Soluble BAFF Is Elevated Following Allogeneic SCT but Is Not an Early Predictor for the Development of cGVHD.
Authors: Dickinson John D. , Pusic Iskra , Rader Christoph , Steinberg Seth , Hakim Fran , Baskar Sivasubramanian , Pavletic Steven Z. 
Published: April 2020

Abstract
Chronic GVHD (cGVHD) is a significant complication following hematopoietic stem cell transplantation (SCT). Yet much remains uncertain regarding the molecular pathogenesis of cGVHD. There is growing evidence that B cells play a role in cGHVD. BAFF is a member of the TNF family, expressed by myeloid cells, that promotes survival and differentiation of mature B cells. Soluble BAFF has been associated with a number of autoimmune diseases and may also play a role in alloimmune diseases such as chronic GVHD. The role of BAFF expression in the context of immune reconstitution, and allogeneic GVL/GVHD is not yet understood. In this study we measured plasma BAFF levels by ELISA at multiple time points following SCT in 63 leukemia/lymphoma patients. Samples were collected at time of enrollment in the NCI cGVHD Natural History Protocol. Of the 50 patients who developed cGVHD, 24 patients had progressive onset type, 6 had quiescent type onset, and 20 had de novo onset type cGVHD. Forty-nine of these cGVHD cases were classified as extensive under the Seattle Classification. BAFF expression was not significantly different in terms of cGVHD onset type (de novo vs. other) (p=0.32) but there was a significant correlation of BAFF with naïve CD19+IgD+CD27- cells (p=0.011), and a negative correlation with memory CD19+IgD-CD27+ cells (p=0.019) by Spearman Correlation. BAFF expression was then compared among those with cGVHD (n=50), those without a clinical history of cGVHD (n=13), normal plasma donors (n=11), and post autologous stem cell transplant breast cancer patients (n=9). Plasma BAFF level was significantly higher in the group with cGVHD (median 2723 pg/mL) compared to normal plasma donors (median 119 pg/mL, p&lt;0.001) and autologous SCT patients (1311 pg/mL, p=0.033). BAFF expression was not significantly different from those post-allotransplant patients without evidence of clinical cGVHD (median 1160 pg/mL, p=0.277). BAFF expression was followed in a longitudinal fashion at the end of conditioning prior to SCT and then at 3, 6, 9, 12, and 18 months. In all cases, BAFF levels were highest at time of conditioning and subsequently declined. There was no major difference over time in BAFF expression between those who developed or did not develop cGVHD. Autologous SCT demonstrated a more precipitous decline in BAFF expression. Finally, plasma BAFF expression was analyzed as a predictor for the development of cGVHD. BAFF was measured at the end of conditioning prior to SCT and at 3 months post transplant in 22 allogeneic SCT patients. There was no significant correlation in the development of clinical cGVHD according to the level of BAFF at either of these time points by log rank analysis, p=0.38 and p=0.53 respectively. In conclusion, BAFF was found at higher levels in allogeneic SCT patients relative to normal donors or autologous SCT patients. While at a higher level, there was no statistical difference in BAFF levels between allogeneic SCT patients with or without clinical cGVHD. Elevated BAFF reflects the allogeneic reaction and it’s expression extends beyond engraftment and G-CSF period. It is less specifically associated with clinical cGVHD. It remains uncertain whether BAFF is a suitable target for therapy that decreases cGVHD and preserves GVL.