Higher Doses of Transplanted T and B Cells Are Associated with Greater Incidence of Extensive Chronic GVHD after PBSC Transplantation from HLA-Identical Sibling Donors.
Authors: Baron Frederic , Sandmaier Brenda M. , Gooley Ted , Martin Paul L. , Flowers Mary E.D. , Linenberger Michael L. , Storb Rainer F. , Appelbaum Frederick R. , Heimfeld Shelly 
Published: October 2019

Background. We investigated the impact of graft composition on GVHD in 1520 allogeneic transplant recipients given PBSC.

Methods. Graft composition was determined by FACS analyses and expressed as cells/kg of recipient weight. Cell types were defined as follows: CD3+ T cell (CD3+CD56−), CD4+ T cell (CD3+CD4+), CD8+ T cell (CD3+CD8+), natural killer (NK) cell (CD3−CD56+), NK/T cell (CD3+CD56+), B cell (CD20+), monocyte (CD14+), and CD34+ cells (CD34+CD14−). Cell doses were modeled as continuous linear variables or by quartiles. Cox (for chronic) and logistic (for acute) regression models were adjusted for conditioning regimen intensity, pt age, female donor to male recipient vs. other gender combination, and disease risk.

Results. The median age among all pts was 52 (45 among myeloablative, 57 among nonmyeloablative); 27% of pts were male transplanted from a female donor; 66% of pts had high-risk disease; 49% were transplanted from an alternative donor (47% unrelated, 2% mismatched sibling); 51% received a nonmyeloablative conditioning. Table 1 shows graft composition and GVHD incidences according to donor type and conditioning intensity. There were no statistically significant associations between cell dose and acute GVHD, although there was a suggestion that the association of NK/T cell was dependent on conditioning. In particular, increasing NK/T cells were associated with an increased probability of grades 2–4 GVHD among myeloablative pts (p=.03) but not among nonmyeloablative pts. There were no statistically significant associations between cell dose and chronic GVHD, but several cell types showed evidence of an interaction between donor and cell dose. In particular, increasing B cells and CD3+, CD4+, and CD8+ T cells were associated with an increased risk of chronic GVHD among pts with an HLA-identical donor (p=.006, p=.0003, p=.0002, p=.02, respectively) while the associations among alternative donors were in the opposite direction and were not statistically significant (p=.68, p=.26, p=.44, and p=.15, respectively). Lack of correlation in the alternative donor group may reflect differences in T-cell responses to the greater minor histocompatability divergence, or changes in T-cell functionality associated with the dose of G-CSF (higher in sibling donors) used for mobilization. Increasing CD34+ cells was not statistically associated with chronic GVHD in either myeloablative (negative association, p=.10) or nonmyeloablative (positive association, p=.11) pts.

Conclusions. Higher numbers of transplanted T and B cells were associated with an increased risk of extensive chronic GVHD in pts given grafts from HLA-identical siblings. Increasing CD34+ cells were not associated with a statistically significant increase in chronic GVHD. Further analyses looking at other clinical outcomes such as survival are forthcoming.

Table 1. Graft composition and GVHD according to conditioning intensity and donor type Nonmyeloablative conditioning and HLA-id sibling Myeloablative conditioning and HLA-id sibling Nonmyeloablative conditioning and alternative donor Myeloablative conditioning and alternative donor Median # of T cell transplanted (× 108/Kg) 3.4 2.5 2.5 2.8 Median # of CD34+ cell transplanted (× 106/Kg) 8.6 7.5 6.9 7.5 Incidence of grade II–IV acute GVHD (%) 47 66 61 81 Incidence of extensive chronic GVHD (%) 40 54 41 49