Expanding the scope of PI3K-δ inhibition: Leniolisib treatment in PRKCD deficiency

Leniolisib, a selective phosphoinositide 3-kinase δ (PI3Kδ) inhibitor, is approved in several countries for the treatment of activated PI3Kδ syndrome (APDS) in patients 12 years of age and older. We report the first successful compassionate use of leniolisib in another inborn error of immunity, protein kinase C δ deficiency. In addition to infectious complications, the 14-year-old patient experienced lymphoproliferation in the form of splenomegaly, lymphadenopathy, and thymic hyperplasia; trilineage cytopenia; multiple forms of autoimmunity; and interstitial lung disease. Decision to initiate treatment with leniolisib was based on multiorgan-disease progression, lack of therapeutic alternatives, molecular evidence, overlap with APDS manifestations, and mammalian target of rapamycin hyperactivity. We observed improvement in lymphoproliferation, cytopenias, hepatic cytolysis, skin manifestations, pulmonary function, favorable changes in immunophenotypes, and no known drug-related adverse events. This experience supports expanding Leniolisib's potential indications to appropriately selected patients and conditions. Broader repurposing strategies for targeted therapies in diseases involving dysregulated PI3K signaling should be systematically evaluated in clinical trials.