Establishing the impact of effective donor-specific antibody (DSA) desensitisation in haploidentical and mismatched donor haematopoietic stem cell transplants: An Australian experience

Abstract Background: The presence of donor-specific antibodies (DSA) in recipients undergoing allogeneic hematopoietic stem cell transplant (alloHSCT) is associated with increased risk of graft failure, poor graft function and inferior survival. Desensitisation treatments to mitigate recipient DSAs improves access by facilitating transplantation with haploidentical and HLA-mismatched unrelated donors, wherein other suitable donor options do not exist. We report a multicentre Australian experience in the management of DSAs in recipients undergoing alloHSCT, with a focus on the impact of desensitisation strategies on DSA dynamics, engraftment, graft dysfunction, and survival outcomes. Methods: Retrospective data on allogeneic transplants performed in recipients with DSAs was collected from eight Australian transplant centres from 2015-2024. DSA specificities towards HLA classes I and II antigens and their median fluorescence intensity (MFI) were measured using the ThermoFisher Luminex LabScreen solid phase Single Antigen Bead assay at screening, pre- and various post-transplant timepoints. Complement-fixing ability of identified DSAs was determined when available. Significant DSAs (MFI > 1000) were further grouped into low (MFI between 1000-5000), moderate (MFI between 5000-10000) and high positivity (MFI > 10000). Engraftment, graft failure and poor graft function were defined according to the European Bone Marrow Transplant Society 2024 recommendations. Donor chimerism testing, including PCR and FISH-based testing on cell-sorted and whole blood assays, was performed as per institutional protocols. Results: With a median follow up of 512 days (range 59-2564), 29 allogeneic transplant recipients with DSAs were identified, including 24 (83%) who underwent desensitisation. Recipients received Rituximab and plasmapheresis with variations, for desensitisation. Addition of Bortezomib was restricted to patients with high DSA MFI at baseline and was utilised in 38% of recipients. Median recipient age was 53 years (range 24-66) with predominance of females (76%). Acute leukemia (52%) was the most common transplant indication, followed by lymphoma (24%). The majority of recipients underwent transplantation in the first complete remission (69%). Reduced intensity conditioning (62%) was more commonly utilised with the remainder receiving myeloablative conditioning. Haploidentical donor transplants comprised 79% of the cohort while the rest were mismatched unrelated donor transplants. Peripheral blood stem cell was the graft source in 97% of patients with a median CD34+ cell dose of 5 x 106/kg. At screening, the incidence of low, moderate and high MFI was 11 (46%), 3 (13%) and 10 (42%), respectively. Median reductions in MFI by day -1 transplant in the low, moderate and high MFI groups were 100%, 76%, and 62%, respectively. However, by day +30, DSAs with high or moderate MFI were no longer detected, with a median MFI reduction of 100%, across all desensitised recipients. Median neutrophil and platelet engraftments were 19 (range 14-32) and 29 (range 10-73) days, respectively. None of the recipients experienced primary or secondary graft failure. Of the 24 desensitised recipients, 4 (17%) experienced persisting poor graft and 1 (4%) experienced poor platelet recovery by day +28. Wherein data was available, 10 (77%) recipients achieved full donor chimerism and 3 (23%) achieved mixed donor chimerism by day +45. As of July 2025, 14 (58%) desensitised recipients were still alive and in remission. At median follow up, whole cohort survival was 65%. Five patients did not receive desensitisation as per institutional protocols. Interestingly, when a desensitisation threshold MFI of 2000 was applied, as per the ASTCT consensus recommendations, all 3 untreated recipients with MFI < 2000 achieved trilineage engraftment and good graft function. Conversely, 1 (50%) out of 2 recipients with MFI > 2000, who did not undergo desensitisation reported poor graft function. Limited numbers did not permit further analysis of this subset. Conclusion: Effective desensitisation of DSAs in recipients undergoing haploidentical or mismatched unrelated allogenic stem cell transplantation facilitates successful engraftment and avoids graft failure. Recipients with initial moderate to high DSA MFI appeared to benefit most from desensitisation, with eventual mitigation of DSAs, indicating a potential additional impact of conditioning and subsequent immunosuppression.