Vδ2 unconventional T cells in the donor graft are associated with improved overall survival after unrelated donor allo-HCT for AML and MDS: An analysis from the DKMS and NMDP graft composition study

Abstract

Abstract Introduction We have established an international collaboration between the DKMS (Germany) and the NMDP (USA) to characterize more than 2000 donor peripheral blood stem cell (PBSC) grafts. Our goal is to correlate graft immunophenotype with patient outcomes. Here, we present an exploratory analysis with data from the first 727 recipients. Microbiome-dependent mucosal-associated invariant T (MAIT) and Vδ2 populations have each been associated with favorable HCT outcomes in prior studies. We hypothesized that receiving a graft bearing higher ‘doses’ of these cell populations would be associated with favorable clinical outcomes. Methods Donor PBSC graft samples were collected, processed, freshly stained (34-color panel for immunophenotyping of lymphocytes and hematopoietic stem cells), and analyzed using high dimensional full spectrum flow cytometry at the NMDP contract laboratory (n = 457; Roswell Park, Buffalo, NY) or the DKMS laboratory in Dresden, Germany (n = 270). Clinical data were collected via CIBMTR reporting from each individual transplant center. We focused on patients who were transplanted for AML or MDS, and for whom at least 12 months of follow-up data was available. The Kaplan-Meier estimates and cumulative incidence rates were determined for survival and competing risks outcomes, respectively, as a univariate analysis. The Cox proportional hazard model was fitted to assess the relationship of MAIT and Vδ2 populations (absolute dose/kg recipient weight in the graft) with transplant outcome and identify significant risk factors, including prophylaxis (PT-Cy vs other), graft cryopreservation status, patient age, donor age, refined disease risk index, HCT-CI, conditioning intensity, and HLA matching. Results 727 patients who received unrelated donor allografts for the treatment of AML or MDS were included in the analysis. Patients were treated at 113 different transplant centers within the US between 2021 and 2024. The median recipient age was 64.2 years. 404 (55.57% of the cohort received post-transplant cyclophosphamide (PT-Cy) as GVHD prophylaxis. MAIT and Vδ2 counts in the graft ranged from 0.1-33.9 (interquartile range [IQR]: 2.28-5.69) and 0-21.2 (IQR: 1.31-4.5) cells/µl, respectively. Univariate analyses revealed that higher (above-median) absolute numbers of Vδ2 cells in the graft were associated with increased OS (p = 0.033), and MAIT cells with lower rates of chronic GVHD (p = 0.043). Interestingly, higher (above-median) MAIT numbers were only associated with improved OS in the absence of PT-Cy as part of GVHD prophylaxis (n = 323; p = 0.031). There were no associations between MAIT/Vδ2 numbers and acute GVHD or relapse in the univariate analyses. In multivariable analyses, recipients of grafts bearing above-median absolute number of Vδ2 cells significantly associated with improved overall survival compared with equal to or below-median (HR=1.337, 95% CI 1.032-1.733, p = 0.0281). Additional clinical factors associated with worse overall survival are high/very high disease risk index (HR=1.637, 95% CI 1.234-2.172, p = 0.0006) compared to low/intermediate group and HCT-CI 3+ (HR=1.597, 95% CI 1.252-2.037, p = 0.0002) compared with the HCT-CI 0-2 group. There were no statistically significant differences in acute or chronic GVHD in patients who received above-median Vδ2 doses in our multivariate models. Multivariable analyses did not reveal any associations between MAIT cell graft content and outcome. Given the OS finding, we next characterized the causes of death in the cohort. Notably, infection was reported as the cause of death in 3.9% in the above-median Vδ2 setting and 7.9% in the recipients of grafts containing below-median numbers of Vδ2 cells (p = 0.034; Fisher's exact test). Conclusions In this exploratory analysis, we observed an association between the Vδ2 content of the donor graft and 12-month overall survival in the recipient. In prior studies, this population has been associated with lower rates of GVHD and improved OS when measured after HCT, however Vδ2 cells have not been previously studied in PBSC grafts. Intriguingly, little is known regarding the post-transplant capacity of these T cells, and further studies will focus on uncovering the mechanism by which they may be protective after HCT.