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Medline ® Abstract for Reference 55

of 'Treatment of relapsed or refractory chronic lymphocytic leukemia'

The role of phosphatidylinositol 3-kinase-δin the immunomodulatory effects of lenalidomide in chronic lymphocytic leukemia.
Herman SE, Lapalombella R, Gordon AL, Ramanunni A, Blum KA, Jones J, Zhang X, Lannutti BJ, Puri KD, Muthusamy N, Byrd JC, Johnson AJ
Blood. 2011;117(16):4323. Epub 2011 Mar 4.
In patients with chronic lymphocytic leukemia (CLL), lenalidomide can promote humoral immune responses but also induces a distinct disease-specific toxicity of tumor flare and cytokine release. These CLL-specific events result from increased expression of costimulatory molecules on B cells. Here we demonstrate that lenalidomide activation of CLL cells depends on the phosphatidylinositol 3-kinase p110δ(PI3K-δ) pathway. Inhibition of PI3K-δsignaling by the PI3K-δ-inhibiting drug, CAL-101, or by siRNA knockdown of p110δ, abrogates CLL cell activation, costimulatory molecule expression, and vascular endothelial growth factor and basic fibroblast growth factor gene expression that is induced by lenalidomide. In addition, CAL-101 attenuates lenalidomide-mediated increases in immunoglobulin M production by normal B cells. Collectively, these data demonstrate the importance of PI3K-δsignaling for lenalidomide immune modulation. These findings may guide development of strategies for the treatment of CLL that combine lenalidomide with CAL-101, with other inhibitors of the PI3K-δpathway, or with other agents that target downstream kinases of this signaling pathway.
Integrated Biomedical Science Graduate Program, The Ohio State University Medical Center, Columbus, OH 43210, USA.