Idelalisib: A PI3K Inhibitor on the Horizon

Seema Bhat, MD, and Myron S.Czuczman, MD
Published Online: January 9, 2014
Seema Bhat, MD

Seema Bhat, MD

Assistant Professor of Oncology
Department of Medicine, Roswell Park Cancer Institute,
Buffalo, NY

Myron S.Czuczman, MD

Myron S.Czuczman, MD

Professor of Oncology
Chief, Lymphoma/Myeloma Service,
Department of Medicine, Roswell Park Cancer Institute,
Buffalo, NY


Idelalisib is a potent and highly selective PI3K inhibitor that promotes apoptosis in primary cells from patients with different B-cell malignancies. Idelalisib has been shown to affect microenvironmental signaling and cell survival both in vitro and in vivo. Data from studies with idelalisib have shown promising clinical efficacy, both as a single agent, as well as in combination with other agents. It is an orally active agent that has been shown to be well tolerated, with diarrhea and a transient increase in transaminases being the most common reported adverse effects. The FDA currently has a New Drug Application under review for use of idelalisib for the treatment of indolent non-Hodgkin lymphoma that is refractory to rituximab and chemotherapy.
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western hemisphere. It is a clonal malignancy of mature B lymphocytes and is characterized by the accumulation of CD5+/ CD23+ monoclonal B cells in the blood and tissue compartments, including bone-marrow and secondary lymphatic tissues.1 However, at a genetic level, there is a difference between CLL cells present in different compartments: CLL cells in the blood compartment are resting cells with a gene expression profile akin to memory B cells,1 whereas CLL cells in the lymph node and bone marrow compartment show characteristics of activated B cells and exhibit increased proliferation.2 Moreover, the biology of CLL cells is influenced by extrinsic signals from the tissue microenvironment. In vitro, CLL cells cannot sustain themselves and undergo apoptosis unless appropriate microenvironmental factors are provided by co-culturing them with accessory stromal cells, like marrow stromal cells (MSCs)3 or monocyte-derived nurse-like cells (NLCs).4 This reliance of CLL cells on pathways that are also involved in promoting normal B-cell development, expansion, and survival 2,5- 8 indicates that these tumor cells are “addicted to the host,” constituting an instance of a novel model termed non-oncogene addiction.9

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