Assessment of thrombotic risk during long-term treatment of immune thrombocytopenia with fostamatinib

Abstract

Background: Patients with immune thrombocytopenia (ITP) are at risk of bleeding and, paradoxically, thromboembolic events (TEEs), irrespective of thrombocytopenia. The risk of thrombosis is increased by advanced age, obesity, and prothrombotic comorbidities: cancer, hyperlipidemia, diabetes, hypertension, coronary artery disease, and chronic kidney disease, among others. Certain ITP treatments further increase the risk of TEE, especially splenectomy and thrombopoietin receptor agonists. Spleen tyrosine kinase (SYK) is a key signaling molecule common to thromboembolic and hemostatic (in addition to inflammatory) pathways. Fostamatinib is an orally administered SYK inhibitor approved in the USA and Europe for treatment of chronic ITP in adults.

Methods: The phase III and extension studies included heavily pretreated patients with long-standing ITP, many of whom had risk factors for thrombosis prior to initiating fostamatinib. This report describes long-term safety and efficacy of fostamatinib in 146 patients with up to 5 years of treatment, a total of 229 patient-years, and assesses the incidence of thromboembolic events (by standardized MedDRA query).

Results: Platelet counts ⩾50,000/µL were achieved in 54% of patients and the safety profile was as described in the phase III clinical studies with no new toxicities observed over the 5 years of follow-up. The only TEE occurred in one patient (0.7%, or 0.44/100 patient-years), who experienced a mild transient ischemic attack. This is a much lower rate than might be expected in ITP patients.

Conclusion: This report demonstrates durable efficacy and a very low incidence of TEE in patients receiving long-term treatment of ITP with the SYK inhibitor fostamatinib.

Clinicaltrialsgov identifiers: NCT02076399, NCT02076412, and NCT02077192.

Keywords: arterial thrombosis; disorders of platelet function; immune thrombocytopenic purpura; platelets; venous thrombosis.

Figure 1.

Platelet count over time in patients with an early response (platelets ⩾50,000/µL by week 12) in dark blue, patients who showed clinical benefit without an early response (platelets ⩾30,000/µL) in green, and patients with limited or no benefit (platelets <30,000/µL) in red. Shaded areas represent the 25th to 75th percentiles. Platelet counts affected by rescue therapy are not included. The number of patients contributing data at each time point is shown below the graph. Data points with ⩽5 patients are shown by a dotted line.

Figure 2.

Exposure-adjusted rate of bleeding events by standard MedDRA query in responders (platelet count ⩾50,000/µL) and others (all counts <50,000/µL). Rate is per 100 patient-years and is shown in 6-month increments. AE, adverse event; M, months; MedDRA, Medical Dictionary for Regulatory Activities.

Figure 3.

SYK-mediated pro-inflammatory and pro-thrombotic pathways in the immune system. Fcy, fragment, crystallizable region; IgG, immunoglobulin G; P, phosphoryl group; SYK, spleen tyrosine kinase.