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.
Although many quality measures exist in oncology, few efforts have been undertaken to prioritize, measure, and report quality and costs for an entire region. A recent multiyear, multistakeholder effort to characterize quality of care and costs for Washington State oncology practices revealed that increased quality may be associated with a reduced cost of care in oncology.
Overactive JAK pathway signaling is a key mechanism of disease in the myeloproliferative neoplasms (MPNs) polycythemia vera and myelofibrosis.1,2 Signaling of the JAK pathway plays a key role in normal cell functioning.3-6 Well-regulated JAK signaling is essential for cell production, cell proliferation, and immune function. Intracellular regulators, such as suppressor [ Read More ]