Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells that depend 
on host factors in the tissue microenvironment for survival and proliferation. 
In vitro, CLL cells rapidly undergo apoptosis unless microenvironmental factors 
are provided that support their survival. Signaling pathways activated in the 
microenvironment in vivo include the B-cell receptor (BCR) and NF-κB pathways. 
Thus, CLL is a disease "addicted to the host" and is dependent on pathways that 
promote normal B-cell development, expansion, and survival; this is particularly 
true in the case of the BCR signaling cascade. Small-molecule inhibitors of 
kinases that are essential for BCR signal transduction abrogate the stimulating 
effects of the microenvironment on CLL cells. The orally administered tyrosine 
kinase inhibitors fostamatinib and ibrutinib and the phosphatidylinositol 
3-kinase inhibitor GS-1101 have induced impressive responses in relapsed and 
refractory CLL patients, mostly with moderate side effects. Reductions in 
lymphadenopathy and splenomegaly are seen within weeks and are frequently 
accompanied by a transient rise in absolute lymphocyte count that is 
asymptomatic and probably the result of changes in CLL cell trafficking. This 
review discusses the biologic basis for kinase inhibitors as targeted therapy of 
CLL and summarizes the exciting early clinical experience with these agents.