A Phase I Trial of SYK Inhibition with Fostamatinib in the Prevention and Treatment of Chronic Graft-Versus-Host Disease

Lin, Chen-Yu; DiCioccio, Rachel A.; Haykal, Tarek; McManigle, William; Li, Zhiguo; Anand, Sarah; Poe, Jonathan C.; Bracken, Sonali; Jia, Wei; Alyea, Edwin P.; Cardones, Adela R.; Choi, Taewoong; Gasparetto, Cristina; Grunwald, Michael R.; Hennig, Therese; Kang, Yubin; Long, Gwynn D.; Lopez, Richard D.; Martin, Melissa; Minor, Kerry K; Quinones, Victor L Perez; Sung, Anthony D.; Wiggins, Kristi; Chao, Nelson J.; Horwitz, Mitchell E.; Rizzieri, David A.; Sarantopoulos, Stefanie

doi:10.1016/j.jtct.2022.12.015

Cited by 7 publications

(6 citation statements)

References 43 publications

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“…We, and others, have demonstrated previously that BCR activation is critical for B-cell dysregulation in cGVHD, 18 , 20 and blocking BCR signaling has therapeutic benefit both in mouse models 19 and in patients. 10 , 11 In this study, we show that BCR-activated B cells from patients with cGVHD are primed for TLR7 responsiveness.…”

Section: Discussionmentioning

confidence: 57%

“… 5 , 6 , 7 , 8 Human studies have identified targetable B-cell pathways in cGVHD. 9 , 10 , 11 The post-HSCT environment is well suited for the alloantibody and autoantibody production noted in patients 12 , 13 , 14 and mice 5 with cGVHD, because alloantigens and B-cell activating factor (BAFF) promote the production of anti-host antibodies and cGVHD manifestations in mice. 6 Patients with clinically active cGVHD have elevated plasma levels of BAFF 15 and demonstrate constitutive B-cell activation 16 and immunoglobulin G (IgG) production.…”

Section: Introductionmentioning

confidence: 99%

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Heightened TLR7 signaling primes BCR-activated B cells in chronic graft-versus-host disease for effector functions

Bracken,

Suthers,

DiCioccio

et al. 2024

Blood Advances

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Chronic graft-versus-host disease (cGVHD) is a debilitating, autoimmune-like syndrome that can occur after allogeneic hematopoietic stem cell transplantation. Constitutively activated B cells contribute to ongoing allo- and autoreactivity in patients with cGVHD. Excessive tissue damage that occurs following transplantation exposes B cells to nucleic acids in the extracellular environment. Recognition of endogenous nucleic acids within B cells can promote pathogenic B cell activation. Therefore, we hypothesized that cGVHD B cells aberrantly signal through RNA and DNA sensors such as Toll-Like Receptor 7 (TLR7) and TLR9. We found that B cells from patients and mice with cGVHD had higher expression of TLR7 than non-cGVHD B cells. Using ex vivo assays, we found that B cells from cGVHD patients also demonstrated increased IL-6 production following TLR7 stimulation with R848. Low-dose B cell receptor (BCR) stimulation augmented B cell responses to TLR7 activation. TLR7 hyperresponsiveness in cGVHD B cells correlated with increased expression and activation of the downstream transcription factor Interferon Regulatory Factor 5 (IRF5). Since RNA-containing immune complexes can activate B cells through TLR7, we used a protein microarray to identify RNA-containing antigen targets of potential pathological relevance in cGVHD. We found that many of the unique targets of active cGVHD IgG were nucleic acid (NA) binding proteins. This unbiased assay identified the autoantigen and known cGVHD target Ro-52, and we found that RNA was required for IgG binding to Ro-52. Herein, we find that BCR-activated B cells have aberrant TLR7 signaling responses that promote potential effector responses in cGVHD.-

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Section: Discussionmentioning

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Heightened TLR7 signaling primes BCR-activated B cells in chronic graft-versus-host disease for effector functions

Bracken,

Suthers,

DiCioccio

et al. 2024

Blood Advances

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“…kinase inhibition, as observed in patients with chronic graftversus-host disease treated with fostamatinib. 6 No patient developed thromboembolism in this study, and the incidence of infection was low.…”

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confidence: 51%

Long‐term treatment with fostamatinib in Japanese patients with primary immune thrombocytopenia: An open‐label extension study following a phase 3 placebo‐controlled, double‐blind, parallel‐group study

Kuwana,

Ito,

Kowata

et al. 2024

American J Hematol

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R788-1301 (NCT04132050) is a phase 3, multicenter, randomized, parallel-group study of fostamatinib, an oral spleen tyrosine kinase inhibitor, in Japanese patients with primary ITP. 1 The study consists of four parts: a placebo-controlled, double-blind study of fostamatinib for 24 weeks (Period I), an open-label study of fostamatinib for 28 weeks (Period II), a washout period of up to 4 weeks, and an open-

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“…Activated CD27 + B cells from cGVHD patients are in an increased metabolic state with bigger size and protein content and are primed for survival via BAFF pathways ( 80 ). The Syk inhibitor Fostamatinib was recently tested in a Phase I clinical trial (NCT02611063) for cGVHD prophylaxis and as steroid-refactory cGVHD treatment ( 83 ). In both arms the proportion of post-GC plasmablas like B cells decreased in the early treatment phase ( 83 ).…”

Section: Communication Of Immune Cells In Cgvhd – the Role Of B Cellsmentioning

confidence: 99%

Complex interactions of cellular players in chronic Graft-versus-Host Disease

et al. 2023

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Chronic Graft-versus-Host Disease is a life-threatening inflammatory condition that affects many patients after allogeneic hematopoietic stem cell transplantation. Although we have made substantial progress in understanding disease pathogenesis and the role of specific immune cell subsets, treatment options are still limited. To date, we lack a global understanding of the interplay between the different cellular players involved, in the affected tissues and at different stages of disease development and progression. In this review we summarize our current knowledge on pathogenic and protective mechanisms elicited by the major involved immune subsets, being T cells, B cells, NK cells and antigen presenting cells, as well as the microbiome, with a special focus on intercellular communication of these cell types via extracellular vesicles as up-and-coming fields in chronic Graft-versus-Host Disease research. Lastly, we discuss the importance of understanding systemic and local aberrant cell communication during disease for defining better biomarkers and therapeutic targets, eventually enabling the design of personalized treatment schemes.

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A Phase I Trial of SYK Inhibition with Fostamatinib in the Prevention and Treatment of Chronic Graft-Versus-Host Disease

Cited by 7 publications

References 43 publications

Heightened TLR7 signaling primes BCR-activated B cells in chronic graft-versus-host disease for effector functions

Heightened TLR7 signaling primes BCR-activated B cells in chronic graft-versus-host disease for effector functions

Long‐term treatment with fostamatinib in Japanese patients with primary immune thrombocytopenia: An open‐label extension study following a phase 3 placebo‐controlled, double‐blind, parallel‐group study

Complex interactions of cellular players in chronic Graft-versus-Host Disease

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