Young Female Donors Do Not Confer an Increased Risk of Graft-Versus-Host Disease in Pediatric Hematopoietic Stem Cell Transplant
Authors: Friedrich Paola , Guerra-Garcia Pilar , Stetson Alyssa E. , Duncan Christine , Lehmann Leslie E. 
Published: November 2019

Abstract
Backgrond: Donor selection is a critical step for the success of hematopoietic stem cell transplantation (HSCT). Donor/recipient sex-mismatch, donor age, and donor parity have been found to play an important role in the adult setting, and minor histocompatibility antigens (mHCA) encoded by the Y-chromosome presumed to be in the causal pathway. The pediatric sibling HSCT setting offers a special opportunity to evaluate donors and to see whether the observed importance of donor sex and age holds true when the donors are young and presumably immunologically naïve to Y-chromosome mHCAs. We hypothesized that if the presence of acquired T and B cells sensitized to H-Y antigens are in fact a major contributing factor to differences in outcomes between sex-matched and sex -mismatched transplants, there should be no such difference when a non-exposed (non-alloimmunized) female donor is involved.
Methods: Retrospective review of pediatric patients receiving myeloablative sibling-donor HSCT from 1996 to 2012 in our institution. Donor sex, donor age, and sex-match were included among clinical predictors. Outcomes included acute and chronic graft versus host disease (aGVHD and cGVHD, respectively). Univariate and multivariate analyses were performed.
Results: Of 244 patients included in this study, 50% were ≤10 years, 61% had a donor ≤12 years of age, 53% had a sex-matched donor, 46% had a female donor, 64% had an oncologic diagnosis, 62% were transplanted between 2005 and 2012, 96% were fully HLA-matched, 96% received bone marrow stem cells, and 91% received cyclosporine and methotrexate for GVHD prophylaxis. Forty-one (17%) patients developed acute GVHD, 31 (14%) of 229 patients alive past 100 days developed chronic GVHD, and 141 (73%) patients were alive at 5 years. No cGVHD was observed among 109 patients <10 years of age who received a 5/5 HLA-matched HSCT using bone marrow as the cell source; regardless of donor age or sex. However, 24 of 113 (21%) of patients ≥10 years of age developed cGVHD despite receiving 5/5 HLA-matched HSCT using bone marrow cells. Multivariate analysis showed older patient age, earlier transplant date and conditioning with cyclophosphamide and total body irradiation as significant predictors of acute GVHD. For cGVHD, older patient age and female donor increased risk of cGVHD while HLA-full match and use of bone marrow as stem cell source decreased risk of cGVHD. Effect modification occurred between donor age and donor sex (p=0.0473). The effect of female donor sex on cGVHD noted in the model adjusted for patient age, HLA-match, and cell source (OR 4.5; 95%CI 1.8-11.6), turned not significant if the donor was <12 years old (OR 2.6; 95%CI 0.7-10.2) and increased in magnitude and significance if the donor was ≥12 years old (OR 13.6; 95%CI 2.8-39.6).
Conclusions: Patient age is a significant predictor of acute and chronic GVHD. However, our results suggest that in the pediatric population, younger donors (<12 years old) can be chosen to be good candidates for their siblings, independent of sex.
Table I. Multivariate analysis and stratification of cGVHD results by donor age Odds Ratio (CI) Waldp-value Max-Rescaled R-Square aGVHD Patient age 1.1 (1.04, 1.2) 0.0018 0.26 Year of SCT 0.8 (0.7, 0.9) <0.0001 Cy-TBI Conditioning 3.2 (1.4, 7.3) 0.0059 cGVHD Patient age 1.2 (1.1, 1.3) <0.0001 0.27 Female donor 4.5 (1.8, 11.6) 0.0017 HLA-full match 0.2 (0.04, 0.93) 0.0405 BM stem cells source 0.2 (0.03, 0.91) 0.0385 cGVHD for Donor <12y/o Patient age 1.3 (1.1, 1.5) 0.0005 0.32 Female donor 2.6 (0.7, 10.2) 0.1737 HLA-full match 0.13 (0.02, 1.2) 0.0698 BM stem cells source 0.3 (0.04, 2.2) 0.2250 cGVHD for Donor ≥12y/o Patient age 1.3 (1.06, 1.4) 0.0066 0.33 Female donor 13.6 (2.8, 39.6) 0.0011 HLA-full match 0.8 (0.03, 28.7) 0.9237 BM stem cells source 0.03 (<0.001, 2.7) 0.1308

Disclosures
No relevant conflicts of interest to declare.