Spleen tyrosine kinase (Syk) signaling is central to phagocytosis‐based, antibody‐mediated platelet destruction in adults with immune thrombocytopenia (ITP). Fostamatinib, an oral Syk inhibitor, produced sustained on‐treatment responses in a phase 2 ITP study. In two parallel, phase 3, multicenter, randomized, double‐blind, placebo‐controlled trials (FIT1 and FIT2), patients with persistent/chronic ITP were randomized 2:1 to fostamatinib (n = 101) or placebo (n = 49) at 100 mg BID for 24 weeks with a dose increase in nonresponders to 150 mg BID after 4 weeks. The primary endpoint was stable response (platelets ≥50 000/μL at ≥4 of 6 biweekly visits, weeks 14‐24, without rescue therapy). Baseline median platelet count was 16 000/μL; median duration of ITP was 8.5 years. Stable responses occurred in 18% of patients on fostamatinib vs. 2% on placebo (P = .0003). Overall responses (defined retrospectively as ≥1 platelet count ≥50 000/μL within the first 12 weeks on treatment) occurred in 43% of patients on fostamatinib vs. 14% on placebo (P = .0006). Median time to response was 15 days (on 100 mg bid), and 83% responded within 8 weeks. The most common adverse events were diarrhea (31% on fostamatinib vs. 15% on placebo), hypertension (28% vs. 13%), nausea (19% vs. 8%), dizziness (11% vs. 8%), and ALT increase (11% vs. 0%). Most events were mild or moderate and resolved spontaneously or with medical management (antihypertensive, anti‐motility agents). Fostamatinib produced clinically‐meaningful responses in ITP patients including those who failed splenectomy, thrombopoietic agents, and/or rituximab. Fostamatinib is a novel ITP treatment option that targets an important mechanism of ITP pathogenesis.

To determine whether inhibition of Syk would be useful in Fc␥R-dependent cytopenias such as immune thrombocytopenic purpura (ITP) or autoimmune hemolytic anemia, mouse models were used to evaluate efficacy of R406, an inhibitor of Syk function, in treating cytopenia. Both disease models responded favorably to treatment, with amelioration of ITP being more dramatic. Thus, phase 2 clinical trial was initiated to study the effects of Syk inhibition in humans with ITP. Sixteen adults with chronic ITP were entered into an open-label, single-arm cohort doseescalation trial beginning with 75 mg and escalating as high as 175 mg twice daily. Doses were increased until a persistent response was seen, toxicity occurred, or 175 mg twice daily was reached. Eight patients achieved persistent responses with platelet counts greater than 50 ؋ 10 9 /L (50 000 mm 3 ) on more than 67% (actually 95%) of their study visits, including 3 who had not persistently responded to thrombopoietic agents. Four others had nonsustained responses. Mean peak platelet count exceeded 100 ؋ 10 9 /L (100 000 mm 3 ) in these 12 patients. Toxicity was primarily GI-related with diarrhea (urgency) and vomiting; 2 patients had transaminitis.

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Understanding of the role played by mast cells in allergic rhinitis (AR) has led to the development of novel therapies. The aim of this study was to determine the safety and tolerability of R112, an inhibitor of the tyrosine kinase Syk, in an allergen challenge model of AR. We also examined the effects of R112 on symptoms, mediator release, and nasal airway volumes. This double-blinded, randomized, placebo-controlled, crossover trial enrolled 20 out-of-season volunteers with AR. One intranasal dose of R112 or vehicle was administered and followed by an allergen challenge. In addition to safety monitoring, symptoms; changes in histamine, tryptase, and prostaglandin D2 (PGD2) content of nasal secretions; and acoustic rhinometry were determined over a 15-minute period. R112 was well tolerated. Adverse events were similar between treatments. Five minutes after allergen instillation, PGD2 was decreased when subjects received R112 compared with vehicle (93.4 +/- 23.0 pg/mL versus 171.6 +/- 23.0 pg/mL; p = 0.03), and this correlated with rhinorrhea (p = 0.05). However, at 10 minutes, changes in PGD2, tryptase, and histamine were not significant (46.8 +/- 9.2 pg/mL versus 68.6 +/- 9.2 pg/mL, p = 0.1; 9.5 +/- 2.7 ng/mL versus 16.6 +/- 2.9 ng/mL, p = 0.09; and 1.5 +/- 1.6 ng/mL versus 3.5 +/- 1.6 ng/mL, p = 0.4). No differences were found in symptoms or in acoustic rhinometry between treatment groups. Single-dose R112 appears safe and significantly reduces PGD2 but not histamine or tryptase release in response to allergen challenge in subjects with AR.

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Two adult patients with T cell acute lymphoblastic leukemia (ALL) received an intensive multiagent therapeutic regimen and failed to enter remission. Following cytoreduction with cyclophosphamide (60 mg/kg x 2) and total body irradiation (1000 rads) they underwent bone marrow transplantation. One patient received marrow from his identical twin brother and the other from his HLA-matched sister. Both patients promptly went into remission. The identical twin recipient is alive and free of disease at 20+ months, but the allogeneic patient died of P. carinii pneumonia at eight months with no evidence of leukemia. These results suggest that even some refractory patients whose disease has multiple negative prognostic features may respond to pretransplant chemoradiotherapy and attain a clinically useful complete remission. Additional patients with longer follow-up will be necessary before the curative potential of bone marrow transplantation in T cell ALL can be assessed.

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