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