Associations Between Short-Term Changes in Disease Activity and Long-Term Clinical Outcomes in Activated Phosphoinositide 3-Kinase Delta Syndrome.

BACKGROUND: Clinical trials in activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS), an ultra-rare disease, have evaluated treatment response to the PI3Kδ inhibitor leniolisib using disease activity endpoints, including those measuring immunodeficiency and immune dysregulation. However, the relationship between disease activity endpoints and long-term clinical outcomes has not been quantified. METHODS: Data from a randomised controlled trial and its open-label extension (OLE) investigating leniolisib were used to evaluate associations between short-term disease activity endpoints and longer-term clinical outcomes. Both single time point and repeated measures analyses were conducted using linear regression modelling and random effects multilevel regression modelling, respectively. RESULTS: In total, 39 patients were included (≤6 years of follow-up). Improvements in multiple immunodeficiency and dysregulation disease activity endpoints were significantly associated with increases in the patient global assessment (PtGA) and the 36-item short form survey (SF-36) physical component score and mental component score (PCS/MCS). Increasing proportion of naïve B cells was associated with reduction in infection rates (2.3% fewer infections per 1% increase in naïve B cells). CONCLUSIONS: In this clinical trial setting, short-term improvements in immunodeficiency and dysregulation following treatment with leniolisib were associated with longer-term improvements in clinical outcomes, including infection rates and quality of life, for patients with APDS.