Mechanism of Action Magnifier – 2016 Desk Reference

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Idelalisib: a Selective Inhibitor of the Delta Isoform of Phosphatidylinositol 3-Kinase

There are 4 isoforms of phosphatidylinositol 3-kinase (PI3K) with distinct functions and expression patterns; among those 4 isoforms, PI3K-alpha and PI3K-beta are ubiquitously expressed and involved in a range of cellular functions.1

Both PI3K-gamma and PI3K-delta are expressed predominantly in normal and malignant hematopoietic cells within the bone marrow.1


PI3K-delta plays an essential, nonredundant role in B-cell signaling.2,3 It is a key driver of proliferation through clonal expansion and supports normal and malignant B-cell survival. In certain B-cell malignancies, over time, malignant cells crowd out healthy blood components.1 PI3K-delta signaling within malignant B cells facilitates their interaction with stromal cells and the nurturing microenvironment of the lymph nodes and bone marrow.4 These interactions promote migration of malignant B cells from the periphery to the lymph nodes and bone marrow, a process known as chemotaxis. Hyperactive chemotaxis, dysregulated apoptosis, and hyperactive adhesion lead to accumulation of malignant B cells within lymphoid tissues, which can contribute to lymph node enlargement.


Idelalisib is an inhibitor of phosphatidylinositol 3-kinase (PI3K-delta), which is expressed in normal and malignant B cells.5 Idelalisib inhibits PI3K-delta and blocks multiple signaling pathways, including B-cell receptor signaling and signaling from the CXCR4 and CXCR5 receptors, which are involved in trafficking and homing of B cells to the lymph nodes and bone marrow.5,6 Idelalisib inhibits malignant B-cell proliferation and inhibits signaling with the microenvironment, disrupting chemotaxis and adhesion, and mobilizing malignant B cells from lymphoid tissues into the peripheral blood.5,7 Blocking PI3K-delta with idelalisib induces apoptosis and reduces malignant B-cell viability.5,7

Through mobilizing malignant B cells to the periphery, idelalisib may reduce lymph node burden.7

Idelalisib is approved for 3 indications5:

  • Relapsed chronic lymphocytic leukemia, in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other comorbidities
  • Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least 2 prior systemic therapies
  • Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least 2 prior systemic therapies.

Accelerated approval was granted for FL and SLL based on overall response rate. Improvement in patient survival or disease-related symptoms has not been established.5


  1. Puri KD, Gold MR. Selective inhibitors of phosphoinositide 3-kinase delta: modulators of B-cell function with potential for treating autoimmune inflammatory diseases and B-cell malignancies. Front Immunol. 2012;3:256.
  2. Jou ST, Carpino N, Takahashi Y, et al. Essential, nonredundant role for the phosphoinositide 3-kinase p110delta in signaling by the B-cell receptor complex. Mol Cell Biol. 2002;22:8580-8591.
  3. Herman SE, Gordon AL, Wagner AJ, et al. Phosphatidylinositol 3-kinase-δ inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood. 2010;116:2078-2088.
  4. Burger JA. Nurture versus nature: the microenvironment in chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2011;2011:96-103.
  5. Zydelig [package insert]. Foster City, CA: Gilead Sciences, Inc; 2014.
  6. Macias-Perez IM, Flinn IW. GS-1101: a delta-specific PI3K inhibitor in chronic lymphocytic leukemia. Curr Hematol Malig Rep. 2013;8:22-27.
  7. Fiorcari S, Brown WS, McIntyre BW, et al. The PI3-kinase delta inhibitor idelalisib (GS-1101) targets integrin-mediated adhesion of chronic lymphocytic leukemia (CLL) cell to endothelial and marrow stromal cells. PLoS One. 2013;8:e83830.
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