Mechanism of Action Magnifier – 2016 Desk Reference
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.
- 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
- 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.
- 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.
- Burger JA. Nurture versus nature: the microenvironment in chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2011;2011:96-103.
- Zydelig [package insert]. Foster City, CA: Gilead Sciences, Inc; 2014.
- Macias-Perez IM, Flinn IW. GS-1101: a delta-specific PI3K inhibitor in chronic lymphocytic leukemia. Curr Hematol Malig Rep. 2013;8:22-27.
- 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.
In B-cell malignancies, such as chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin lymphoma, the malignant B cells rely on a number of internal and external stimuli to survive, such as the activation of the B-cell receptor, cytokine and chemokine signaling, or direct cell-to-cell interactions. Attracted by chemokines, including CXCL12 and [ Read More ]
Although the cost of care can have severe effects on patients with cancer and their families, oncologists rarely address financial toxicity, according to Hanna K. Sanoff, MD, MPH, Medical Director, University of North Carolina (UNC) NC Cancer Hospital Clinics.