By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved an oral tablet for the treatment of chronic immune thrombocytopenia. Fostamatinib disodium hexahydrate is a first-in-class tyrosine kinase inhibitor against spleen tyrosine kinase.1 Fostamatinib has demonstrated a reduction in antibody-mediated destruction of platelets. It is marketed as Tavalisse.
Fostamatinib is indicated for the treatment of thrombocytopenia in adults with chronic immune thrombocytopenia (ITP) with insufficient response to a previous treatment.1
The recommended dose is 100 mg twice daily, with or without food.1 After four weeks, the dose may be increased to 150 mg twice daily, if needed, to achieve a platelet count of at least 50 × 109/L as necessary to reduce the risk of bleeding. The drug should be discontinued after 12 weeks if the platelet count does not increase to a level adequate to avoid clinically important bleeding.1 Fostamatinib is available as 100 mg and 150 mg tablets.
Fostamatinib provides another treatment option that targets a new mechanism in the pathogenesis of ITP.2
The most common adverse reactions (vs. placebo) are diarrhea (31% vs. 15%), hypertension (28% vs. 13%), nausea (19% vs. 8%), dizziness (11% vs. 8%), respiratory infections (11% vs. 6%), and increase in alanine transaminase (11% vs. 0%).2 Dose modification may be required for the following adverse reactions: hypertension, hepatotoxicity, diarrhea, and neutropenia.1
Complete blood counts, platelet counts, liver function tests, and blood pressure readings should be monitored appropriately.1 Concomitant use with a strong CYP3A4 inhibitor increases the risk of adverse reactions.1
The approval of fostamatinib was based on two identical, double-blind, placebo-controlled studies.1,2 Subjects exhibited persistent, chronic ITP, with average platelet counts < 30 × 109/L within the three months preceding study entry. These subjects with long-standing ITP were difficult to treat (75% ≥ 3 years, with a median number of three prior unique treatments, and a median platelet count of 16 × 109/L).2
Subjects were randomized to placebo (n = 25 in Study 1, n = 24 in Study 2) or fostamatinib (n = 51 in Study 1, n = 50 in Study 2). Fostamatinib was initiated at 100 mg twice daily and could be increased to 150 mg twice daily after four weeks or later, depending on platelet count. The dose could be reduced to 100 mg or 150 mg once daily if dose-limiting adverse effects occurred. The primary efficacy endpoint was a stable response by week 24, defined as platelet count ≥ 50 × 109/L on at least four of the six clinic visits (assessed every two weeks).
Stable responses occurred in 18% of subjects in Study 1 and 16% of subjects in Study 2. Corresponding responses for placebo were 0% and 4%, respectively. Forty-three percent of subjects on fostamatinib exhibited ≥ 1 platelet count ≥ 50 × 109/L within the first 12 weeks compared to 14% on placebo.2 The median time to response was 15 days, and 83% responded within eight weeks.
Primary ITP is an acquired autoimmune bleeding disorder characterized by low platelet count in the absence of other causes. This is because of the combination of platelet destruction and inhibition of platelet production.3,4 Platelet destruction is mediated via the spleen tyrosine kinase signaling pathway, the target for fostamatinib. The current American Society of Hematology and other international guidelines recommend corticosteroids (generally with intravenous immune globulin) as first-line treatment.5,6 For those unresponsive or relapsed, options include splenectomy, thrombopoietin receptor agonists (romiplostim, eltrombopag), or rituximab. The international guidelines also include immunosuppressives, such as azathioprine, cyclosporine A, and cyclophosphamide.6 Fostamatinib provides an orally administered option for those who have failed or relapsed after first- or second-line therapy. The cost for fostamatinib was not available at the time of this review.
- Tavalisse Prescribing Information. Rigel Pharmaceuticals, Inc., April 2018.
- Bussel J, Arnold DM, Grossbard E, et al. Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: Results of two phase 3, randomized, placebo-controlled trials. Am J Hematol 2018 Apr 26. doi: 10.1002/ajh.25125. [Epub ahead of print].
- Newland A, Lee EJ, McDonald V, Bussel JB. Fostamatinib for persistent/chronic adult immune thrombocytopenia. Immunotherapy 2018;10:9-25.
- Liebman HA, Pullarkat V. Diagnosis and management of immune thrombocytopenia in the era of thrombopoietin mimetics. Hematology Am Soc Hematol Educ Program 2011;2011:384-390.
- Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood 2011;117:4190-4207.
- Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 2010;115:168-186.