Fostamatinib, a Spleen Tyrosine Kinase (SYK) Inhibitor, for the Treatment of Warm Antibody Autoimmune Hemolytic Anemia (wAIHA): Final Results of the Phase 2, Multicenter, Open-Label Study

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.

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