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SPLTRAK Abstract Submission
Treatment of Immune Thrombocytopenia with the Spleen Tyrosine Kinase Inhibitor Fostamatinib: Restoring Hemostatic Balance While Avoiding a Prothrombotic State
Ivy Altomare1, Vadim Markovtsov2, Leslie Todd2, Dheepika Weerasinghe2, Robert P Numerof2, Sandra Tong2, Esteban Masuda2, James B Bussel3
1Duke University School of Medicine, Durham, NC, United States/2Rigel Pharmaceuticals, Inc., South SanFrancisco, CA, United States/3New York Presbyterian Hosp. Weill Cornell Medical Center, New York, NY, United States

Background: While immune thrombocytopenia (ITP) is associated with bruising and bleeding, a two-fold higher risk of venous thromboembolic events (TEEs) was observed in chronic ITP patients compared to the general population.1 ITP patients have higher levels of prothrombin fragments 1+2, D-dimer, PAI-1 and soluble P-selectin, which may contribute to a procoagulant profile.2,3 Increased risk of TEEs is associated with: age >60 years, diabetes, hypertension, coronary disease, history of TEEs, anti-phospholipid antibodies, chronic kidney disease, male sex, prolonged corticosteroid use, use of thrombopoietin receptor agonists (TPO-RAs) and splenectomy. Fostamatinib is a spleen tyrosine kinase (SYK) inhibitor, approved for the treatment of adults with ITP, and prevents platelet phagocytosis by inhibiting SYK signaling in macrophages. In a mouse model of acute stroke, platelet-specific SYK deficiency protected mice from aortic thrombosis. These mice also showed diminished size of brain infarctions.4 These results were duplicated using a SYK inhibitor.4 TPO-RAs promote platelet production and may be associated with an increased risk of TEEs (Table 1).
Objectives: We reviewed the incidence of TEEs in ITP patients during fostamatinib clinical studies and published TPO-RA studies.
Methods: We reviewed the incidence of TEEs with fostamatinib and TPO-RAs during published phase 3 clinical trials and post-phase 3 extension studies (Table 1).
Results: Published fostamatinib clinical trials included 146 ITP patients. Additional risk factors for TEEs were age >65 years in 37 (26%), splenectomy in 51 (35%), and male sex in 58 (40%). Total fostamatinib exposure was163 patient-years. One TEE (0.7%) was reported, a transient ischemic attack in a patient with pre-existing atherosclerosis, which spontaneously resolved. In published TPO-RA studies in ITP, the incidence of TEEs ranged from 0 to 9% (Table 1).
Discussion: We observed a rate of TEEs of <1% in ITP patients who received fostamatinib compared with a rate of up to 9% in ITP patients who received a TPO-RA. TPO-RA treatment may cause an increase in PAI-1, P-selectin, and elevate microparticles and platelet apoptosis, all of which can promote the incidence of TEEs in ITP.2,3 By contrast, SYK is a key signaling component of the ITAM receptors GPVI and CLEC-2 in platelets. GPVI and CLEC-2 are not necessary for hemostasis but play an important role in thrombosis. In vivo experiments have shown that SYK inhibition with R406, the active metabolite of fostamatinib, reduced both GPVI and CLEC-2 mediated platelet aggregation with minimal effect on hemostasis.5 Thus, SYK inhibition by fostamatinib may reduce platelet destruction and decrease the risk of TEEs in ITP.
Summary: This analysis of the Phase 3 and extension studies in ITP shows a lower incidence of TEEs with fostamatinib in comparison with TPO-RAs. Additional studies are needed to prospectively confirm the protective role of fostamatinib.
1. Rodeghiero F. Am J Hematol, 2016. 91: 39-45.
2. Garabet, L., et al. Platelets, 2019. 30: 206-12.
3. Justo Sanz, R., et al. Thromb Haemost, 2019. 119: 645-59.
4. van Eeuwijk JM, et al. Arterioscler Thromb Vasc Biol, 2016. 36: 1247-53.
5. Spalton, J.C., et al. J Thromb Haemost, 2009. 7: 1192-9.