Abstract
Numerous analyses have linked increasing donor age with poor outcomes after HSCT. The consequences of using an older donor vary by study with increased relapse, GVHD, non-relapse mortality, decreased overall survival (OS), or a combination of these findings associated with older donors. The age at which donors impact outcomes also varies by analysis with an identified optimal range anywhere from < 30 to < 60 years. Biological age is likely more important than chronological age, affecting allogeneic graft dose and composition at different rates in different donors. Older donors have been found to produce grafts with a higher content of CD3/4 T cells compared to their young counterparts-a possible explanation for differences in HSCT outcomes based on donor age. The goals of this analysis were to 1) assess quantitative differences in donor T cell subsets based on age, 2) identify a transitional donor age range for these differences, and 3) perform a preliminary assessment of the relationship between T cell subsets in the donor graft and early immune reconstitution and the development of aGVHD. Information generated from this analysis would help inform donor selection and serve as the basis for future multivariate analyses testing the effects of donor age on HI HSCT outcomes.
Patients underwent HI HSCT using the Jefferson 2 step approach in which after myeloablative (MA-12 Gy TBI) or reduced intensity (RIC-fludarabine-based chemotherapy + 2 Gy TBI) patients receive an unmanipulated donor lymphocyte product (DLI) at a fixed dose of 2 x 108/kg CD3 cells. Cyclophosphamide is given 2-3 days after the DLI for tolerization, followed 2 days later by a CD34 selected product. Because donors provide the DLI product prior to CD34 cell mobilization, the approach provides a unique opportunity to study donor T cell subsets without the influence of growth factor and at identical T cell doses. Bivariate correlation was performed to assess the relationship between age and graft composition. A box plot was used to express the CD3/4 to CD3/8 ratios in the DLI products according to donor age ranges in approximately 10 year increments. Independent samples T Test was used to measure the impact of both graft T cell content and donor age on the incidence of grades 2-4 aGVHD. OS by donor age was tested using Kaplan Meier analysis.
179 consecutive HI HSCT donors and recipients, median ages 41 (range 18-68) and 53 (range 19-77) years, respectively, were analyzed. For inclusion, recipients had to be alive and engrafted at day+28. 57% and 43% recipients underwent MA vs RIC HSCT, respectively. There was a positive correlation between donor age and CD3/4 cells/ml/kg (R= .441, p=0.001), a negative correlation between donor age and CD3/8 cells/ml/kg (R= -.331, p=0.001), and a positive correlation between donor age and CD3/4 to CD3/8 ratio (R= .397, p= 0.001). Higher CD3/4 to CD3/8 ratios were associated with donors >46 year old (Figure). In a subset of 130 patients steroid naive at the time of initial immune reconstitution studies at d+28, there was a positive correlation between CD3/4 to CD3/8 ratio in the DLI and recipient CD3/4 count (R= .832. p=0.001) and a negative correlation with recipient CD3/8 count (R= -.875, p= 0.001). In the whole group, older donor age was associated with a higher incidence of grades 2-4 aGVHD (p=0.016), while a higher mean CD3/4 to CD3/8 cell ratio in the DLI product was associated with a higher incidence of grades 2-4 aGVHD, significant in MA recipients only (p=0.044). Neither donor age nor CD3/4 to CD3/8 ratio were significantly associated with OS.
In this analysis, older donors produced allogeneic grafts that were higher in CD3/4 and lower in CD3/8 cells than their younger counterparts. This difference was reflected in recipient CD3/4 and CD3/8 counts at d+28. The transition to a higher CD3/4 to CD3/8 ratio began in a donor age range of 46-55 years. Older donor age and CD3/4 to CD3/8 ratio in the DLI product was associated with a greater frequency of grades 2-4 aGVHD but did not significantly affect OS. The results support further studies of the role of age-dependent differences in the T-cell composition of donor grafts in determining HI HSCT outcomes. If confirmed, the results suggest that graft composition, not age, may be a superior method of donor selection. Because the DLI is infused separately from CD34 cells in the 2 step approach, it may be possible to optimize the CD3/4 to CD3/8 ratio in the products of older donors with partial CD3/4 depletion.
Wagner: Novartis: Research Funding.
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