Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia

摘要: Certain malignant B cells rely on B-cell receptor (BCR)-mediated survival signals. Spleen tyrosine kinase (Syk) initiates and amplifies the BCR signal. In in vivo analyses of lymphoma cell lines primary tumors, Syk inhibition induces apoptosis. These data prompted a phase 1/2 clinical trial fostamatinib disodium, first clinically available oral inhibitor, patients with recurrent non-Hodgkin (B-NHL). Dose-limiting toxicity 1 portion was neutropenia, diarrhea, thrombocytopenia, 200 mg twice daily chosen for 2 testing. Sixty-eight B-NHL were then enrolled 3 cohorts: (1) diffuse large (DLBCL), (2) follicular (FL), (3) other NHL, including mantle (MCL), marginal zone (MZL), mucosa-associated lymphoid tissue lymphoma, lymphoplasmacytic lymphomas, small lymphocytic leukemia/chronic leukemia (SLL/CLL). Common toxicities included fatigue, cytopenias, hypertension, nausea. Objective response rates 22% (5 23) DLBCL, 10% (2 21) FL, 55% (6 11) SLL/CLL, 11% (1/9) MCL. Median progression-free 4.2 months. Disrupting BCR-induced signaling by inhibiting represents novel active therapeutic approach NHL SLL/CLL. This registered at www.clinicaltrials.gov as #NCT00446095.