Normal B lymphocytes receive signals from B-cell antigen receptor (BCR) that are 
triggered by binding of the BCR to an external antigen. Tonic signaling through 
the BCR provides growth and signals to chronic lymphocytic leukemia (CLL) cells, 
and plays an important role in the pathogenesis and progression of the disease. 
Antigen engagement of BCR is followed by intracellular recruitment and 
activation of BCR-associated kinases including spleen tyrosine kinase (Syk), 
Bruton's tyrosine kinase (Btk) and phosphatidylinositol 3-kinases (PI3K). 
Inhibition of signaling pathways downstream of the BCR induces disruption of 
chemokine-mediated CLL cell migration and cell killing. BCR signal transduction 
inhibitors represent a promising new strategy for targeted CLL treatment. A 
number of therapeutic agents have recently been developed with significant 
activity in CLL. The compounds that are currently investigated in patients with 
CLL include ibrutinib -inhibitor of Btk, fostamatinib-inhibitor of Syk and 
idelalisib (GS-1101) -a specific isoform of the PI3K (PI3K) inhibitor. The 
clinical activity of ibrutinib, GS-1101 and fostamatinib in patients with CLL is 
associated with marked lymphocytosis due to release of tumor cells from the 
lymph nodes into the peripheral blood. Further studies are ongoing with single 
agents and their combinations with other targeted and conventional therapies. 
This article will review the preclinical rationale of BCR signaling inhibitors 
in the treatment of CLL, and the clinical evidence supporting the use of these 
agents in CLL patients.