Leniolisib and rapamycin in Activated PI3-Kinase-δ-syndrome: a retrospective ESID registry-based analysis

Activated PI3K-delta syndrome (APDS) is a rare inborn error of immunity characterized by variable immune dysregulation, recurrent infections, and increased risk of malignancy. Clinical management is challenging. Rapamycin has been widely used off-label to control immune dysregulation, while the selective PI3Kδ inhibitor leniolisib has recently become available as a disease-specific targeted therapy. Real-world data on these treatment approaches remain limited.

To assess real-world treatment indications, clinical course, immunological changes, and tolerability in patients with APDS treated with rapamycin and leniolisib.

We performed a retrospective analysis of the ESID-APDS registry including 95 APDS patients treated with rapamycin (81) and/or leniolisib (28) through a Managed Access Program. Clinical manifestations, immunological parameters, and treatment-associated complications were assessed.

Lymphoproliferation was the predominant indication (81% and 52% respectively) for treatment initiation. Overall responses (complete or partial) were observed in 67% of rapamycin- and 64% of leniolisib-treated patients. Across other disease manifestations, responses were documented in 35% and 50% of patients. Leniolisib was initiated for recurrent infections in 3 patients, whereas recurrent infections were not a primary indication for rapamycin. Treatment interruption due to adverse events occurred only in the rapamycin group. Lymphoma cases were observed during follow-up.

In this real-world registry cohort, both rapamycin and leniolisib were associated with improvement of lymphoproliferation in APDS. Treatment-limiting adverse events were reported under rapamycin. Prospective long-term studies are needed to better define the role of these therapies and their long-term impact on disease outcome, including malignancy risk.

In a real-world APDS cohort, leniolisib and rapamycin reduced benign lymphoproliferation, with treatment-limiting adverse events reported only under rapamycin.