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Effective ‘Activated PI3Kdelta Syndrome’-targeted therapy with PI3Kdelta inhibitor leniolisib

Rao, Koneti V, Webster, Sharon, Dalm, Virgil ASH, Sediva, Anna, van Hagen, Martin P, Holland, Steven, Rosenzweig, Sergio D, Christ, Andreas Dominik, Sloth, Birgitte, Cabanski, Maciej, Joshi, Aniket, De Buck, Stefan, Doucet, Julie, Guerini, Danilo, Kalis, Christoph, Pylvaenaeinen, Ilona, Soldermann, Nicolas, Kashyap, Anuj, Gulbu, Uzel, Leonardo, Michael J, Patel, Dhavalkumar, Lucas, Carrie L and Burkhart, Christoph (2017) Effective ‘Activated PI3Kdelta Syndrome’-targeted therapy with PI3Kdelta inhibitor leniolisib. Blood, 130 (21). pp. 2307-2316. ISSN 0006-4971


Gain-of-function mutations in PI3Kdelta (phosphoinositide 3-kinase delta) leads to accumulation of senescent T cells, lymphadenopathy and immune-deficiency (Activated PI3Kdelta Syndrome, APDS). We assessed leniolisib (CDZ173), a novel, potent and selective oral PI3Kdelta inhibitor in six APDS patients in a 12-week, open-label, multi-site, within-subject dose-escalation study to assess safety, pharmacokinetics and effects on lymphoproliferation and immune dysregulation. Leniolisib led to a dose-dependent reduction in PI3K/AKT pathway activity and resolved the immune dysregulation with normalization of circulating transitional and naïve B cells and reduction in PD-1+CD4+ and senescent CD57+CD8+ T cells. Elevated serum levels of IgM and soluble markers including IFNgamma, TNF, CXCL13 and CXCL10 declined with leniolisib. All patients showed amelioration of lymphoproliferation with lymph node sizes and spleen volumes reduced by 39% and 40%, respectively. The results demonstrate the safety and efficacy of leniolisib and support the idea that inhibition of PI3Kdelta is a new targeted therapeutic approach in APDS.

Item Type: Article
Date Deposited: 09 Dec 2017 00:45
Last Modified: 09 Dec 2017 00:45


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