Biologic indicators of donor socioeconomic disadvantage and recipient mortality following allogeneic hematopoietic cell transplantation.
Authors: Knight Jennifer M. , Cole Steven W , Beyer Kirsten M. , Wang Tao , Spellman Stephen R. , Allbee-Johnson Mariam , Zhou Yuhong , Verneris Michael R. , Rizzo J. Douglas , Turcotte Lucie Marie 
Published: June 2023

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Background: Allogeneic hematopoietic cell transplantation (HCT) carries significant risks, with low socioeconomic status (SES) being predictive of increased mortality. Our team recently discovered that socioeconomic disadvantage among unrelated HCT donors results in decreased recipient overall survival (OS) and increased treatment-related mortality (TRM) within a cohort from the Center for International Blood and Marrow Transplant Research (CIBMTR). We also demonstrated that upregulation of the stress- and SES-related gene expression profile termed the ‘conserved transcriptional response to adversity’ (CTRA) is associated with low SES and worse outcomes among HCT recipients. Here, we hypothesize that donor immunologic characteristics associated with neighborhood socioeconomic disadvantage (CTRA) will confer prognostic risk to HCT recipients as indicated by inferior long-term recipient outcomes. Methods: Among a subset of the above cohort for which donor whole blood samples were available from the CIBMTR repository, we evaluated whether donor cell CTRA gene regulation was associated with inferior HCT outcomes at 3 years in recipients being treated for hematologic malignancy. Multivariable models adjusted for donor and recipient characteristics evaluated associations between donor CTRA and recipient OS, TRM, disease free survival (DFS), relapse, and acute and chronic graft versus host disease. Results were considered significant if P<0.05. Results: We identified 263 donor-recipient pairs for study inclusion. Median recipient age at hematologic malignancy diagnosis was 53 years (range 19-77), 46% were female, and 54% had acute myeloid leukemia. Donors were 35% female and median age at donation was 31 years (range 18-60). In RNA sequencing data from HCT donors, greater CTRA expression was associated with reduced OS (covariate-adjusted HR=1.94/CTRA SD, 95% CI [1.01, 3.71], p=.046) which was driven predominately by increased TRM (adjusted HR=5.04, [2.20, 11.50], p=.0001). These clinical outcomes are consistent with those observed to be associated with donor SES in our prior work. Donor cell effects on transplant outcomes derived predominately from the pro-inflammatory component of the CTRA (OS: adjusted HR=1.67, [1.20, 2.33], p = .0026; TRM: adjusted HR=2.21, [1.21, 4.06], p=.010) and emerged above and beyond the effects of the recipients’ own SES, as well as multiple other recipient disease, treatment, and demographic factors. Donor CTRA was not associated with relapse, DFS, or other transplant outcomes. Conclusions: For the first time, we show that transcriptome patterning among HCT donors, consistent with neighborhood SES disadvantage, results in adverse recipient HCT outcomes. These findings suggest that SES has a biologic impact at either the stem or immune cell level that persists even when transplanted into a new host.