Warm antibody autoimmune hemolytic anemia (wAIHA) is characterized by hemolysis and symptomatic anemia with no approved treatment options. Fostamatinib is an oral spleen tyrosine kinase inhibitor approved in the US and Europe for treatment of adults with chronic immune thrombocytopenia. In this phase 3 study, patients with an insufficient response to ≥1 prior wAIHA treatment were randomized to fostamatinib or placebo. The primary endpoint was the proportion of patients to achieve a durable hemoglobin (Hgb) response (Hgb ≥10 g/dL and increase from baseline of ≥2 g/dL on 3 consecutive visits) during the 24-week treatment period. Ninety patients were randomized, 45 to each arm. Of the fostamatinib-treated patients, 35.6% achieved a durable Hgb response versus 26.7% on placebo ( p =  .398). A post hoc analysis revealed a large placebo response in Eastern European patients. Significantly more patients on fostamatinib from North America, Australia and Western Europe exhibited a durable Hgb response compared to placebo (36% vs. 10.7%, p  = .030). After censoring for Hgb values impacted by steroid rescue received during screening and excluding 2 placebo patients found to likely not have wAIHA, a reanalysis demonstrated a difference in durable Hgb response between fostamatinib and placebo (15/45 [33.3%] vs. 6/43 [14.0%], p  = .0395). At least 1 AE was reported in 42 (93.3%) and 40 (88.9%) patients receiving fostamatinib and placebo, respectively. The most common AEs in the fostamatinib group were diarrhea (26.7%), hypertension (24.4%), and fatigue (15.6%). In this study, fostamatinib demonstrated a clinically meaningful benefit for patients in Western regions, and no new safety signals were identified.

e23289 Background: Immune thrombocytopenia (ITP) is an autoantibody-mediated disease in which platelets are prematurely phagocytosed by Fcg-receptor-bearing macrophages in a spleen tyrosine kinase (SYK)-dependent signaling pathway. Corticosteroids (CS) are used to suppress the immune response, but long-term use carries a heavy burden of toxicity. Subsequent treatments for ITP include fostamatinib, a potent oral SYK inhibitor approved in 2018 based on two randomized, placebo-controlled, phase 3 trials. In trial patients, who received fostamatinib as second-line therapy following CS with or without immunoglobulins (IVIG), 25 of 32 (78%) patients achieved a platelet response of ≥50,000/µL, which was sustained for a median of 83% of treatment days. Here, we report real-world experience with fostamatinib as second-line therapy for ITP from a multi-center, prospective, observational study. Methods: The study (FORTE; NCT04904276) enrolled adult patients with ITP and an insufficient response to prior CS and/or IVIG. Patients were treated according to their clinician’s discretion, and data were collected for up to 12 months at clinic visits. Results: Sixteen patients were enrolled, and 15 were treated. Of the 15, 9 (60%) were female and the median age was 48 years (range, 20-92). 12 (80%) patients had prior CS and 6 (40%) prior IVIG. 7 (47%) patients completed the study and 8 discontinued treatment due to adverse events (4), lack of efficacy (2), and patient decision (2). After initiation of fostamatinib, 93% (14/15) of patients achieved ≥1 platelet count ≥50,000/μL. Median platelet count increased over time from 43,000/μL (IQR 19,000-105,000) at baseline to 167,000/μL (IQR 96,000-180,000) at Month 12. The median cumulative duration of elevated platelet count was 32 weeks (IQR 6.4-49.4). Concomitant CS were used by 7 (47%) patients at baseline, all of whom were able to taper as early as Month 1 and discontinue their dose by Month 3 in 4 patients, Month 6 in 2 patients, and Month 9 in 1 patient. Five patients had ITP-related AEs (4 Grade 1 and 1 Grade 2): gingival bleeding (2), mucosal haemorrhage (2), fatigue (1), contusion (3), headache (1) and epistaxis (1). There were 3 serious AEs in 2 patients: Grade 3 diarrhea in 1 and Grade 2 dyspnea and chills in 1. Overall safety results were consistent with previous studies of fostamatinib. Conclusions: Real world use of fostamatinib as documented in this observational study demonstrated efficacy and safety as second-line therapy for ITP. Fostamatinib allowed successful tapering and discontinuation of CS while maintaining platelet counts above 50,000/μL. Clinical trial information: NCT04904276 .

e19041 Background: Olutasidenib is a potent, selective, oral inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1). Olutasidenib is FDA approved for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) based on the registrational cohort (n = 153) of the Phase 2 trial, which demonstrated a rate of complete remission (CR) or CR with partial hematologic recovery (CRh) of 35%, with a duration of response of 25.9 months. Venetoclax (VEN) in combination with a hypomethylating agent (HMA) is standard treatment for AML patients unfit for chemotherapy and has adequate efficacy in IDH1-mutated AML. The sequence of therapy following failure of a VEN-based regimen in IDH1-mutated AML has not been established. We evaluated the efficacy and safety of olutasidenib in a subset of 17 patients from the Phase 2 trial (NCT02719574) previously treated with VEN combination regimens. Methods: Adults with mIDH1 R/R AML received olutasidenib 150 mg twice daily alone (n = 15) or in combination with azacitadine (AZA) (n = 2). The primary endpoint was achievement of a CR/CRh. Secondary endpoints included time to and duration of CR+CRh and rate of transfusion independence (TI). Data cut-off for the analysis was 18 June 2021. Results: Of 17 patients with prior VEN treatment, 5 are ongoing and 12 discontinued due to progressive disease (6), adverse events (4), or withdrawal by subject (2). Median age was 73 (range 65-83). Median time since diagnosis was 19.5 months (1.2-41). Cytogenetic risk class was intermediate in 9, poor in 6, favorable in 1 and unknown in 1. Most patients had relapsed; 6 were refractory to prior treatment. The median number of prior regimens was 2 (range 1-6); 13 had prior HMA, 2 had prior olutasidenib. VEN was generally used for induction. Some patients received VEN in multiple regimens. VEN was used with azacytidine (AZA) in 8 patients, after AZA (1), and with decitabine (5), cytarabine +/- idarubicin (5), and dinaciclib (2). The best response to olutasidenib was CR/CRh in 5/17 (29.4%), of which 4 (23.5%) were CR. In the 8 patients who previously received the combination of VEN-AZA, 3 (37.5%) patients achieved a CR/CRh. Time to CR/CRh was median 2.1 months (actual: 1, 1.9, 2.1, 2.8 and 2.8). Duration of CR/CRh was median 18.5+ months (4.8, 9.0+, 18.5+, 22.6+, and 28.5+ months as of cut-off date). Other responses included CR with incomplete blood count recovery (CRi) in 2 patients, stable disease (SD) in 2, progressive disease (PD) in 3, not done (ND) in 2, not evaluable (NE) in 1 and not listed in 2. At baseline 14/17 were red blood cell (RBC) dependent, and 4 of the 14 (28%) had a 56-day period of RBC transfusion independence (TI). Ten were platelet dependent at baseline and 5 of the 10 (50%) had a 56-day period of platelet TI while receiving olutasidenib. Conclusions: Olutasidenib induced durable remissions in patients with mIDH1 R/R AML, including those failing prior treatment with a venetoclax-based regimen. Clinical trial information: NCT02719574 .

Patients with relapsed warm antibody autoimmune hemolytic anemia (wAIHA) have limited treatment options. Fostamatinib is a potent, orally administered spleen tyrosine kinase inhibitor approved in the United States and Europe for the treatment of adults with chronic immune thrombocytopenia (ITP). This phase 2 study evaluated the response to fostamatinib, administered at 150 mg BID orally with or without food in adults with wAIHA and active hemolysis with hemoglobin (Hgb) <10 g/dL who had failed at least one prior treatment. Hemoglobin levels and safety assessments were performed at visits every 2 weeks. The primary endpoint was Hgb >10 g/dL with an increase of ≥2 g/dL from baseline by week 24 without rescue therapy or red blood cell transfusion. Eleven of 24 (46%) patients achieved the primary endpoint. Increases in median Hgb were detected at week 2 and sustained over time. Median lactate dehydrogenase levels and reticulocyte counts generally declined over time with little change in median haptoglobin levels. The most common adverse events (AEs) were diarrhea (42%), fatigue (42%), hypertension (27%), dizziness (27%), and insomnia (23%). AEs were manageable and consistent with the fostamatinib safety database of over 3900 patients across multiple diseases (rheumatoid arthritis, B-cell lymphoma, COVID-19, and ITP). No new safety signals were detected. Fostamatinib may be a promising therapeutic option for wAIHA. A randomized, double-blind, phase 3 study is nearing completion.

Background. Warm antibody autoimmune hemolytic anemia (wAIHA) is a rare disorder that can be potentially serious. In wAIHA, autoantibodies react with protein antigens on red blood cells (RBCs) at body temperature, leading to RBC phagocytosis and destruction by Fcg receptor-bearing macrophages in a spleen tyrosine kinase (SYK) dependent signaling pathway (see figure). Fostamatinib is a potent oral SYK inhibitor, approved for the treatment of chronic immune thrombocytopenia (ITP). Fostamatinib prevents platelet destruction in ITP through inhibition of SYK-dependent platelet phagocytosis by Fcγ receptor-bearing macrophages. Fostamatinib was evaluated in a phase 2, open-label, multicenter study (NCT02612558) for the treatment of wAIHA. Results of the study demonstrated that 11 of 25 (44%) patients had markedly improved hemoglobin (Hgb) levels after fostamatinib treatment. Adverse events (AEs) were consistent with those in the fostamatinib safety database of >4000 patients across multiple diseases. Based on the results of the phase 2 study, a phase 3 randomized, double-blind, placebo-controlled, global study (NCT03764618) was initiated to investigate the safety and efficacy of fostamatinib in patients with wAIHA. The phase 3 study began enrolling patients this year and intends to enroll approximately 90 patients at 103 sites in 22 countries across North America, Europe, and Australia. This is the first randomized, double-blind, placebo-controlled, phase 3 study to evaluate a SYK inhibitor for the treatment of wAIHA (see diagram). Study Design and Methods Inclusion Criteria include: Age ≥18;Diagnosis of primary or secondary wAIHA (documented by an IgG or IgA positive direct antiglobulin test [DAT]);failure of ≥1 prior treatment for wAIHA;Haptoglobin ULN (upper limit of normal) or lactate dehydrogenase (LDH) >ULN;Baseline hemoglobin level ≤9 g/dL or, if hemoglobin is >9 g/dL to <10 g/dL, subject must be on a permitted wAIHA treatment AND have symptoms associated with anemia. Exclusion Criteria include: Presence of other forms of AIHA;Uncontrolled or insufficiently controlled hypertension;Neutrophil count <1,000/µL,Platelet count <30,000/μL (unless patient has Evans syndrome);Transaminase levels >1.5 x ULN. Eligible patients will be randomized 1:1 to fostamatinib or placebo for 24 weeks. Randomization will be stratified by concomitant steroid use and severity of anemia at baseline. The starting dose of fostamatinib is 100 mg BID and will be increased to 150 mg BID at Week 4, based on tolerability. The dose may be reduced in the event of dose-limiting AEs. At screening, patients may continue selected concurrent wAIHA therapies including steroids (maximum of 2 therapies) throughout the 24-week study period. A steroid taper protocol will allow reduced used of steroids in patients who have a hemoglobin response. Rescue therapy will be allowed as needed. Patients who complete the phase 3 study can rollover to an open-label extension study. The efficacy endpoints will include hemoglobin response, defined as a hemoglobin level ≥10 g/dL with a ≥2 g/dL increase from baseline (Day 1) in the absence of rescue therapy; duration of hemoglobin response; and the need for wAIHA rescue treatment. The safety endpoints will include the incidence of adverse events. Patients will be evaluated in the clinic, including safety and laboratory assessments, at two-week intervals. Statistics: A sample size of 90 subjects (randomized 1:1) would be required to provide 80% power to detect a difference in the response between the active and placebo groups using the Cochran-Mantel-Haenszel test at a two-sided significance level of 0.05 (based on results of the phase 2 study). The response rate will be compared between groups using a chi-square test adjusted for randomization stratification factors. Current enrollment status: As of July 2, 2020, 83 sites are open to screening (subject to local regulations about the COVID-19 pandemic), and 43 patients have been randomized. Most patients (88%) had primary wAIHA, 12% had secondary disease including chronic lymphocytic leukemia, monoclonal B cell lymphocytosis, scleroderma, smoldering Waldenström's macroglobulinemia, and systemic lupus erythematosus in 1 patient each. The median age at baseline is 61 years (range 28-87), and 63% are female. Figure Disclosures Cooper: Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Numerof:Rigel: Current Employment, Current equity holder in publicly-traded company. Tong:Rigel: Current Employment, Current equity holder in publicly-traded company. Kuter:Incyte: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Immunovant: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Dova: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; UCB: Consultancy, Honoraria; Up-To-Date: Consultancy, Honoraria, Patents & Royalties; Zafgen: Consultancy, Honoraria; Sanofi (Genzyme): Consultancy, Honoraria; Shionogi: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Principia: Consultancy, Research Funding; Protalix Biotherapeutics: Consultancy; Shionogi: Consultancy; Actelion (Syntimmune): Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Alnylam: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Argenx: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Immunovant: Other: Travel Expenses, Research Funding; Caremark: Consultancy, Honoraria; CRICO: Consultancy, Honoraria; Kezar Life Sciences, Inc: Other, Research Funding; Principia Biopharma: Consultancy, Honoraria, Other, Research Funding; Protalex: Consultancy, Honoraria, Other, Research Funding; Rigel: Consultancy, Honoraria, Other, Research Funding; Takeda (Bioverativ): Consultancy, Honoraria, Other, Research Funding; Protalex: Consultancy, Honoraria, Research Funding; Kyowa-Kirin: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria.

Background: In immune thrombocytopenia (ITP), autoantibody-bound platelets are targeted for phagocytosis by Fcγ-receptors on macrophages in a spleen tyrosine kinase (SYK)-dependent signaling pathway. Fostamatinib is a potent oral SYK inhibitor that demonstrated efficacy for the treatment of ITP in two phase 3 randomized, placebo-controlled, double-blind studies and long-term durable responses in the phase 3 open-label extension study. In these studies, 146 patients with ITP were treated with fostamatinib, and 54% had a platelet response (platelet count ≥50,000/µL), which was maintained over a median of 86% of treatment days. These studies led to approval of fostamatinib in the US, Europe, and Canada as a therapy for chronic ITP in adult patients who have had an insufficient response to a prior treatment. Further, a post-hoc analysis showed that, in those who received fostamatinib as second-line therapy (following steroids ± immunoglobulins), 78% achieved a platelet response, which was maintained over a median of 83% of treatment days. 1 Adverse events (AEs) were reported in 72% of second-line patients and 86% of all patients, and common AEs were similar between second-line patients and the total patient population. 1, 2 Bleeding events were reported in 24% of second-line patients vs. 41% of all patients. The results of the post hoc analysis underscored the necessity for further evaluation of fostamatinib as a second-line therapy for ITP.

Background : Management of ITP became increasingly challenging during the COVID-19 pandemic. Immunosuppressive treatments increase susceptibility of patients to COVID-19. Therapies increasing the thrombotic risk are suboptimal due to coagulopathy observed with COVID-19. The need to minimize office visits to limit potential viral exposure renders intravenous administration or injections less suitable. Consequently, ITP management requires careful patientcentric consideration during the pandemic. Fostamatinib is a potent oral SYK inhibitor that abrogates SYKmediated destruction of platelets and may abrogate SYK-mediated thromboinflammation. Aims : To evaluate fostamatinib as an ITP treatment during the COVID-19 era. Methods : Review of safety, immunotoxicology, and mechanism of action and administration for fostamatinib. Results : Preclinical studies demonstrated intact innate and humoral responses to immune challenges in fostamatinib (R406) treated rodents. 1 In ITP clinical trials, the incidence of adverse events (including infections) was somewhat higher with fostamatinib vs placebo (83% vs 75%), which is consistent with the 2.4-fold increase in exposure to fostamatinib vs. placebo (29 vs. 12 patient-exposure years, respectively). No patients had opportunistic infections. The rate of thromboembolic events with fostamatinib (0.7% over 5 years) was low compared with similar studies with other ITP treatments (2.6-8.9% over 2-8 years). Office visits can be minimized due to oral administration of fostamatinib and simplified titration: fostamatinib is initiated at 100mg BID and increased to 150mg BID after 4 weeks if needed. Thrombocytosis was uncommon (1.4% over 5 years). Conclusions : Fostamatinib is an immunomodulatory treatment for ITP that may lower the risk of thrombosis. The need for office visits may be reduced due to oral administration, simplified titration, and infrequency of thrombocytosis. Fostamatinib is an appropriate option for the treatment of ITP in the COVID-19 era.

Introduction: Fostamatinib is an oral, potent inhibitor of spleen tyrosine kinase (SYK) with proven efficacy and a manageable safety profile for the treatment of ITP. SYK is situated in an intracellular signaling pathway upstream of Bruton's tyrosine kinase (BTK). Long-term safety data on fostamatinib at various dosing regimens (up to 150 mg BID) has been collected in >4000 patients with ITP, rheumatoid arthritis (RA), and other autoimmune, allergic and neoplastic disorders. The safety and tolerability of fostamatinib were consistent across different patient populations (apart from disease specific events). We present a summary analysis of the fostamatinib safety data from the ITP and RA studies. Methods: Fostamatinib safety data from 2 randomized, double-blind, placebo-controlled, phase 3 studies and the long-term, open-label, extension (OLE) study in ITP were pooled and are based on a starting dose of 200 mg/day, which was increased to 300 mg/day after 4 weeks in 88% of patients. Fostamatinib safety data from 13 phase 2/3 studies in RA were pooled and are based on a dosing regimen of 100-150 mg/day (n=1232) or 200-300 mg/day (n=2205). Results: The pooled data set for ITP included 146 patients; 60% were female, and the median age was 53 years (range 20-88). The mean duration of fostamatinib treatment was 19 months (range <1-62 months), representing 229 patient exposure years. Adverse events (AEs) were reported in 87% of patients, and 63% were mild to moderate. Serious AEs were reported in 31% of patients. The incidence of diarrhea, hypertension, alanine aminotransferase increase (ALT), and aspartate aminotransferase (AST) increase was evaluated in 58 patients who received fostamatinib for ≥1 year. This enabled a comparison of the incidence of these AEs in quartiles over the first year to assess the cumulative effects of fostamatinib. The AEs were reported with decreasing frequency during the second, third, and fourth quarters of fostamatinib treatment compared with the first quarter of the initial year of treatment in the 58 patients (see Figure 1). In the same 58 patients, the use of rescue therapy decreased while median platelet counts increased each quarter of the first year. The pooled data set for RA included 3437 patients who received fostamatinib; 83% were female, and the median age was 54 (range 18 -87). The mean duration of treatment was 18 months (range <1-81) representing 5134 patient exposure years. AEs were reported in 86% of RA patients and were mild to moderate in 73% of RA patients. Serious AEs occurred in 14%. In the placebo-controlled RA studies, 2414 patients received fostamatinib with 823 patient exposure years and 1169 received placebo with 367 patient exposure years. Despite a two-fold (125%) increase in exposure with fostamatinib vs placebo (823 vs 367 patient exposure years), there was only a 26% increase in AEs with fostamatinib vs placebo (68% vs 54%). The most common events in the ITP and RA studies were diarrhea (36% and 24%), hypertension (22% and 19%) and nausea (19% and 8%), apart from disease-related AEs. Epistaxis (19% and 0.5%), petechiae (15% and 0.3%), contusion (12% and 2%), and fatigue (10% and 2%) are associated with ITP and were uncommon in the RA population. Rheumatoid arthritis was reported as an AE in 9% of patients with RA and in none with ITP. Some AEs may be dose-related, and one-third of the RA patients were on lower dosages (100-150 mg/day) than were generally given in the ITP trials (200-300 mg/day). Conclusions: Fostamatinib has been evaluated in >4000 patients across different disease populations. Fostamatinib has a consistent and manageable safety profile. No new safety signals and no cumulative toxicity were observed with up to 81 months (6.8 years) of continuous treatment. Figure 1 Disclosures Tong: Rigel: Current Employment, Current equity holder in publicly-traded company. Numerof:Rigel: Current Employment, Current equity holder in publicly-traded company. Datangel:Rigel: Current Employment, Current equity holder in publicly-traded company. Masuda:Rigel: Current Employment, Current equity holder in publicly-traded company.

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.

Introduction. wAIHA is a rare and often serious disease in which red blood cells (RBCs) coated with autoantibodies bind to Fcγ receptor-bearing macrophages, triggering a spleen tyrosine kinase (SYK) dependent signaling pathway that leads to RBC phagocytosis. Fostamatinib is a potent SYK inhibitor administered orally that was approved by the US FDA for the treatment of chronic ITP in adults. A phase 2, multicenter, open-label study (the SOAR study; NCT02612558) evaluated the response to fostamatinib in adult patients with wAIHA. We report the final results of the initial 24-week treatment period and the extension period of the phase 2 study. Methods. The study included adult patients with primary or secondary wAIHA, documented by IgG positive direct antiglobulin test (DAT), who had: failed ≥1 prior treatment for wAIHA, hemoglobin (Hgb) <10 g/dL, haptoglobin <10 mg/dL and lactate dehydrogenase (LDH) >ULN (upper limit of normal). Patients were initiated on fostamatinib at 150mg BID with dose reduction permitted based on tolerability. Patients were seen every 2 weeks for 12 weeks, then every 3 weeks for 12 weeks, and every 6 weeks thereafter. The primary efficacy endpoint was achieving Hgb >10 g/dL with an increase of ≥2 g/dL from baseline by Week 24 without rescue therapy or RBC transfusion. Patients who responded or showed clinical benefit were allowed to enter the extension period as long as they were tolerating the study drug. Results. The study included 25 evaluable patients (15 women) with median age 61 (range 27-88) years, median duration of wAIHA of 2 years (<1 to 26 years), and median Hgb of 9.0 g/dL (range 6.8-10.6). Most (80%) had primary AIHA; 3 patients had lymphoproliferative disease, 1 had systemic lupus erythematosus, and 1 had other secondary cause. Patients had received a median of 2 unique prior treatments (range 1-9), including corticosteroids (84%), splenectomy (20%) and rituximab (52%), and 52% were on corticosteroids at baseline. As of June 2019, median exposure to fostamatinib was 110.0 days (range, 26-847); median treatment compliance 100%. Eleven of 25 (44%) achieved the primary efficacy endpoint by Week 24 plus 1 late responder at Week 30 (total of 12 responders [48%]). Increases in median Hgb were generally detected at Week 2 (first visit) and sustained over time, with 24% achieving the primary endpoint by Week 2 (Figure). Median Hgb of responders increased by >2.0 g/dL from baseline by Week 4 vs. no change for nonresponders. 13 eligible patients entered the extension period of the study, including 9 of 11 responders, 1 late responder, and 3 patients with a beneficial trend. Seven patients are still on treatment, and 6 discontinued the study, including 3 who withdrew, 1 was lost to follow up, and 2 had a loss of response (1 of whom also had increased alanine aminotransferase). Overall, adverse events (AE) were manageable and consistent with the fostamatinib safety database of >3500 patients across all disease programs. No new safety signals were detected. The most common AEs during the initial treatment period were diarrhea in 9, fatigue in 8, hypertension in 7, and dizziness in 6. AEs were mostly mild to moderate. Seven patients had serious AEs, including anemia, acute myocardial infarction, fall, Hgb decreased, inappropriate secretion of antidiuretic hormone, infection, pneumonia, rhabdomyolysis, sepsis, skin necrosis, and systemic inflammatory response syndrome. Two patients had AEs leading to death: one had infection with skin necrosis and calciphylaxis; the other had pneumonia. Neither were considered related to treatment, and both patients were immunosuppressed due to steroids. Six subjects (24%) received rescue therapy, including RBC transfusion, prednisone and/or immunoglobulins. Conclusions. In this phase 2, multicenter, open-label study, fostamatinib markedly improved Hgb levels in 48% of 25 evaluable patients with wAIHA. Adverse events were manageable and consistent with those previously reported with fostamatinib in other conditions. Figure Disclosures Rogers: Janssen: Research Funding; AbbVie: Research Funding; Genentech: Research Funding; Acerta Pharma: Consultancy. Boxer:Arizona Oncology: Employment; Incyte: Speakers Bureau; Best Doctors: Consultancy; Abbvie: Honoraria, Speakers Bureau; Gerson Lerman: Consultancy; Rigel: Speakers Bureau; Takeda: Honoraria, Speakers Bureau. Choi:Oncternal: Research Funding; Gilead: Consultancy, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau; Rigel: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau. Arnold:Novartis: Honoraria, Research Funding; Rigel: Consultancy, Research Funding; Principia: Consultancy; Bristol-Myers Squibb: Research Funding. Broome:Cellphire: Research Funding; Alexion: Honoraria, Research Funding; Incyte: Research Funding; Sanofi Genzyme: Honoraria, Research Funding; Rigel: Research Funding. Field:Ironwood: Consultancy, Research Funding; Rigel: Research Funding; Prolong: Research Funding; Incyte: Research Funding. Murakhovskaya:Momenta: Membership on an entity's Board of Directors or advisory committees. Chow:Rigel: Employment, Equity Ownership. Numerof:Rigel: Employment, Equity Ownership. Zheng:Rigel: Employment, Equity Ownership. Tong:Rigel: Employment, Equity Ownership. Kuter:Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Dova: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria; Alnylam: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Alnylam: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb (BMS): Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Shinogi: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Rigel: Consultancy, Honoraria, Research Funding; Rigel: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria; Shinogi: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Principia: Consultancy, Honoraria, Research Funding; Protalix: Consultancy, Honoraria; Protalex: Consultancy, Honoraria, Research Funding; Principia: Consultancy, Honoraria, Research Funding; Argenx: Consultancy, Honoraria, Research Funding; Protalix: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Kezar: Research Funding; Actelion (Syntimmune): Consultancy, Honoraria, Research Funding; Caremark: Consultancy, Honoraria; Bristol Myers Squibb (BMS): Consultancy, Honoraria, Research Funding; Caremark: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; UCB: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; UCB: Consultancy, Honoraria; Zafgen: Consultancy, Honoraria; Up-to-Date: Consultancy, Honoraria, Patents & Royalties: 3 Up-to-Date chapters; Zafgen: Consultancy, Honoraria; Protalex: Consultancy, Honoraria, Research Funding; Dova: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Merck Sharp Dohme: Consultancy, Honoraria; Argenx: Consultancy, Honoraria, Research Funding; Kezar: Research Funding; Momenta: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Actelion (Syntimmune): Consultancy, Honoraria, Research Funding. 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.

Background Immune thrombocytopenia (ITP) results from autoimmune antibody-mediated destruction of platelets. Bruising and bleeding are hallmarks of ITP, but thromboembolic events (TEEs) are also observed in ITP patients, even thrombocytopenic ones. In population-based cohort studies, chronic ITP patients had two-fold higher risk of a venous TEE compared to the general population.1 The risk of venous or arterial TEE is further elevated in splenectomized ITP patients and those on thrombopoietin receptor agonists (TPO-RAs). Other risk factors include: age > 60 years, prolonged corticosteroid treatment, diabetes, hypertension, coronary disease, history of TEEs, presence of anti-phospholipid antibodies, chronic kidney disease, and male sex. Fostamatinib, an inhibitor of spleen tyrosine kinase (SYK), is approved for treatment of thrombocytopenia in adults with ITP. Extensive preclinical data suggest that inhibition of SYK signaling may also have an anti-thrombotic effect. In a model of acute stroke, mice with platelet-specific SYK deficiency were protected from aortic thrombosis and also had diminished size of brain infarction with only marginal effect on hemostasis.2 These results were reproduced by a SYK inhibitor in this model.2 We assessed rates of thrombosis among ITP patients treated with fostamatinib compared to those reported with TPO-RAs. Methods We reviewed the incidence of TEEs during fostamatinib clinical trials in ITP, including 2, randomized, double-blind, placebo-controlled, phase 3, multicenter clinical trials and an open-label extension study. The incidence of TEEs with TPO-RAs during published phase 3 clinical trials and post-phase 3 extension studies was also reviewed. Results The study population comprised 145 ITP patients who received fostamatinib and included 37 (26%) patients >65 years, 51 (35%) splenectomized patients, and 58 (40%) male patients. The 3 fostamatinib clinical trials represent 163 patient-years of fostamatinib exposure. The only reported TEE was a transient ischemic attack (0.7%), which resolved spontaneously in a patient with pre-existing atherosclerosis. The rate of TEEs reported in ITP patients receiving TPO-RAs in multiple studies ranged from 0 to 9% (Table). Discussion The rate of TEEs observed in ITP patients receiving fostamatinib was very low (< 1%) in comparison with the rates of TEEs reported in ITP patients receiving a TPO-RA (up to 9%). ITP patients have higher levels of prothrombin fragments 1 + 2, D-dimer, PAI-1 and soluble P-selectin, which contribute to a procoagulant profile. TPO-RA treatment may cause an increase in PAI-1, P-selectin, and increase microparticles and platelet apoptosis, all of which predispose to onset of TEEs.3,4 What explains the apparent paradox of fostamatinib? SYK plays a key role in signaling of the ITAM receptors GPVI and CLEC-2 in platelets. Both GPVI and CLEC-2 play an important role in thrombosis but are dispensable for normal hemostasis. Consequently, SYK inhibition likely reduces the incidence of TEEs by abrogating the GPVI and CLEC-2 pathways in platelets. R406, the active metabolite of fostamatinib, diminished GPVI and CLEC-2 mediated platelet aggregation with marginal effect on normal hemostasis in vivo.2,5 These mechanisms potentially explain why ITP patients treated with fostamatinib are protected from developing TEEs despite often substantial platelet increases. SYK also plays a key role in Fcγ receptor dependent phagocytosis of auto-antibody coated platelets, the primary disease mechanism in ITP. Thus, SYK inhibition in ITP may simultaneously decrease platelet destruction (increasing platelet count) and decrease the incidence of TEEs. Suumary Current clinical trial experience with fostamatinib in ITP patients demonstrates much lower rates of thrombosis than would be expected in ITP patients compared to other agents. Future work will prospectively evaluate this and confirm in vivo downregulation of platelet activation via inhibition of SYK signaling in platelets. 1. Rodeghiero F. Am J Hematol, 2016. 91: 39-45. 2. van Eeuwijk JM, et al. Arterioscler Thromb Vasc Biol, 2016. 36: 1247-53. 3. Garabet, L., et al. Platelets, 2019. 30: 206-12. 4. Justo Sanz, R., et al. Thromb Haemost, 2019. 119: 645-59. 5. Spalton, J.C., et al. J Thromb Haemost, 2009. 7: 1192-9. Disclosures Altomare: Novartis: Consultancy; Amgen: Consultancy; Rigel: Consultancy; Incyte: Consultancy, Speakers Bureau. Markovtsov:Rigel: Employment, Equity Ownership. Todd:Rigel: Employment, Equity Ownership. Weerasinghe:Rigel: Employment. Numerof:Rigel: Employment, Equity Ownership. Tong:Rigel: Employment, Equity Ownership. Masuda:Rigel: Consultancy, Employment, Equity Ownership. Bussel:Amgen: Consultancy, 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; GSK: 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; argenx: 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; Regeneron: 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; Physician Education Resource: Speakers Bureau; Tranquil: 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; 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. 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.