fostamatinib and Leukemia

The B-cell receptor (BCR) delivers antigen-dependent and -independent signals that have been implicated in the pathogenesis of several common B-cell malignancies. Agents that can efficiently block BCR signaling have recently been developed and are currently being evaluated as novel targeted therapies. Among these, agents that inhibit the Syk kinase appear particularly promising in preclinical and early clinical studies.. The manuscript provides an overview of recent findings that implicate Syk and the BCR signaling pathway in the pathogenesis of several common lymphoid malignancies. It outlines preclinical and early clinical experiences with the Syk inhibitor fostamatinib disodium (R788) and discusses various options for further clinical development of this compound.. Inhibitors of Syk or other components of the BCR signaling pathway are emerging as an exciting novel class of agents for the treatment of common B-cell malignancies. Future efforts should focus on defining the disease entities that are most likely to benefit from these agents, although considerable evidence is already available to pursue such studies in patients with chronic lymphocytic leukemia. Combinations with chemo-immunotherapy, treatment of early-stage disease and consolidation therapy should all be explored and could lead to the development of novel therapeutic approaches with improved efficacy, tolerability and toxicity profiles.

Topics: Aminopyridines; Animals; Humans; Intracellular Signaling Peptides and Proteins; Leukemia; Lymphoma; Molecular Targeted Therapy; Morpholines; Oxazines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Syk Kinase

Intensified and central nervous system (CNS)-directed chemotherapy has improved outcomes for pediatric B cell acute lymphoblastic leukemia (B-ALL) but confers treatment-related morbidities. Moreover, many patients suffer relapses, underscoring the need to develop new molecular targeted B-ALL therapies. Using a mouse model, we show that leukemic B cells require pre-B cell receptor (pre-BCR)-independent spleen tyrosine kinase (SYK) signaling in vivo for survival and proliferation. In diagnostic samples from human pediatric and adult B-ALL patients, SYK and downstream targets were phosphorylated regardless of pre-BCR expression or genetic subtype. Two small-molecule SYK inhibitors, fostamatinib and BAY61-3606, attenuated the growth of 69 B-ALL samples in vitro, including high-risk (HR) subtypes. Orally administered fostamatinib reduced heavy disease burden after xenotransplantation of HR B-ALL samples into immunodeficient mice and decreased leukemia dissemination into spleen, liver, kidneys, and the CNS of recipient mice. Thus, SYK activation sustains the growth of multiple HR B-ALL subtypes, suggesting that SYK inhibitors may improve outcomes for HR and relapsed B-ALL.

Topics: Administration, Oral; Adult; Aminopyridines; Animals; Cell Proliferation; Cell Survival; Child; Female; Humans; Intracellular Signaling Peptides and Proteins; Leukemia; Male; Mice; Mice, SCID; Morpholines; Mutation; Neoplasm Transplantation; Niacinamide; Oligonucleotide Array Sequence Analysis; Oxazines; Phosphorylation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cells, B-Lymphoid; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Recurrence; Signal Transduction; Spleen; Syk Kinase; Treatment Outcome

Acute graft-versus-host disease (GvHD) limits the applicability of allogeneic hematopoietic cell transplantation for the treatment of leukemia. GvHD occurs as a consequence of multiple activating events in antigen-presenting cells (APCs) and T cells (Tcs). Spleen tyrosine kinase (Syk) is an intracellular non-receptor tyrosine kinase involved in multiple signaling events of immune cells. Therefore, we hypothesized that Syk may be a promising target to inhibit GvHD, which involves activation of different immune cell populations. In vivo expansion of luciferase(+) donor Tcs in mice developing GvHD was reduced by treatment with the Syk inhibitor Fostamatinib, which led to increased survival and reduced histologically confirmed GvHD severity. Importantly, in vivo and in vitro cytotoxicity against leukemia target cells and anti-murine cytomegalovirus immune responses were not impacted by Fostamatinib. In APCs Syk inhibition reduced the expression of costimulatory molecules and disrupted cytoskeletal organization with consecutive APC migratory defects in vitro and in vivo while phagocytic activity remained intact. On the basis of these immunomodulatory effects on different cell populations, we conclude that Syk targeting in alloantigen-activated Tcs and APCs with pharmacologic inhibitors, already applied successfully in anti-lymphoma therapy, has clinical potential to reduce GvHD, especially as anti-leukemia and anti-viral immunity were preserved.

Topics: Aminopyridines; Animals; Antigen-Presenting Cells; Blotting, Western; Bone Marrow Transplantation; Cell Movement; Cell Proliferation; Cytomegalovirus; Cytomegalovirus Infections; Dendritic Cells; Female; Flow Cytometry; Graft vs Host Disease; Graft vs Leukemia Effect; Intracellular Signaling Peptides and Proteins; Leukemia; Lymphocyte Activation; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Morpholines; Oxazines; Phosphorylation; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Spleen; Syk Kinase; T-Lymphocytes; Transplantation, Homologous