Idelalisib: First-in-Class PI3K Delta Inhibitor for the Treatment of Chronic Lymphocytic Leukemia, Small Lymphocytic Leukemia, and Follicular Lymphoma

Abstract

Idelalisib [Zydelig (Gilead Sciences, Inc.), also known as CAL-101 and GS-1101] was approved in 2014 in the United States and European Union for the treatment of three indolent B-cell neoplasms: relapsed/refractory chronic lymphocytic leukemia (CLL, in combination with rituximab), relapsed follicular lymphoma, and relapsed small lymphocytic lymphoma (as monotherapy). Furthermore, it was approved in the European Union as first-line therapy for poor-prognosis CLL with 17p deletions or TP53 mutations and in patients unsuitable for chemoimmunotherapy. Idelalisib is an orally bioavailable ATP-competitive kinase inhibitor that targets the PI3K p110 isoform δ (PI3Kδ) with high potency and selectivity. PI3Kδ is hyperactivated in B-cell malignancies and plays a pivotal role in the B-cell receptor pathway, a key oncogenic driver in B-cell malignancies. The near exclusive expression of the PI3Kδ isoform in hematopoietic cells and the selectivity of idelalisib for the PI3Kδ isoform are essential for its efficacy and tolerability, even in elderly patients unfit for chemotherapy. Idelalisib is the first PI3K inhibitor approved by the regulatory agencies; this approval will change the treatment landscape of indolent B-cell malignancies.

Figure 1. BCR pathway and the role of PI3K

Antigen binding activates the BCR pathway through recruitment and activation of Lyn/Syk, which phosphorylates tyrosine residues on CD19, Nck and BCAP. PI3K regulatory subunit is recruited to the cell membrane by docking to BCAP and CD19 leading to the activation of p110δ. Activated PI3K phosphorylates PIP2 into PIP3. PIP3 recruits and activates PH domain containing signaling molecules including AKT and PDK1. AKT activates various downstream effectors such as MDM2 and mTOR, whereas it inhibits the functions of FOXO and GSK-3β upon phosphorylation. Activation of the BCR pathway also leads to BTK and MAPK pathways activation. BTK initiates a transduction cascade leading to the activation of PLCγ2, intracellular calcium release, PKC activation and initiation of NF-κB transcriptional program. This process is facilitated through interaction with PIP3 at PH domain to recruit BTK and PLCγ2 to the cell membrane. P on various molecules indicates that they are phosphorylated. Solid arrows indicates recruitment and/or activation, dotted arrows indicate interaction through PH domain, and inhibitory signs indicates inhibition.