Spleen Tyrosine Kinase Inhibitor Research Articles

Results from an open-label phase 2a study of cerdulatinib, a dual spleen tyrosine kinase/janus kinase inhibitor, in relapsed/refractory peripheral T-cell lymphoma.

In this phase-2a study (NCT01994382), patients aged ≥18 years with relapsed/refractory peripheral T-cell lymphoma (PTCL; angioimmunoblastic T-cell lymphoma/T follicular helper [AITL/TFH], n = 29); PTCL-not otherwise specified [NOS], n = 11; and Other, n = 25) received 30 mg oral cerdulatinib, a reversible dual inhibitor of spleen tyrosine kinase and Janus kinase, twice daily in 28-day cycles until disease progression or unacceptable toxicity. Overall response rate (ORR) was 36.2% (12 complete responses [CR],9 partial responses [PR], and 14 stable disease); median time to response was 1.9 months. ORR was 51.9% for AITL/TFH (10 CR, 4 PR) and 31.8% for Other (2 CR, 5 PR); median duration of response was 12.9 and 5.3 months, respectively. The most common grade ≥3 treatment-emergent adverse events were asymptomatic amylase elevation (23.1%), anemia (20.0%), and asymptomatic lipase elevation (18.5%). These data suggest clinical activity and acceptable tolerability for cerdulatinib in patients with relapsed/refractory PTCL.

Sovleplenib in patients with primary or secondary warm autoimmune haemolytic anaemia: results from phase 2 of a randomised, double-blind, placebo-controlled, phase 2/3 study.

Spleen tyrosine kinase inhibitors are potential treatment options for warm autoimmune haemolytic anaemia. This study aimed to assess the preliminary efficacy and safety of sovleplenib-an oral spleen tyrosine kinase inhibitor-in patients with warm autoimmune haemolytic anaemia in China. Here we report on the phase 2 results. This randomised, double-blind, placebo-controlled, phase 2 part from the phase 2/3 study was conducted at 13 centres in China. Eligible patients, aged 18-75 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of no more than 2, had primary or secondary warm autoimmune haemolytic anaemia (stable underlying disease not requiring drug intervention) with no response to previous glucocorticoid treatment, haemoglobin of less than 100 g/L with active haemolysis, and a positive direct antiglobulin test. The study comprised two periods; patients were randomly assigned (3:1) to receive sovleplenib or placebo at 300 mg orally once a day in the 8-week double-blind period. Upon completion, all patients entered an open-label treatment period for at least 16 weeks and received sovleplenib 300 mg once a day until 24 weeks after the last patient was randomly assigned. The primary endpoint for phase 2 of the trial was overall haemoglobin response rate (haemoglobin ≥100 g/L with an increase of ≥20 g/L from baseline at least once, and haemoglobin not affected by rescue therapy, such as red blood cell transfusions, intravenous immunoglobulin, and glucocorticoids) by week 24. Efficacy analyses in the 0-8 week double-blind period included all patients who were randomly assigned, analysed by intention-to-treat. Safety analysis in the double-blind period included patients in the intention-to-treat population who received at least one dose of the study medication. This phase 2/3 study is registered with ClinicalTrials.gov, NCT05535933, and the phase 3 part is ongoing. Between Sept 26, 2022, and May 9, 2023, 34 patients were screened and 21 patients (four [19%] male and 17 [81%] female) were enrolled in the study and randomly assigned to receive either sovleplenib (n=16) or placebo (n=5). All 21 patients completed the 0-8-week double-blind treatment and entered the open-label treatment period. The overall haemoglobin response rate was 67% (14 of 21 patients) by week 24, and durable haemoglobin response rate was 48% (ten of 21 patients) by week 24. During the 0-8-week double-blind treatment, 13 (81%) of 16 patients in the sovleplenib group versus five (100%) of five patients taking placebo reported treatment-emergent adverse events (TEAEs), and four (25%) of 16 patients versus four (80%) of five patients reported grade 3 adverse events. Although all 21 patients had a TEAE during the 24-week treatment with sovleplenib, only seven (33%) patients had grade 3 events. The most common grade 3 TEAE was anaemia (four [19%] patients), which was not related to treatment. There were no grade 4 or 5 TEAEs. Sovleplenib treatment achieved an encouraging overall haemoglobin response in Chinese patients with warm autoimmune haemolytic anaemia and was well tolerated. The phase 3 part of the study (ESLIM-02) is currently ongoing to further substantiate the efficacy and safety of sovleplenib in this setting. HUTCHMED.

Targeting spleen tyrosine kinase (SYK): structure, mechanisms and drug discovery.

Spleen tyrosine kinase (SYK) is a crucial non-receptor tyrosine kinase involved in signaling pathways that regulate various cellular processes. It is primarily expressed in hematopoietic cells and myeloid cells, which are crucial for B-cell development, maturation and antibody production, and it is a key therapeutic target for autoimmune and allergic diseases. Overexpression of SYK is also associated with cancer and cardiovascular, cerebrovascular and neurodegenerative diseases, contributing to their initiation and progression. SYK is a promising target for drug development, and several inhibitors have already been reported. This review covers the structure and regulatory pathways of SYK, as well as its links to various diseases. It also highlights key small-molecule SYK inhibitors, their design strategies and their potential therapeutic benefits, aiming to enhance our understanding and aid in the discovery of more-effective SYK inhibitors.

Platelet spleen tyrosine kinase is a key regulator of anti-PF4 antibody-induced immunothrombosis.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but serious prothrombotic adverse event following vaccination with adenovector-based COVID-19 vaccines. Laboratory findings indicate that anti-platelet factor 4 (PF4) immunoglobulin G antibodies are the causing factor for the onset of thromboembolic events in VITT. However, molecular mechanisms of cellular interactions, signaling pathways and involvement of different cell types in VITT antibody-mediated thrombosis are not fully understood. Moreover, uncertainty exists regarding current treatment protocols since the sole anticoagulation was shown to be inefficient to prevent thrombosis progression in severe VITT cases. In this study, we demonstrate that platelet spleen tyrosine kinase (SYK) modulates anti-PF4 VITT-mediated thrombus formation in an ex vivo model of immunothrombosis. Our study showed that the selective inhibition of SYK can abrogate VITT antibody-driven procoagulant platelet formation, activation of plasmatic coagulation as well as platelet-leukocyte interplay. Most importantly, the specific inhibition of SYK in platelets but not in neutrophils prevented VITT antibody-induced multicellular thrombus formation, without perturbing the platelet function. Our findings indicate that the specific targeting of platelet SYK might be a promising therapeutic approach to prevent thrombotic complications in patients with antibody-mediated immunothrombosis.

Fostamatinib for Hospitalized Adults With COVID-19 and Hypoxemia: A Randomized Clinical Trial.

Fostamatinib, a spleen tyrosine kinase inhibitor, has been reported to improve outcomes of COVID-19. To evaluate the efficacy and safety of fostamatinib in adults hospitalized with COVID-19 and hypoxemia. This multicenter, phase 3, placebo-controlled, double-blinded randomized clinical trial was conducted at 41 US sites and 21 international sites between November 17, 2021, and September 27, 2023; the last follow-up visit was December 31, 2023. Participants were adults aged 18 years or older hospitalized with acute SARS-CoV-2 infection and hypoxemia. Data were analyzed between January 10 and March 8, 2024. Fostamatinib, 150 mg orally twice daily for 14 days, or placebo. The primary outcome was oxygen-free days, an ordinal outcome classifying a participant's status at day 28 based on mortality and duration of supplemental oxygen use. An adjusted odds ratio (AOR) greater than 1.0 was considered to indicate superiority of fostamatinib over placebo. A key secondary outcome was 28-day all-cause mortality. Safety outcomes included elevated transaminase values, neutropenia, and hypertension. Of the 400 participants randomized (median age, 67 years [IQR, 58-76 years]; 210 [52.5%] men), 199 received fostamatinib and 201 received placebo. The mean (SD) number of oxygen-free days was 13.4 (12.4) in the fostamatinib group and 14.2 (12.1) in the placebo group (unadjusted mean difference, -1.26 days [95% CI, -3.52 to 1.00 days]; AOR, 0.82 [95% credible interval (CrI), 0.58-1.17]). Mortality at 28 days occurred in 22 of 195 patients (11.3%) in the fostamatinib group and 16 of 197 (8.1%) in the placebo group (AOR, 1.44; 95% CrI, 0.72-2.90). Aspartate aminotransferase elevation occurred more commonly in the fostamatinib group (23 [11.6%]) than in the placebo group (11 [5.5%]; AOR, 2.28; 95% CrI, 1.07-4.84). Other safety outcomes were similar between groups. In this randomized clinical trial of adults hospitalized with COVID-19 and hypoxemia, fostamatinib did not increase the number of oxygen-free days compared with placebo. These results do not support the hypothesis that fostamatinib improves outcomes among adults hospitalized with hypoxemia during the Omicron era. ClinicalTrials.gov Identifier: NCT04924660.

Activation of spleen tyrosine kinase (SYK) contributes to neuronal pyroptosis and cognitive impairment in diabetic mice via the NLRP3/Caspase-1/GSDMD signaling pathway.

Diabetes mellitus (DM) patients are at increased risk of cognitive impairment. The precise mechanisms underlying the association between DM and cognitive impairment remain unclear. Spleen tyrosine kinase (SYK), a crucial regulator of signal transduction, has been implicated in microglial pyroptosis in experimental ischemic stroke models. The present study investigated the potential role of SYK in DM-associated cognitive impairment. Diabetes was induced by streptozotocin (STZ) in C57BL/6 mice, and cognitive function and cerebral injury were assessed 12weeks later using the Morris water maze (MWM), TUNEL assay and Western blotting. In vitro, the inhibition of SYK was investigated in a mouse hippocampal neuronal cell line cultured with high glucose. Compared with control mice, DM mice presented impaired spatial learning and memory. Additionally, SYK activation was linked to neuronal pyroptosis, as evidenced by increases in the number of TUNEL-positive cells and protein levels of NLRP3, ASC, procaspase-1, caspase-1, GSDMD, the GSDMD N-terminal fragment, pro-IL-1β, and IL-1β in the hippocampus of DM mice. Compared with no treatment, SYK knockdown markedly attenuated cognitive impairment and histologic and ultrastructural pathological changes in the hippocampus of DM mice. The increased expression of pyroptosis-associated proteins and the increased number of TUNEL-positive cells were also significantly reduced. In vitro, high glucose significantly activated SYK to trigger the canonical pyroptotic pathway in cultured HT22 cells. The inhibition of SYK with a small interfering RNA or specific inhibitor significantly ameliorated the neuronal pyroptosis mediated by high glucose. Our findings demonstrate that SYK activation plays a pivotal role in promoting the cognitive impairment associated with DM. This effect is mediated by triggering neuronal pyroptosis through the canonical NLRP3/Caspase-1/GSDMD pathway. These results suggest that SYK may serve as a potential target for preventing or mitigating cognitive impairment in patients with DM.

Spleen tyrosine kinase inhibitors disrupt human neutrophil swarming and antifungal functions.

Neutrophils can amplify their destructive power through swarming, a crucial process against large targets that individual neutrophils cannot destroy. However, the molecular mechanisms controlling this process are just emerging. Here, we leveraged microscale tools to probe the biology of swarming against fungi. We used multiple chemical inhibitors and mapped SYK, PI3Ky, and JNK signaling roles during human neutrophil swarming against fungal clusters of Candida albicans. We also found that treating human neutrophils with GCSF and GM-CSF rescues some neutrophil antifungal function during SYK inhibition. These findings advance our understanding of swarming biology in humans while laying the foundation for developing therapeutics that enhance neutrophil function during immunosuppression.

Spleen tyrosine kinase: a novel pharmacological target for sepsis-induced cardiac dysfunction and multi-organ failure.

Sepsis is a systemic condition caused by a dysregulated host response to infection and often associated with excessive release of proinflammatory cytokines resulting in multi-organ failure (MOF), including cardiac dysfunction. Despite a number of effective supportive treatments (e.g. ventilation, dialysis), there are no specific interventions that prevent or reduce MOF in patients with sepsis. To identify possible intervention targets, we re-analyzed the publicly accessible Gene Expression Omnibus accession GSE131761 dataset, which revealed an increased expression of spleen tyrosine kinase (SYK) in the whole blood of septic patients compared to healthy volunteers. This result suggests a potential involvement of SYK in the pathophysiology of sepsis. Thus, we investigated the effects of the highly selective SYK inhibitor PRT062607 (15mg/kg; i.p.) on sepsis-induced cardiac dysfunction and MOF in a clinically-relevant, murine model of sepsis. PRT062607 or vehicle (saline) was administered to 10-weeks-old C57BL/6 mice at 1h after the onset of sepsis induced by cecal ligation and puncture (CLP). Antibiotics (imipenem/cilastatin; 2mg/kg; s.c.) and analgesic (buprenorphine; 0.05mg/kg; i.p.) were administered at 6h and 18h post-CLP. After 24h, cardiac function was assessed in vivo by echocardiography and, after termination of the experiments, serum and cardiac samples were collected to evaluate the effects of SYK inhibition on the systemic release of inflammatory mediators and the degree of organ injury and dysfunction. Our results show that treatment of CLP-mice with PRT062607 significantly reduces systolic and diastolic cardiac dysfunction, renal dysfunction and liver injury compared to CLP-mice treated with vehicle. In addition, the sepsis-induced systemic inflammation (measured as an increase in inflammatory cytokines and chemokines in the serum) and the cardiac activation of NF-kB (IKK) and the NLRP3 inflammasome were significantly reduced in CLP-mice treated with PRT062607. These results demonstrate, for the first time, that SYK inhibition 1h after the onset of sepsis reduces the systemic inflammation, cardiac dysfunction and MOF, suggesting a potential role of the activation of SYK in the pathophysiology of sepsis. Novel therapeutic strategies that inhibit SYK activity may be of benefit in patients with diseases associated with local or systemic inflammation including sepsis.

Fostamatinib, a Spleen Tyrosine Kinase Inhibitor, Exerts Anti-Inflammatory Activity via Inhibiting STAT1/3 Signaling Pathways.

Fostamatinib is the first spleen tyrosine kinase inhibitor approved for the treatment of chronic adult immune thrombocytopenia via blocking autoantibody-mediated platelet phagocytosis. Nevertheless, the potential of fostamatinib as therapeutic agent against acute inflammatory diseases has not been examined. This study aimed to investigate the effects of fostamatinib on the activation of macrophages and neutrophils and its therapeutic effects on SIRS. First, RT-qPCR and ELISA were used to detect the effects of fostamatinib on the expression and secretion of inflammatory factors by peritoneal macrophages (PMs) induced with TLR agonists. The activation and ROS release of neutrophils were detected by flow cytometry. Subsequently, the therapeutic effect of fostamatinib on LPS-induced SIRS in mice was examined. Finally, we also explored the underlying mechanisms of fostamatinib exerting pharmacodynamic effects by analyzing its effects on LPS-induced gene expression profile and the activation of signaling pathways in PMs through transcriptome sequencing and Western blot. We found that fostamatinib inhibited the expression and secretion of TNF-α, IL-6, CCL2, CCL3, and CXCL10 (*P < 0.05) in PMs induced by LPS. Fostamatinib also reduced the activation of neutrophils stimulated by LPS, and suppressed the release of ROS by neutrophils. In SIRS mice, fostamatinib diminished the levels of inflammatory factors, and inhibited the excessive consumption of neutrophils in bone marrow. Transcriptome sequencing results showed that fostamatinib significantly inhibited the transcription of Cxcl10, Isg20, Mx1, Rsd2, etc. (*P < 0.05) in PMs induced by LPS. Meanwhile, fostamatinib selectively blocked the phosphorylation of STAT1 and STAT3 in PMs induced by LPS and cytokines (IFN-γ and IL-6). Fostamatinib can significantly inhibit LPS-induced inflammatory response through blocking STAT1/3 signaling pathways and has the potential to be used in the therapy of acute inflammatory diseases, especially SIRS and sepsis, which are resulting from the infection of Gram-negative bacteria.

Fostamatinib Inhibits the Proliferation of Ovarian Cancer Cells Through Apoptosis Induction.

Ovarian cancer remains a significant challenge due to its high mortality rate and poor prognosis, especially in advanced stages. Despite treatment advancements, issues with resistance and recurrence persist, highlighting the urgent need for new and effective therapies. This study aimed to evaluate fostamatinib, an oral spleen tyrosine kinase inhibitor initially developed for autoimmune diseases, as a potential treatment for ovarian cancer. The effects of fostamatinib on ovarian cancer cell lines were assessed using WST-1 assays for cell proliferation. Apoptosis was evaluated through TUNEL assays, DNA fragmentation analysis, and flow cytometry. Western blot analysis was used to detect cleavage of apoptotic proteins, including caspase-3 and PARP, and flow cytometry analyzed cell cycle changes. Fostamatinib treatment resulted in a dose- and time-dependent reduction in ovarian cancer cell growth and induced apoptosis, as indicated by increased TUNEL-positive cells, DNA fragmentation, and rises in both early and late apoptosis. Western blot analysis showed increased cleavage of apoptotic proteins, including caspase-3 and PARP. Flow cytometry also demonstrated an increase in the sub-G1 phase of the cell cycle, further supporting apoptosis induction. Fostamatinib, by inhibiting cell proliferation and inducing apoptosis, shows promise as a repurposed therapeutic agent for ovarian cancer, potentially offering a new approach to improve patient outcomes.

Platelet Responses After Tapering and Discontinuation of Fostamatinib in Patients with Immune Thrombocytopenia: A Continuation of the Fostasur Study.

Background/objectives: Fostamatinib is a spleen tyrosine kinase (SYK) inhibitor approved for the treatment of adult patients with chronic immune thrombocytopenia (ITP). There is little information about dose tapering and sustained remission after discontinuation in ITP. In this retrospective multicenter study, we evaluated efficacy and safety of fostamatinib in adult patients with ITP before, during, and after tapering/discontinuation (T/D). Methods: T/D was performed on subjects who achieved complete platelet response (CR) with progressive, conditional dose reduction every four weeks. Results: Sixty-one patients were included from 14 reference centers between October 2021 and May 2023. In subjects that completed T/D (n = 9), the median time from treatment initiation to response was 21 days (IQR: 7.5-42), median time from treatment initiation to CR was 28 days (IQR: 28-42), median time from treatment initiation to the start of tapering was 116 days (IQR: 42-140), and duration of tapering was 112.5 days (IQR: 94.5-191). The median platelet count was 232 × 109/L (IQR: 152-345 × 109/L) at tapering and 190 × 109/L (IQR: 142.5-316.5 × 109/L) at discontinuation. With a median follow-up since discontinuation of 263 days (IQR: 247-313 days), only two patients have relapsed (at 63 and 73 days). Fostamatinib was restarted, achieving a new CR. Platelet counts higher than 100 × 109/L in week 12 were the only positive predictive factors for successful tapering and discontinuation. Conclusions: Sustained response in patient with ITP treated with fostamatinib could be developed. The prognostic factors and recommended scheme of tapering still have to be evaluated.

Kidney injury: the spleno-renal connection and splenic tyrosine kinase.

Kidney injury is a major medical burden and one of the most common reasons for hospitalization and poor life quality. Kidney injury can include acute kidney injury, chronic kidney disease, and immune-mediated kidney diseases most of which have no definitive therapy. The spleen is a secondary lymphoid organ in the reticuloendothelial system that plays an important role in protecting the body from various diseases. Notably, spleen tyrosine kinase, a non-receptor tyrosine kinase, is a crucial player that aids in immunity and protection and is highly expressed in the kidney and hematopoietic cells. It has been shown that alterations in spleen tyrosine kinase function or expression could lead to a wide range of diseases and abnormalities. Over the past decade, the role of spleen and spleen tyrosine kinase in multiple kidney diseases has emerged. Evidence suggests that modulating the spleno-renal connection through activation of the cholinergic anti-inflammatory pathway can be a promising strategy for protecting against kidney injury. Imitating the protective function of the spleen through interleukin-10-extracellular vesicles can also be of therapeutic value. In addition, evidence showed that inhibition of the spleen tyrosine kinase leads to amelioration of the kidney injury. However, further exploration and long-term studies are needed to unravel the spleno-renal connection, as well as the efficacy of spleen tyrosine kinase inhibitors, before they can be used as means for treatment of kidney injury.

Abstract C067: Immune thrombocytopenia induced by PD-1/PD-L1 inhibitors in a patient with non-small cell lung adenocarcinoma: A case report and literature review

Abstract Introduction: The introduction of immunotherapy, particularly programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors, has transformed the treatment paradigm for non-small cell lung adenocarcinoma (NSCLC), significantly improving patient survival rates. However, alongside their immune-activating effects, these agents can also lead to immune-related adverse events (irAEs), affecting various organ systems. Among these, immune thrombocytopenia (ITP) is a rare but potentially life-threatening complication characterized by the destruction of platelets by autoantibodies, resulting in decreased platelet counts and an increased risk of bleeding. While ITP has been identified as a complication of immunotherapy, particularly PD-1 or PD-L1 inhibitors, its incidence, clinical presentation, and management remain poorly understood. Case Presentation: The 73-year-old female with stage IIIA poorly differentiated NSCLC who received chemotherapy with Taxol/Carboplatin and concurrent radiation therapy followed by a right upper lobectomy, initiated on immunotherapy with durvalumab, a PD-L1 inhibitor, developed severe thrombocytopenia (grade 4) after receiving two cycles of durvalumab. Despite steroid treatment, her condition persisted, indicating immune-related adverse events (irAEs). After confirming the diagnosis through further investigation, including molecular analysis, the patient was treated with intravenous immunoglobulin (IVIG), which significantly increased her platelet counts. Durvalumab was discontinued, and fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, was initiated to manage the irAEs effectively. Discussion: ITP is recognized as an immune-related adverse event (irAE) associated with PD-1 or PD-L1 inhibitors, although it remains rare and poorly understood. Several case reports have highlighted the occurrence of ITP induced by these inhibitors, demonstrating varied clinical presentations and responses to treatment. Mechanisms underlying ITP induction by PD-1/PD-L1 inhibitors are not fully elucidated but may involve immune dysregulation, including CD4+ and CD8+ T cell activation, production of antiplatelet antibodies, and increased expression of PD-L1 on platelets. Management strategies for ITP induced by PD-1/PD-L1 inhibitors include steroids, intravenous immunoglobulin (IVIG) therapy, recombinant human thrombopoietin (TPO), interleukin-6 (IL-6) receptor antagonists, and immunosuppressive agents. However, the effectiveness of these treatments varies among patients, highlighting the need for individualized approaches and further research to optimize management strategies. Conclusion: The prompt recognition and management of ITP induced by PD-1/PD-L1 inhibitors are essential for ensuring favorable patient outcomes. Further research is needed to understand the underlying mechanisms and develop effective prevention and management strategies for this rare but serious immune-related adverse event. Citation Format: Aliya M Khan, Richa Dawar. Immune thrombocytopenia induced by PD-1/PD-L1 inhibitors in a patient with non-small cell lung adenocarcinoma: A case report and literature review [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C067.

Dual Inhibition of SYK and EGFR Overcomes Chemoresistance by Inhibiting CDC6 and Blocking DNA Replication.

Targeting multiple signaling pathways has been proposed as a strategy to overcome resistance to single-pathway inhibition in cancer therapy. A previous study in epithelial ovarian cancers identified hyperactivity of spleen tyrosine kinase (SYK) and EGFR, which mutually phosphorylate and activate each other. Given the potential for pharmacologic inhibition of both kinases with clinically available agents, this study aimed to assess the antitumor efficacy of both pharmacologic and genetic SYK and EGFR coinhibition using a multifaceted approach. We assessed the coinactivation effects in chemoresistant ovarian cancer cell lines, patient-derived organoids, and xenograft models. Dual inhibition of SYK and EGFR in chemoresistant ovarian cancer cells elicited a synergistic antitumor effect. Notably, the combined inhibition activated the DNA damage response, induced G1 cell-cycle arrest, and promoted apoptosis. The phosphoproteomic analysis revealed that perturbation of SYK and EGFR signaling induced a significant reduction in both phosphorylated and total protein levels of cell division cycle 6, a crucial initiator of DNA replication. Together, this study provides preclinical evidence supporting dual inhibition of SYK and EGFR as a promising treatment for chemoresistant ovarian cancer by disrupting DNA synthesis and impairing formation of the prereplication complex. These findings warrant further clinical investigation to explore the potential of this combination therapy in overcoming drug resistance and improving patient outcomes. Significance: SYK and EGFR coinhibition exerts synergistic anticancer effects in chemoresistant ovarian cancer, providing a strategy to treat chemotherapy-resistant ovarian cancers using clinically available agents by targeting critical signaling pathways involved in DNA replication.

Post-marketing safety surveillance of fostamatinib: an observational, pharmacovigilance study leveraging FAERS database

ABSTRACT Objective Fostamatinib, an FDA-approved oral small-molecule spleen tyrosine kinase (SYK) inhibitor, is used to treat thrombocytopenia in adults with chronic immune thrombocytopenia (ITP) who have not responded to previous treatments. However, comprehensive safety data is lacking. This study uses the FDA Adverse Event Reporting System (FAERS) database to explore real-world adverse events (AEs) related to fostamatinib, aiming to inform its clinical use. Methods The FAERS database was retrospectively queried to extract reports associated with fostamatinib from 2019 to 2023. To identify and evaluate potential AEs in patients receiving fostamatinib, various disproportionality analyses such as the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) were employed. Results A total of 23 AE signals were included in our analysis. Among them, hypertension, blood pressure increase, blood pressure abnormality, hepatic enzyme increase, and diarrhea were consistent with the common AEs described for fostamatinib in clinical trials. In addition, unexpected serious AEs were detected including cerebral thrombosis and necrotizing soft tissue infection. The median time to onset of fostamatinib-related AEs was 86 days. Conclusion Our investigation revealed several possibly emergent safety concerns associated with fostamatinib in real-world clinical practice, which might provide essential vigilance evidence for clinicians and pharmacists to manage the safety issues of fostamatinib.

Real-world clinical outcomes with fostamatinib for the treatment of refractory chronic immune thrombocytopenia: a single-center experience.

Fostamatinib is a spleen tyrosine kinase inhibitor indicated for the treatment of chronic immune thrombocytopenia (ITP) unresponsive to a previous treatment. Real-world studies evaluating the utilization and effectiveness of fostamatinib outside the context of a clinical trial are lacking. The objective of this analysis was to evaluate the effectiveness of fostamatinib for the treatment of ITP in a real-world cohort. We conducted a single-center, retrospective, observational study to evaluate the effectiveness of fostamatinib for the treatment of ITP. The primary endpoint was durable response as defined by the American Society of Hematology ITP response criteria. Secondary endpoints included overall response rate, time to response, and safety. Subgroup analysis was performed to assess frequency of durable response in key subgroups of patients based on prior therapies. Thirty-one patients treated with fostamatinib for ITP were included in our analysis. Patients had received a median of four prior lines of therapy. Ten patients (32%) achieved a durable response. Most durable responders maintained their response at 24 months ( n = 7; 70%). The median time to response was 9 days. Four patients (13%) discontinued fostamatinib due to an adverse event. Subgroups who had higher rates of durable responses included those who had received two to three prior lines of therapy (40%), splenectomized patients (50%), and those who had not received prior rituximab (55%). Fostamatinib therapy in a real-world population of patients with heavily pretreated ITP led to a durable response in a third of patients, which was maintained for most responders.

Fostamatinib for immune thrombocytopenic purpura in adult patients: A systematic review and meta-analysis.

Immune thrombocytopenic purpura (ITP) is an immune disorder characterized by thrombocytopenia. Fostamatinib is an orally administered spleen tyrosine kinase inhibitor intended to treat refractory ITP. To evaluate the efficacy and safety of fostamatinib as a subsequent-line therapy for ITP in adults. We searched four electronic databases for primary studies of any design. Primary efficacy outcomes included proportions of patients achieving overall (≥30×109 cells/L), partial (≥50×109 cells/L), and stable (as defined in original studies) platelet response. Safety outcomes included rescue medication use and other adverse events. We used narrative synthesis and Mantel-Haenszel random effect meta-analysis to summarize results. Our systematic review included 11 studies for analyses (n=722). Weighted mean proportions of patients achieving overall, partial, and stable responses with fostamatinib treatment were 0.70 [0.62, 0.76], 0.48 [0.36, 0.61], and 0.28 [0.16, 0.44], respectively. Fostamatinib was favored over placebo for partial (relative risk [RR]=3.04, 95% confidence interval [CI] [1.53, 6.06]) and stable (RR=6.43, 95% CI [1.58, 26.23]) responses. Patients on fostamatinib required less rescue medication and were more likely to experience hypertension. Fostamatinib is a viable subsequent-line therapy option for refractory ITP. Given the heterogeneous data and large number of small studies, these results should be interpreted cautiously.

Efficacy and safety of sovleplenib (HMPL-523) in adult patients with chronic primary immune thrombocytopenia in China (ESLIM-01): a randomised, double-blind, placebo-controlled, phase 3 study

Sovleplenib, a novel spleen tyrosine kinase (SYK) inhibitor, showed promising safety and activity in patients with primary immune thrombocytopenia in a phase 1b/2 trial. We aimed to evaluate the efficacy and safety of sovleplenib in patients with chronic primary immune thrombocytopenia. This randomised, double-blind, placebo-controlled, phase 3 trial (ESLIM-01) was done in 34 clinical centres in China. Eligible patients, aged 18-75 years, had chronic primary immune thrombocytopenia, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and received one or more previous treatments. Patients were randomly assigned (2:1) to receive oral sovleplenib or placebo, 300 mg once daily, for 24 weeks. Randomisation was stratified by baseline platelet counts, previous splenectomy, and concomitant treatment for anti-immune thrombocytopenia at baseline. The primary endpoint was durable response rate (proportion of patients with a platelet count of ≥50 × 109/L on at least four of six scheduled visits between weeks 14 and 24, not affected by rescue treatment) assessed by intention-to-treat. The trial is registered with ClinicalTrials.gov, NCT05029635, and the extension, open-label phase is ongoing. Between Sept 29, 2021, and Dec 31, 2022, 188 patients were randomly assigned to receive sovleplenib (n=126) or placebo (n=62). 124 (66%) were female, 64 (34%) were male, and all were of Asian ethnicity. Median previous lines of immune thrombocytopenia therapy were 4·0, and 134 (71%) of 188 patients had received previous thrombopoietin or thrombopoietin receptor agonist. The primary endpoint was met; durable response rate was 48% (61/126) with sovleplenib compared with zero with placebo (difference 48% [95% CI 40-57]; p<0·0001). The median time to response was 8 days with sovleplenib compared with 30 days with placebo. 125 (99%) of 126 patients in the sovleplenib group and 53 (85%) of 62 in the placebo group reported treatment-emergent adverse events (TEAEs), and most events were mild or moderate. Frequent TEAEs of grade 3 or higher for sovleplenib versus placebo were platelet count decreased (7% [9/126] vs 10% [6/62]), neutrophil count decreased (3% [4/126] vs 0% [0/62]), and hypertension (3% [4/126] vs 0% [0/62]). Incidences of serious TEAEs were 21% (26/126) in the sovleplenib group and 18% (11/62) in the placebo group. There were no deaths in the study. Sovleplenib showed a clinically meaningful sustained platelet response in patients with chronic primary immune thrombocytopenia, with a tolerable safety profile and improvement in quality of life. Sovleplenib could be a potential treatment option for patients with immune thrombocytopenia who received one or more previous therapy. HUTCHMED and Science and Technology Commission of Shanghai Municipality.

Development of SYK NanoBRET Cellular Target Engagement Assays for Gain-of-Function Variants.

Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase that is activated by phosphorylation events downstream of FcR, B-cell and T-cell receptors, integrins, and C-type lectin receptors. When the tandem Src homology 2 (SH2) domains of SYK bind to phosphorylated immunoreceptor tyrosine-based activation motifs (pITAMs) contained within these immunoreceptors, or when SYK is phosphorylated in interdomain regions A and B, SYK is activated. SYK gain-of-function (GoF) variants were previously identified in six patients that had higher levels of phosphorylated SYK and phosphorylated downstream proteins JNK and ERK. Furthermore, the increased SYK activation resulted in the clinical manifestation of immune dysregulation, organ inflammation, and a predisposition for lymphoma. The knowledge that the SYK GoF variants have enhanced activity was leveraged to develop a SYK NanoBRET cellular target engagement assay in intact live cells with constructs for the SYK GoF variants. Herein, we developed a potent SYK-targeted NanoBRET tracer using a SYK donated chemical probe, MRL-SYKi, that enabled a NanoBRET cellular target engagement assay for SYK GoF variants, SYK(S550Y), SYK(S550F), and SYK(P342T). We determined that ATP-competitive SYK inhibitors bind potently to these SYK variants in intact live cells. Additionally, we demonstrated that MRL-SYKi can effectively reduce the catalytic activity of SYK variants, and the phosphorylation levels of SYK(S550Y) in an epithelial cell line (SW480) stably expressing SYK(S550Y).

A pathological study on the efficacy of Syk inhibitors in a Candida albicans-induced aortic root vasculitis murine model

The activation of innate immunity may be involved in the development of Candida albicans-induced murine vasculitis, which resembles Kawasaki disease (KD) vasculitis. This study aimed to histologically clarify the time course of the development of vasculitis in this model in detail and to estimate the potential role of spleen tyrosine kinase (Syk) inhibitors in KD vasculitis. DBA/2 male mice were intraperitoneally injected with a vasculitis-inducing substance and treated with a Syk inhibitor (R788 or GS-9973). Systemic vasculitis, especially in the aortic annulus area, was histologically evaluated. Regarding lesions in the aortic annulus area, some mice in the untreated control group already showed initiation of vasculitis 1 day after the final injection of a vasculitis-inducing substance. The vasculitis expanded over time. Inflammation occurred more frequently at the aortic root than at the coronary artery. The distribution of inflammatory cells was limited to the intima, intima plus adventitia, or all layers. In the Syk inhibitor-treated groups, only one mouse had vasculitis at all observation periods. The severity and area of the vasculitis were reduced by both Syk inhibitors. Candida albicans-induced murine vasculitis may occur within 1 day after the injection of a vasculitis-inducing substance. Additionally, Syk inhibitors suppress murine vasculitis.