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In patients with ALPS-FAS, DNTs have been reported to exhibit increased activity in the phosphoinositide 3-kinase \u03b4 (PI3K\u03b4)\/mammalian target of rapamycin (mTOR) pathway. Although mTOR inhibition with sirolimus has improved autoimmune cytopenias and organomegaly in patients with ALPS, it requires monitoring of serum levels, and common adverse events frequently hamper long-term use. As leniolisib, a selective PI3K\u03b4 inhibitor, reduced lymphoproliferation in another IEI known as activated PI3K\u03b4 syndrome, efficacy was examined in a murine model of ALPS. Changes in organ weight and key immune subsets in MRL\/lpr\u2212\/\u2212 mice receiving vehicle or leniolisib (40 or 80 mg\/kg\/day) by oral gavage were assessed. Leniolisib limited the canonical features of ALPS, including lymphadenopathy, splenomegaly, and elevated DNTs, in a dose-dependent manner. 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