How to Train Your Pathway: Leniolisib Initiated in a Paediatric Case of Activated PI3K Delta Syndrome

Background Activated phosphoinositide 3-kinase (PI3K) delta syndrome (APDS) type 2 is a rare primary immunodeficiency caused by loss-of-function mutations in the PIK3R1 gene encoding the regulatory subunit of the enzyme PI3K delta. It is characterized biochemically by excessive activation of the key PI3K/AKT/mTOR intracellular signaling pathway and clinically by recurrent sinopulmonary infection with bronchiectasis, lymphoproliferative disease, propensity to autoimmunity, and long-term risk of lymphoid neoplasia. Clarity regarding the underlying mechanism of disease renders APDS an excellent candidate for targeted pharmacological therapy with the small molecule inhibitor leniolisib, which selectively inhibits PI3K. Case Our patient is a 9-year-old male with a history of recurrent sinopulmonary infection and persistent cervical lymphadenopathy, short stature, and non-familiar facial features. He was seen with acute cervical lymphadenitis, and immunological investigations demonstrated an inverted CD4:CD8 ratio, reduced naïve and class-switched memory B cells, expansion of the transitional B cell population, and absent IgA, IgG, and IgE. Genetic analysis demonstrated a de novo pathogenic variant in PIK3R1, confirming a diagnosis of ADPS type 2. Management Initial management was with subcutaneous immunoglobulin replacement and antibiotic prophylaxis. Compassionate access for use of leniolisib, which has been approved by the FDA for those >12 years old for treatment of ADPS-associated mutations in genes encoding PI3K delta, was obtained. Treatment in this patient with leniolisib has been well tolerated without significant adverse effects, and monitoring for clinical progress is ongoing. Conclusion APDS, a rare cause of paediatric immunodeficiency, shows great promise as a disorder amenable to targeted therapy. We present here a pediatric patient in Australia commenced on leniolisib for treatment of APDS.