Syk inhibition with fostamatinib leads to transitional B lymphocyte depletion

Abstract

Cell signaling initiated by the B cell receptor is critical to normal development of B lymphocytes, most notably at the transitional B cell stage. Inhibition of this signaling pathway with the syk inhibitor, fostamatinib, has produced significant efficacy in lymphoid malignancies and autoimmune conditions. Here, we demonstrate that short-term use of fostamatinib impairs B lymphocyte development at the transitional stage without affecting mature B cell populations. Additionally, IL-10 producing B cells remained relatively constant throughout the treatment period. These findings provide insight into the mechanism of action of B cell receptor inhibition in autoimmune disease. As the development of agents targeting B cell receptor signaling proceeds, monitoring for long-term consequences as well as functional evaluation of B cell subsets may further improve our understanding of this rapidly growing class of novel agents.

B-cell selection and the development of autoantibodies

“…Just how R788 works in vivo is not entirely clear, but in one study where R788 delayed spontaneous diabetes in NOD mice, it also reduced total B-cell numbers and serum immunoglobulin levels while at the same time increasing the numbers of IL-10-producing B cells [106]. Fostamatinib may be more effective at depleting human transitional B cells than mature B cells [107], and thus potentially could be useful for treating autoimmune diseases where RP B cells are a source of autoAb-producing cells.…”

Management strategies and outcomes for very elderly patients with diffuse large B‐cell lymphoma

“…Outcomes with standard therapy vary because of patient and disease‐related factors . The median age at diagnosis is currently in the near 70s . The proportion of elderly patients with DLBCL appears to be increasing, at least in part because of an increase in the life expectancy of the general population .…”

“…[1][2][3] The median age at diagnosis is currently in the near 70s. 4 The proportion of elderly patients with DLBCL appears to be increasing, at least in part because of an increase in the life expectancy of the general population. 2 Most clinical trials exclude the very elderly, and the outcomes for these patients vary widely because of heterogeneity in management.…”

Phosphorothioate‐modified CpG oligodeoxynucleotides mimic autoantigens and reveal a potential role for Toll‐like receptor 9 in receptor revision

“…[47][48][49][50] Nevertheless, it was recently suggested that CpG PTO induces proliferation of transitional B cells, 51 a B-cell subset expressing polyreactive IgM and sensitive to treatment with syk inhibitors. 52 Albeit the frequency of these cells in freshly isolated peripheral blood B cells from the donors used in this study was very low (0Á1-1%), and blast formation was not observed in the CD27fraction (Fig. 6a), we cannot exclude transitional B cells as the target subpopulation undergoing TLR9-induced receptor revision.…”