-Y) contributing to the graft-versus-leukemia effect. Thus, how to best select a donor while considering these factors (donor age and sex-mismatch) is unclear.
Objective:
Examine the impact of donor characteristics [age (younger &lt;35 years vs older &gt;35 years), donor-recipient CMV and sex mismatch (F-to-M vs others)], along with patient and HCT-related variables on outcomes after HLA-matched unrelated (MUD, n=14,147) or sibling (MSD, n=1593) donor HCT from 2008-2018 with calcineurin inhibitor-based GVHD prophylaxis using publicly available Center for International Blood and Marrow Transplant Research datasets.
Results:
Median follow-up was 47.8 months [interquartile range (IQR), 24.8 - 71.2]. Patients had acute myeloid leukemia (59%), myelodysplastic syndrome (24%), or acute lymphoblastic leukemia (18%); mostly with early-intermediate risk (67%). Median age at HCT was 56 years (IQR, 39-65). Median donor age was 28.5 years (IQR, 24 - 38). Most patients were male (58%), had high HCT comorbidity index (&gt; 2), received peripheral blood graft (81%) and myeloablative conditioning (60%).
In multivariate analysis (MVA), both donor age (&gt; 35 years: HR 1.19, 95% CI 1.13-1.25, p&lt;.0001) and sex-mismatch (F-to-M: HR 1.11, 95% CI 1.04-1.18, p=.002) were the only significant predictors of worse overall survival (OS).
Next, we created a composite variable of donor age and sex-mismatch to assess their combined effect and to address donor selection question when multiple donors with these characteristics are available. In MVA, the hazards of overall mortality increased in a stepwise fashion from younger donor/not F-to-M (reference) to younger donor/F-to-M (HR 1.1, 95% CI 1.02 - 1.19, p=.01), to older donor/Not F-to-M (HR 1.2, 95% CI 1.12 - 1.24, p&lt;.0001), to older donor/F-to-M ( HR 1.3, CI 95% 1.21-1.46, p&lt;.0001).
To address whether a younger donor or avoidance of F-to-M should be prioritized, we conducted direct pairwise comparisons and noted no significant difference in OS between younger donor/F-to-M (ref) vs older donor/not F-to-M (HR 1.07, 95% CI 0.98-1.17, p=0.12).
Similar patterns were observed for non-relapse mortality. Hazards increased from the younger donor/not F-to-M group to younger donor/F-to-M (HR 1.19 95% CI 1.06-1.33, p=.003), to older donor/not F-to-M (HR 1.23 95% CI 1.14-1.33, p&lt;.0001) to older donor/F-to-M (HR 1.53, 95% CI 1.33-1.75, p&lt;.0001). In pairwise comparison, no difference was noted between younger donor/F-to-M (ref) vs older donor/not F-to-M (HR 1.04, 95% CI 0.92 - 1.18, p=.56).
The risk of grade II-IV acute GVHD at day 100 (p=.1) and relapse (p=.07) did not differ between groups. Contrary to the hypothesis, F-to-M donor vs not F-to-M was not associated with any relapse protection in either younger donor (HR 1.04, 95% CI 0.94-1.14, p=.5) or older donor (HR 1.02, 95% CI 0.89-1.16, p=.78) group.
In contrast, the groups differed significantly with respect to chronic GVHD risk, p&lt;.0001. Compared to the younger donor/not F-to-M, the younger donor/F-to-M (HR 1.17, 95% CI 1.08 - 1.26, p&lt;.0001), older donor/not F-to-M (HR 1.09, 95% 1.02- 1.15, p=.005) and older donor/F-to-M (HR 1.13 95% CI 1.02-1.25, p=.02) had higher risks. Pairwise comparison did not reveal a significant difference between the younger donor/F-to-M (ref) vs older donor/not F-to-M (HR 0.93, 95% CI 0.85 - 1.01, p=.08).
Data on female donor parity, ABO-matching, molecular classification of disease are lacking.
Conclusion:
Our study suggests that older donor age and sex-mismatch (F-to-M) are independent negative predictors of OS. When feasible, selection of younger donor and avoidance of F-to-M (both favorable factors) should be considered; donors with both unfavorable factors should be avoided (older donor/F-to-M). Patients with donors who have one favorable and one unfavorable factor (e.g., older donor but not F-to-M or younger donor but F-to-M) may have similar outcomes. Donor selection in such cases may be based on logistics or other factors. Validation in independent datasets and with novel GVHD prophylaxis regimens is needed.