title: PI3-kinase inhibitors in chronic lymphocytic leukemia.
abstract: The phosphatidylinositol 3-kinase (PI3K) pathway is being explored as a target of inhibition for B-cell lymphoproliferative disorders, with agents specific for inhibition of the PI3K-δ subunit showing significant clinical activity in chronic lymphocytic leukemia (CLL). Idelalisib (CAL-101, GS-1101) and IPI-145 (INK-1147) are novel oral PI3K-δ inhibitors in development, with rates of objective response of 40-60 % and nodal responses exceeding 70 % in relapsed and refractory CLL. High rates of response have been seen in high-risk CLL (i.e., 17p and 11q deletions), and may allow for more effective therapy in inherently chemotherapy-resistant disease. Combination chemotherapy regimens with idelalisib have similarly demonstrated favorable tolerability and activity. Like other agents that target the B-cell receptor pathway, peripheral lymphocytosis, due to drug-induced changes in lymphocyte trafficking, is common. Noteworthy toxicities include transaminitis and pneumonia/pneumonitis. Multiple studies are evaluating PI3K-δ inhibitor combination regimens, and the rationale for these ongoing and planned studies is reviewed.
authors.affiliation: University of Wisconsin School of Medicine and Public Health, 1111 Highland Ave., 4007 Wisconsin Institute for Medical Research, Madison, WI, 53705, USA, jc2@medicine.wisc.edu.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Chang
authors.forename: Brad S
authors.initials: BS
authors.lastname: Kahl
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D002986:Clinical Trials as Topic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors