Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-d, as therapy for previously treated indolent non-Hodgkin lymphoma

Indolent non-Hodgkin lymphomas (iNHL) are a group of slowgrowing, but incurable, B-cell malignancies constituting approximately one-third of all cases of NHL and include follicular lymphoma (FL), small lymphocytic lymphoma/leukemia (SLL), marginal zone lymphoma (MZL), and lymphoplasmacytic lymphoma [Waldenström’s macroglobulinemia (LPL/WM)]. In 2013, it is estimated that ;20 000 people in the United States will be diagnosed with iNHL, and;7000 will die of this disease Although initially effective inmost patients, current chemotherapy treatments for iNHL demonstrate decreasing efficacy with repeated administrations and are associated with shortand long-term toxicities, includingmyelosuppression, cardiac toxicity, and secondary malignancies. The most recent advances in therapy for iNHL that had amajor influence on disease control include anti-CD20 antibodies such as rituximab (approved in the US in 1997), bendamustine (approved in the US in 2008), which demonstrated good activity and tolerability, and radioimmunotherapies, including I-Tositumomab (Bexxar, approved in the US in 2003), and Y-Ibritumomab (Zevalin, approved in the US in 2002), which, while active, have potential long-lasting toxicities and are rarely used. Indeed, Bexxar has now been withdrawn from the market. Thus, for iNHL patients who relapse, there is a need for drugs with new mechanisms of action that can control disease with an acceptable safety profile, either when used as single agents or in combination with existing therapies. Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase having a catalytic subunit that exists in 4 different isoforms: a, b, g, and d. Activation of PI3K generates lipid second messengers at the cell membrane that recruit and activate multiple intracellular enzymes that are regulators of cell proliferation, survival, and motility. The a and b isoforms are widely expressed in many tissues, whereas the g and d isoforms are highly restricted to hematopoietic cells. In B lymphocytes, the d isoform (PI3Kd) plays a central role in normal B-cell development and function, transducing signals from theB-cell receptor aswell as from receptors for various cytokines, chemokines, and integrins. PI3Kd signalingpathways are commonlyhyperactive in B-cell malignancies, making inhibition of PI3Kd a promising target in the therapy of iNHL. Idelalisib (5-fluoro-3-phenyl-2-[(s)-1-(9H-purin-6-ylamino)propyl]-H-quinazolin-4-one) is a potent, small-molecule inhibitor of PI3Kd that is highly selective for the d isoform compared with the a, b, and g isoforms. In lymphoid cell lines and primary patient