Abstract
Introduction: HLA alloimmunization occurs through exposure to non-self HLA antigens from allogeneic blood products or pregnancy. The resulting anti-HLA antibodies (HLA-Abs), when directed at donor-specific HLA antigens (DSA), are a prognostic biomarker for hematopoietic cell transplantation (HCT) engraftment failure and mortality, necessitating either selection of an alternate donor or immunodepletion of the existing DSA. Current registry-level modeling of donor availability is not informed by the presence of HLA-Abs; therefore, it is unknown to what degree this phenomenon limits access to unrelated donors (URD).
Methods: We conducted a retrospective cohort study of 1,197 consecutive patients that were referred for HCT evaluation at Memorial Sloan Kettering Cancer Center between 2021-2024. All subjects underwent high-resolution HLA genotyping (HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1/B1 and -DPA1/B1) and HLA-Abs evaluation using commercially available solid-phase immunoassays at the time of initial HCT evaluation. The primary aim of the study was to determine the effects of HLA-Abs on donor availability by performing URD searches using the NMDP registry before and after exclusion of donors with DSA, considering different antibody mean fluorescence intensity (MFI) cut points (1000, 10000 MFI). URDs considered were 5-8/8 matched among HLA-A, -B, -C and -DRB1 and age 18-30.
Results: The median age of evaluated patients was 63 (interquartile range: 49-70) and 511 (42.4%) of patients were female. Self-reported race/ancestry was non-Hispanic White (NHW) in 710 patients (59.3%), Black/African-American (AFA) in 134 (11.2%) of patients, Latino/Hispanic (HIS) in 121 (10.1%), and Asian/Pacific-Islander (API) in 102 (8.5%). Persons of mixed ancestry, declined to provide or who declared unknown ancestry were grouped into a single cohort (UNK, n = 130, 10.9%). The most common diseases were acute myeloid leukemia (n = 379, 31.7%), myelodysplastic or proliferative syndromes (n = 354, 29.6%), and non-Hodgkin lymphoma (n = 191, 16.0%). HLA-Abs with MFI >1,000 were detected in 445 (37.2%) of patients. HLA-Abs frequency did not differ significantly between NHW and other groups (38.9% vs. 34.5%, P = 0.12); however, HLA-Abs were much more frequent in female patients compared to male patients (49.7% vs. 26.8%, P <0.0001). High titer (MFI >10,000) HLA-Abs were found in 14.8% of patients and were also much more frequent in female compared to male patients (26.4% vs. 5.7%, P <0.0001).
Among all patients with detected HLA-Abs (MFI >1,000), the rate of no available URD was 1.8% without considering HLA-Abs and 8.3% when considering HLA-Abs. Among patients with high-titer HLA-Abs, the rate of no donor availability was 4.5% without considering HLA-Abs and 7.9% after considering HLA-Abs.
Among women with HLA-Abs MFI >1,000 (N = 254) the rate of no donor availability was 1.6% without considering HLA-Abs and 11.0% when considering HLA-Abs. Further, 18.5% of female patients with HLA-Abs would be forced to select a lower matched donor to avoid DSA and 4.3% of female patients would lose available HLA-8/8 matched donors due to antibodies against HLA-DRB3/4/5, DQ or -DP. Among AFA and HIS female patients, 14.7% and 29.6%, respectively, did not have an available donor after considering HLA-Abs although the sample size was small at n=34 and n=27, respectively. Examining female patients with HLA-Abs with MFI >10,000 (N=135), the rate of no donor availability was 7.4% and 11.1% would require selection of an HLA lesser matched donor due to DSA. Consideration of older donors (up to age 60) led to only incremental improvements in donor availability.
Overall, the likelihood of no donor availability in NHW female patients with high-titer HLA-Abs was 2.9% compared to 15.7% in women of other ancestries, after exclusion of donors with DSA.
Conclusions: Consideration of HLA mismatched URDs provides access to suitable donors, particularly in patients of racial or ethnic minority ancestry. Here, we demonstrate that among racial/ethnic minority women, HLA-Abs are common and have a significant impact on donor availability. However, in a small subset of patients methods to address this problem by improving current HLA-Abs immunodepletion may improve access to HCT in this population.
