Personalized Desensitization for Donor-Specific Anti-HLA Antibodies in Allogeneic Blood or Marrow Transplantation.

[BACKGROUND] Donor-specific anti-HLA antibodies (DSAs) are associated with increased graft failure in allogeneic blood or marrow transplantation (alloBMT). We previously demonstrated that a personalized desensitization strategy may mitigate this risk. However, standardized guidelines for its implementation-and broader impact on donor selection, transplant timelines, and graft outcomes-remain undefined.

[OBJECTIVES] To describe in detail and evaluate a patient-tailored approach to DSA assessment and desensitization decision-making in alloBMT, and to determine: (1) the impact of antibodies on donor selection, and (2) the efficacy of our strategies regarding transplant outcomes.

[STUDY DESIGN] We retrospectively reviewed 408 first nonmyeloablative alloBMTs (2014-2022) in patients possessing at least one anti-HLA antibody against any potential donor. Patients were analyzed in 2 ways. In the first analysis, we examined the impact of antibodies on donor screening and time-to-BMT by classifying patients according to their highest antibody level against any potential donor. In the second analysis, we evaluated transplant outcomes by comparing cohorts consisting of 208 patients who had DSAs (71 desensitized, 137 not) and an additional 200 with an antibody against a potential donor but not their actual donor (DSA-avoidance).

[RESULTS] Patients with elevated anti-HLA antibodies (Ab) experienced significantly prolonged time-to-BMT (median 120 versus 90 days, P < .001), particularly Ab minority patients requiring unrelated donors (mean 219 versus 145 days, P = .032; P = .027 multivariate). Minorities were overall less likely to receive an unrelated transplant (odds ratio 0.5, P = .01), all of which were mismatched. Desensitization (n = 71) reduced median MFI from 7197 to 1331, comparable to DSA-positive patients (1567) whose levels were deemed low enough to be permissible for alloBMT without desensitization (untreated; n = 137). At day 30, neutrophil engraftment was 92% in desensitized, 91% in untreated, and 97% in DSA-avoided cohorts. Platelet recovery at day 60 was 87%, 87%, and 90%, respectively. Stratified by actual donor DSA levels, engraftment was slightly decreased in patients with MFI ≥10,000 (30-day neutrophil recovery 86% versus 92% with MFI <5000; 60-day platelet recovery 82% versus 89%). Graft failure occurred in 7% of desensitized and 5.8% of untreated DSA-positive patients (P = .74), compared with 1% of DSA-avoided patients. Independent predictors of graft failure included TBI dose (6.7% with 200 cGy versus 0.9% with 400 cGy), prior immune checkpoint inhibitor exposure (22% versus 3%), and age ≥60 years (5% versus 3%).

[CONCLUSIONS] Personalized decision-making and desensitization in DSA-positive alloBMT patients was associated with successful engraftment and low graft failure rates, comparable to those with low-level DSAs. However, high-level antibodies prolonged donor search and exacerbated disparities in transplant access, possibly reflecting reliance on mismatched donors among minority patients. These data highlight the need to mitigate DSA-driven delays in access to transplantation.