Enhanced Responses to Fostamatinib As Second-Line Therapy and in Persistent Immune Thrombocytopenia (ITP) Patients
Authors: Boccia Ralph , Boxer Michael A. , Ghanima Waleed , Hill Quentin A. , Sholzberg Michelle , Tarantino Michael D. , Kreychman Yuliya , Numerof Robert P. , Olender Brian , Todd Leslie , Tong Sandy , Duliege Anne-Marie , Cooper Nichola , Bussel James B. 
Published: November 2019

Introduction. Immune thrombocytopenia (ITP) is characterized by autoantibody-mediated platelet destruction resulting in thrombocytopenia and often at least a degree of bruising and bleeding. Platelet destruction occurs within activated macrophages that signal via spleen tyrosine kinase (SYK) following Fcγ receptor engagement by platelet-bound IgG antibodies. Fostamatinib is a SYK inhibitor, taken orally twice daily with or without food. In the three phase 3 clinical studies (2 randomized, controlled trials and 1 open-label extension study), 145 adults with ITP received fostamatinib. These patients had a median of 3 prior therapies (range 1-13) and a median of 8.4 years (range <1-53 years) since ITP diagnosis, making them the most difficult-to-treat ITP population studied thus far in registration trials. Since gaining FDA approval in April 2018, fostamatinib has been prescribed to a wide range of ITP patients, including those with persistent disease and those for whom fostamatinib is second-line therapy. We conducted a post hoc analysis of the phase 3 clinical study data in patients for whom fostamatinib was second-line therapy as well as in patients with earlier stage disease, eg ITP of duration <2 years.
Methods. The phase 3 trials included patients with persistent or chronic ITP, who had failed ≥1 prior treatment and had ≥3 platelet counts <30,000/μL at screening. Patients were initiated on fostamatinib at 100mg BID PO and increased to 150mg BID based on tolerability and if platelets were <50,000/μL after 4 weeks. An overall platelet response was defined as achieving ≥1 platelet count of ≥50,000/µL (without rescue therapy) at any visit. Patients who had previously received corticosteroids (+/- immunoglobulins) but no other therapies for ITP were included in this analysis of fostamatinib as second-line therapy. Patients were also categorized by duration of ITP: 3 months to <1 year (persistent), 1 to <2 years, and ≥2 years duration of ITP.
Results. Of 145 patients, 32 (22%) received fostamatinib as second-line therapy. Baseline characteristics of the 32 patients included median age of 50 years (range 20-88), median duration of ITP of 2.7 years, and median platelet count of 21,000/μL. Of these 32 patients, 25 (78%) had an overall platelet response, which compares favorably with the 47% response rate in the 113 patients who received fostamatinib as 3rd line or later therapy. The most commonly reported adverse events (AEs) in the 32 fostamatinib-as-second-line-therapy patients were hypertension, diarrhea, upper respiratory tract infection, nausea, vomiting, elevated liver enzymes, petechiae, and headache. AEs were primarily mild to moderate in severity and resolved or were managed by dose reduction, dose interruption, and/or secondary medication. The type and frequency of AEs in the second-line patients were consistent with that of the overall study population.
We also assessed the subgroup of 29 patients with early-stage disease (of whom 11 received fostamatinib as second-line therapy). An overall response to fostamatinib was achieved by 9 of 10 (90%) patients with persistent ITP (<1 year), 11 of 19 (57%) patients with one to <2 years of ITP, and 58 of 116 (50%) patients with 2 to 53 years of ITP. The overall response rate in the entire phase 3 population was 54% (78/145).
Conclusions. A higher percentage of patients had an overall response to fostamatinib as second-line therapy for ITP (78%) compared with later lines of therapy (47%), and a higher percentage with persistent ITP (90%) responded than those with earlier stage (1-2 years) chronic ITP (57%) or later stage chronic ITP (50%). These data suggest that higher response rates may be seen with the use of fostamatinib as second-line therapy for ITP and in persistent ITP patients as compared with later lines of therapy and later stage ITP.

Disclosures
Boccia: SecuraBio: Consultancy; AMAG: Consultancy; Bristol Myers Squibb: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Rigel: Speakers Bureau; Daiichi Sankyo, Inc.: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Boxer:Takeda: Honoraria, Speakers Bureau; Arizona Oncology: Employment; Incyte: Speakers Bureau; Best Doctors: Consultancy; Abbvie: Honoraria, Speakers Bureau; Gerson Lerman: Consultancy; Rigel: Speakers Bureau. Ghanima:Bayer: Honoraria, Research Funding; Pfizer/BMS: Research Funding; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Hill:Bioverativ, a Sanofi company: Honoraria; Apellis: Honoraria; Novartis: Speakers Bureau; Alexion: Research Funding. Sholzberg:Amgen: Honoraria, Research Funding; Novartis: Honoraria. Tarantino:Michael Tarantino, MD SC: Other: President, Owner- Private Practice ; Magellan Healthcare: Consultancy; Roche: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Octapharma: Consultancy, Speakers Bureau; Grifols: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bleeding and Clotting Disorders Institute: Employment. Kreychman:Rigel: Employment, Equity Ownership. Numerof:Rigel: Employment, Equity Ownership. Olender:Rigel: Employment, Equity Ownership. Todd:Rigel: Employment, Equity Ownership. Tong:Rigel: Employment, Equity Ownership. Duliege:Rigel: Employment, Equity Ownership. Cooper:Principia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bussel:Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Momenta Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kezar Life Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tranquil: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; 3S Bio: Speakers Bureau; Physician Education Resource: Speakers Bureau; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; RallyBio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; argenx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; UCB: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

OffLabel Disclosure:
Fostamatinib is a tyrosine kinase (SYK) inhibitor for the treatment of adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment. The use of fostamatinib in other diseases is off-label.