Pharmacological inhibition of phosphatiylinositide-3-kinase (PI3K)-mediated 
signaling holds great promise for treating chronic lymphocytic leukemia (CLL). 
Therefore we assessed three structurally related PI3K inhibitors targeting the 
PI3K-δ isoform for their ability to inhibit the survival of freshly isolated CLL 
cells. The purely PI3K-δ-selective inhibitor idelalisib was compared to 
copanlisib (BAY 80-6946) and duvelisib (IPI-145), with isoform target profiles 
that additionally include PI3K-α or PI3K-γ, respectively. The concentrations 
leading to half-maximal reduction of the survival of CLL cells were more than 
ten-fold lower for copanlisib than for idelalisib and duvelisib. At 
concentrations reflecting the biological availability of the different 
inhibitors, high levels of apoptotic response among CLL samples were attained 
more consistently with copanlisib than with idelalisib. Copanlisib selectively 
reduced the survival of CLL cells compared to T cells and to B cells from 
healthy donors. In addition copanlisib and duvelisib impaired the migration of 
CLL cells towards CXCL12 to a greater extent than equimolar idelalisib. 
Similarly copanlisib and duvelisib reduced the survival of CLL cells in 
co-cultures with the bone marrow stroma cell line HS-5 more strongly than 
idelalisib. Survival inhibition by copanlisib and idelalisib was enhanced by the 
monoclonal CD20 antibodies rituximab and obinutuzumab (GA101), while 
antibody-dependent cellular cytotoxicity mediated by alemtuzumab and peripheral 
blood mononuclear cells was not substantially impaired by both PI3K inhibitors 
for the CLL-derived JVM-3 cell line as target cells. Taken together, targeting 
the α- and δ- p110 isoforms with copanlisib may be a useful strategy for the 
treatment of CLL and warrants further clinical investigation.