Recent advances in understanding spleen tyrosine kinase (SYK) in human biology and disease, with a focus on fostamatinib

Spleen tyrosine kinase (SYK) is an important regulatory molecule of signal transduction pathways involved in the pathogenesis of autoimmune diseases such as immune thrombocytopenia (ITP), and the SYK-signaling pathway has emerged as a potential target for the treatment of numerous diseases. The aim of this narrative review is to summarize the biological properties of SYK and its involvement in disease pathways, provide an update on SYK inhibitors in the treatment of ITP, and consider other potential applications. Fostamatinib, the only licensed SYK inhibitor to date, produces clinical response in ITP patients, including those who are refractory to other treatments. It appears to reduce the risk of thrombotic events and may therefore be a drug to consider for patients with an increased thrombotic risk. Encouraging results have also been obtained in the treatment of warm autoimmune hemolytic anemia. Several other SYK inhibitors have entered clinical trials for a range of indications, reflecting the ability of these drugs to affect multiple signaling pathways. SYK inhibitors have the potential to target several aspects of COVID-19 pathogenesis including thrombosis, without affecting normal hemostasis, and data from the first study of fostamatinib in COVID-19 are encouraging. It is hoped that ongoing trials in autoimmune indications other than ITP, as well as in hematological malignancies and other disorders, confirm the promise of SYK inhibitors. Immune thrombocytopenia (ITP) is an autoimmune disease that usually happens when your immune system mistakenly attacks and destroys platelets, which are cells that help blood to clot. Individuals with ITP can experience easy or excessive bruising and bleeding. Scientists have identified that an enzyme called spleen tyrosine kinase (SYK) is involved in numerous biological processes that are associated with the immune system response, inflammation, and some types of cancer in humans. Therefore, it has become a target for new drugs which inhibit the action of SYK. In this review article, the authors provide a summary of the biological properties and actions of SYK and its involvement in various diseases, discuss information about drugs that have been developed as SYK inhibitors for the treatment of ITP, and consider other potential uses for drugs that inhibit SYK. Although several drugs are being developed, the only SYK inhibitor that is currently available for the treatment of ITP is a drug called fostamatinib. In patients with ITP, including those who no longer respond to other treatments, fostamatinib has been shown to improve platelet counts and reduce bleeding events. Researchers are also currently investigating the use of drugs that inhibit SYK, including fostamatinib, for the potential treatment of other diseases associated with inflammation (e.g. rheumatoid arthritis, COVID-19), autoimmunity (e.g. warm autoimmune hemolytic anemia), and blood cancers (e.g. lymphoma, chronic lymphocytic leukemia, and acute myeloid leukemia). eng

Anti-SARS- CoV- 2 vaccines do not induce a hypercoagulable state in healthy individuals

Background: Anti-SARS- CoV- 2 adenoviral-vectored- DNA vaccines have been linked to a rare but serious thrombotic post-vaccine complication called the vaccine-induced immune thrombotic thrombocytopenia (VITT). VITT has raised concerns regarding the possibilities of increased thrombotic risk and/thrombocytopenia after anti-COVID- 19 vaccines. Aim(s): To investigate whether anti-SARS- CoV- 2 vaccines can cause subclinical coagulation activation and increased thrombin generation leading to a hypercoagulable state. Method(s): The study included 567 healthcare personnel from two hospitals in Norway. Of these, 521 were recruited 11-57 days post-vaccination with the first dose of ChAdOx1-S (Vaxzevria, AstraZeneca, UK) vaccine, and 46 were recruited prospectively prior vaccination with an mRNA vaccine, either elasomeran (Spikevax, Moderna, n = 38) or tozinameran (Comirnaty, Pfize-BioNTech, n = 8). In the latter group, samples were acquired before and 1-2 weeks after vaccination. In addition to pre-vaccination samples, 56 unvaccinated blood donors were recruited as controls (total n = 102). Thrombin generation, D-dimer and free tissue factor pathway inhibitor antigen (free TFPI) were analyzed. Result(s): None of the participants developed thrombosis/VITT or thrombocytopenia (platelet count < 100.109/L) after vaccination. There were no significant differences in D-dimer, free TFPI or the parameters of thrombin generation between the two vaccine groups and the controls (Table 1). No differences in thrombin generation or free TFPI between the ChAdOx1-S group and the mRNA group, the median D-dimer level was slightly higher in the ChAdOx1-S group, but both were within the normal range (Table 2). Thrombin generation, D-dimer and free TFPI showed no changes after mRNA vaccination compared with baseline. Conclusion(s): Anti-COVID- 19 vaccines, both ChAdOx1-S and mRNA, were not associated with significant increase in thrombin generation, D-dimer or free TFPI compared with controls. Neither significant differences were observed between ChAdOx1-S and mRNA vaccines nor changes after mRNA vaccines compared with baseline levels. Our results are reassuring in the sense that no subclinical activation in the coagulation system was observed with these vaccines. (Table Presented).

Recent advances in understanding spleen tyrosine kinase (SYK) in human biology and disease, with a focus on fostamatinib

Spleen tyrosine kinase (SYK) is an important regulatory molecule of signal transduction pathways involved in the pathogenesis of autoimmune diseases such as immune thrombocytopenia (ITP), and the SYK-signaling pathway has emerged as a potential target for the treatment of numerous diseases. The aim of this narrative review is to summarize the biological properties of SYK and its involvement in disease pathways, provide an update on SYK inhibitors in the treatment of ITP, and consider other potential applications. Fostamatinib, the only licensed SYK inhibitor to date, produces clinical response in ITP patients, including those who are refractory to other treatments. It appears to reduce the risk of thrombotic events and may therefore be a drug to consider for patients with an increased thrombotic risk. Encouraging results have also been obtained in the treatment of warm autoimmune hemolytic anemia. Several other SYK inhibitors have entered clinical trials for a range of indications, reflecting the ability of these drugs to affect multiple signaling pathways. SYK inhibitors have the potential to target several aspects of COVID-19 pathogenesis including thrombosis, without affecting normal hemostasis, and data from the first study of fostamatinib in COVID-19 are encouraging. It is hoped that ongoing trials in autoimmune indications other than ITP, as well as in hematological malignancies and other disorders, confirm the promise of SYK inhibitors.

ITP World Impact Survey (I-WISh) 2.0: Further Exploration of the Impact of ITP on Patients

Immune thrombocytopenia (ITP) is an acquired autoimmune disorder defined by a platelet count < 100 × 109/L without explanation, and an increased risk of bleeding. ITP itself as well as its treatments have multifaceted, often poorly understood impacts on patients’ quality of life (QoL). These effects include impact on activities of daily living, emotional health, energy, ability to think well and clearly, and productivity in the workplace. There are limited data on which individual aspects of ITP are perceived both by patients and physicians as having the greatest impact on QoL. Understanding patients’ perspectives is vital to optimize their QoL by specifying particular areas in need of therapy. I-WISh 1.0 was an exploratory, cross-sectional survey in which 1507 patients with ITP and 472 physicians across 13 countries completed separate, but related, online surveys that included assessments of ITP signs and symptoms, impact of symptoms, and patient-physician relationships. These findings have been presented at previous ASH and EHA congresses, and manuscripts are currently in preparation. However, although I-WISh 1.0 provided considerable insights into unexplored facets of the effects of ITP, an all-too-large number of gaps in understanding still remain. In response to this, I-WISh 2.0 is currently being developed. The objectives of the I-WISh 2.0 patient and physician cross-sectional surveys include: (1) to further explore the burden of fatigue and how it affects patients' lives, including what makes it better or worse;(2) to assess the emotional impact of living with chronic ITP, especially in relation to depression;(3) to assess how treatments for ITP can impact activities of daily living (positively and negatively);(4) to further relate effects of treatment to patients' QoL;and (5) to explore how telemedicine affects healthcare delivery for patients with ITP. Furthermore, data from subsets of patients will address (6) the impact of COVID-19 in patients with ITP;and (7) special issues affecting ITP in pregnancy. A steering committee of ITP expert physicians and patient advocacy group representatives are designing and will endorse the patient and physician surveys now nearing readiness after several meetings to determine the areas of greatest need of assessment. In addition, a control group will be included. Survey launch and data collection are scheduled to commence in early Q4 2020. Patients and physicians will complete similar online surveys. Both patient and physician surveys include a screener and sections of questions related to the specific objectives of I-WISh 2.0. The surveys include updates to key topics in I-WISh 1.0 (impact of fatigue, impact on daily life, treatment of ITP, emotional impact of ITP);validated patient-reported outcome tools to measure fatigue (MFIS-5), presence and severity of depression (PHQ-9), work-related burden (WPAI), and impact on quality of life (ILQI) tools;and questions related to COVID-19, telemedicine (remote patient monitoring), and pregnancy and ITP. Patients will be recruited to I-WISh 2.0 via treating physicians and patient advocacy groups, and will be included if they are ≥ 18 years of age, diagnosed with ITP, and agree to participate. Participating physicians will be required to be actively managing patients with ITP and have a minimum caseload of 3 ITP patients currently under their care;physicians must also have a primary specialty of hematology or hematology-oncology. Approval will be sought from an independent centralized Institutional Review Board. Data analysis will be primarily descriptive and correlative in nature. Breakdown by country and geographic areas will be included. A global sample is planned from 21 countries across 6 continents, with the aim of surveying more than 2000 patients and 600 physicians. I-WISh 2.0 will be the largest observational global survey ever conducted in ITP. If accepted, preliminary data are planned to be presented at the ASH meeting. I-WISh 2.0 will build on the strengths of I-WISh 1.0, which highlighted areas requir ng further assessment and will explore aspects of ITP of great interest that were neither conclusively addressed in the first survey nor well-studied in the past. Disclosures: Ghanima:Bristol Myers Squibb:Research Funding;Principia:Honoraria, Speakers Bureau;Pfizer:Honoraria, Research Funding, Speakers Bureau;Amgen:Honoraria, Speakers Bureau;Novartis:Honoraria, Speakers Bureau;Bayer:Research Funding.Provan:ONO Pharmaceutical:Consultancy;MedImmune:Consultancy;UCB:Consultancy;Amgen:Honoraria, Research Funding;Novartis:Honoraria, Research Funding.Cooper:Amgen:Honoraria, Speakers Bureau;Novartis:Honoraria, Speakers Bureau.Matzdorff:Roche Pharma AG:Other: Family stockownership;Amgen GmbH:Consultancy, Other: Honoraria paid to institution;Grifols Deutschland GmbH:Consultancy, Other: Honoraria paid to institution;Swedish Orphan Biovitrium GmbH:Consultancy, Other: Honoraria paid to institution;UCB Biopharma SRL:Consultancy, Other: Honoraria paid to institution;Novartis Oncology:Consultancy, Other: Honoraria paid to institution.Santoro:Novartis:Honoraria, Speakers Bureau;Takeda:Honoraria, Speakers Bureau;Amgen:Honoraria, Speakers Bureau;Novo Nordisk:Honoraria, Speakers Bureau;Bayer:Honoraria, Speakers Bureau;CSL Behring:Honoraria, Speakers Bureau;Roche:Honoraria, Speakers Bureau;Sobi:Honoraria, Speakers Bureau.Morgan:Sobi:Other: Consultancy fees paid to the ITP Support Association;UCB:Other: Consultancy fees paid to the ITP Support Association;Novartis:Other: Consultancy fees paid to the ITP Support Association.Kruse:Principia:Other: Grant paid to PDSA;Pfizer:Other: Grant and consultancy fee, all paid to PDSA;Argenx:Other: Grant paid to PDSA;Novartis:Other: PDSA received payment for recruiting patients to I-WISh and for promoting I-WISh on the globalitp.org website. Grant and consultancy fee, all paid to PDSA outside the submitted work;CSL Behring:Other: Grant paid to PDSA;UCB:Other: Grant and consultancy fee, all paid to PDSA;Rigel:Other: Grant paid to PDSA;Amgen:Other: Grant and honorarium, all paid to PDSA.Zaja:Janssen-Cilag:Honoraria, Speakers Bureau;Takeda:Honoraria, Speakers Bureau;Bristol Myers Squibb:Honoraria, Speakers Bureau;Grifols:Honoraria, Speakers Bureau;Amgen:Honoraria, Speakers Bureau;AbbVie:Honoraria, Speakers Bureau;Kyowa Kirin:Honoraria, Speakers Bureau;Mundipharma:Honoraria, Speakers Bureau;Novartis:Honoraria, Patents & Royalties: Pending patent (No. PAT058521) relating to TAPER trial (NCT03524612), Speakers Bureau;Roche:Honoraria, Speakers Bureau.Lahav:Novartis:Other: Consultancy fees paid to the Israeli ITP Support Association.Tomiyama:Novartis:Consultancy, Honoraria;Kyowa Kirin:Honoraria;Sysmex:Consultancy.Winograd:Novartis:Other: Consultancy fees paid to the Israeli ITP Support Association.Lovrencic:UCB:Other: Consultancy fees paid to AIPIT;Novartis:Other: Honorarium paid to AIPIT.Bailey:Adelphi Real World:Current Employment;Novartis:Other: Employee of Adelphi Real World, which has received consultancy fees from Novartis.Haenig:Novartis:Current Employment.Bussel:Novartis:Consultancy;Argenx:Consultancy;UCB:Consultancy;CSL Behring:Consultancy;Shionogi:Consultancy;Regeneron:Consultancy;3SBios:Consultancy;Dova:Consultancy;Principia:Consultancy;Rigel:Consultancy;Momenta:Consultancy;RallyBio:Consultancy;Amgen:Consultancy.

A Phase II Study to Assess the Sustained Response Off Treatment in Patients with ITP Receiving Eltrombopag, Who Had a Previous Insufficient Response to Corticosteroids (TAPER): A Recruitment Update

Corticosteriods (CSs) remain the standard of care for immune thrombocytopenia (ITP);however, many patients relapse after initial treatment, and long-term CS use is associated with considerable toxicity and tolerability issues (Provan et al. Blood 2010). Clinically, there is a need for a less toxic regimen that will provide sustained response. Eltrombopag is a thrombopoietin receptor agonist (TPO-RA) currently approved in the United States for the treatment of ITP in patients who have had an insufficient response to CSs, immunoglobulins, or splenectomy. Limited evidence from retrospective studies and the phase II ESTIT study (NCT02402998) suggests that earlier use of TPO-RAs after ITP diagnosis may allow a larger proportion of patients to achieve sustained responses after tapering off drug (Červinek et al. Int J Hematol 2015;Gonzalez-Lopez et al. Am J Hematol 2015;Newland et al. Br J Haematol 2016;Lucchini, et al. Haematologica 2019). TAPER (NCT03524612) is an ongoing phase II, open-label, prospective, single-arm study assessing sustained response off treatment in adult patients with ITP receiving eltrombopag, who had relapsed or failed to respond to initial CS treatment. Eligible patients are adults (≥ 18 years old) with ITP who are not responsive to or are in relapse after first-line CS therapy ± immunoglobulins used as rescue therapy, with platelet counts < 30×109/L, and assessed as needing treatment. Patients receive a starting dose of 50 mg eltrombopag QD (East/Southeast Asian ancestry: 25 mg QD;Japanese patients treated in Japan: 12.5 mg QD per approved starting dose in the Japanese prescribing information). The primary endpoint is the number (%) of patients with sustained responses off treatment by Month 12. Sustained response is defined as a complete response (platelet count ≥ 100×109/L) with platelet counts ≥ 70×109/L maintained for 2 months, followed by dose reduction and treatment discontinuation while maintaining platelet counts ≥ 30×109/L, without bleeding or rescue therapy, until Month 12. Platelet counts are assessed weekly during the first 8 weeks of treatment, and biweekly thereafter, depending on patient response. Rescue therapy is permitted within the first 14 days of study treatment and does not preclude patients from reaching the primary endpoint criteria, if successful discontinuation of eltrombopag is reached and maintained at Month 12. The proportion of patients who reach the primary endpoint will be summarized with the 95% confidence interval (Clopper-Pearson method). A binomial test for one proportion, H0: P = 0.15 vs. H1: P > 0.15 will be performed to test if the proportion of remission patients is greater than 15%, using a target alpha level of 0.05. Patients who meet the primary endpoint at 12 months will be followed up for an additional 12 months.Patients who relapse between Months 12 and 24 will be offered retreatment with eltrombopag until the end of Month 24. Secondary endpoints will include measures of quality of life, and exploratory endpoints will include biomarker assessments of immunomodulation. Here, we report an update on trial recruitment and patient baseline characteristic data from an early data cut (November 15, 2019). An estimated 101 patients across 50 sites will be enrolled;47 sites are currently active and 3 are pending site initiation visits. As of November 15, 2019, 66 patients had been screened, 53 of whom had been enrolled and had undergone treatment. Of the patients enrolled, 60.4% were female and the mean (± standard deviation) age was 49.4 (± 19.0) years. The majority of patients were White (88.7%). On June 24, 2020, patients from 15 countries worldwide were committed to screening (Figure 1);the number of patients screened had risen to 98, with 82 patients enrolled. The planned study timeline has been disrupted due to the COVID-19 pandemic. Enrollment is expected to complete in November 2020, with final results expected in 2023. Conclusion: The purpose of this trial is to assess sustained response off treatment following eltrombopag therap in patients with ITP who failed to respond to or have relapsed after initial treatment with steroids. The data generated by TAPER will provide insights into whether eltrombopag could be a viable treatment option after first-line steroid treatment. If this were confirmed, the earlier use of eltrombopag could have the potential to reduce the toxicity from repeated steroid exposure in patients with ITP. [Formula presented] Disclosures: Cooper: Novartis: Honoraria, Speakers Bureau;Amgen: Honoraria, Speakers Bureau. Ghanima: Amgen: Honoraria, Speakers Bureau;Bristol Myers Squibb: Research Funding;Bayer: Research Funding;Novartis: Honoraria, Speakers Bureau;Principia: Honoraria, Speakers Bureau;Pfizer: Honoraria, Research Funding, Speakers Bureau. Haenig: Novartis: Current Employment. Lee: Novartis: Current Employment, Other: Novartis AG equity holder. Rahman: Novartis: Other: Full time employee of IQVIA which provides services to Novartis;IQVIA: Current Employment. Zaja: Kyowa Kirin: Honoraria, Speakers Bureau;Mundipharma: Honoraria, Speakers Bureau;Novartis: Honoraria, Patents & Royalties: Pending patent (No. PAT058521) relating to TAPER trial (NCT03524612), Speakers Bureau;Roche: Honoraria, Speakers Bureau;AbbVie: Honoraria, Speakers Bureau;Amgen: Honoraria, Speakers Bureau;Grifols: Honoraria, Speakers Bureau;Bristol Myers Squibb: Honoraria, Speakers Bureau;Takeda: Honoraria, Speakers Bureau;Janssen-Cilag: Honoraria, Speakers Bureau.