Clinical Experience with Use of the PI3Kdelta Inhibitor Leniolisib to Treat Immune Dysregulation in Patients with CVID and CVID-Like Disorders

Objective Approximately half of common variable immunodeficiency (CVID) patients develop debilitating and life-threatening clinical manifestations of immune dysregulation, including lymphoproliferation, cytopenias, interstitial lung disease (ILD), nodular regenerative hyperplasia of the liver (NRH), and other complications. Recent research suggests a shared endotype among CVID patients with immune dysregulation and activated PI3 kinase delta syndrome (APDS). The objective of the current work was to summarize experience among clinicians treating patients with CVID and CVID-like disorders with investigational leniolisib via the appropriate expanded access pathways available in the USA, Italy, and Spain. Methods Information was collected from physicians treating 5 CVID patients and 1 patient with homozygous pathogenic variants in PRKCD (c.1352+1G>A). Results Five CVID patients and 1 PKCδ deficiency patient received leniolisib after failing multiple treatments. Ages ranged from 13 to 64 years with equal distribution of males and females. Predominant clinical manifestations of immune dysregulation included nonmalignant lymphoproliferation (6/6), cytopenias (5/6), ILD (4/6), and NRH (4/6). Leniolisib was initiated at 10 mg BID with escalation over 2–3 months to 40–70 mg BID. Median duration of treatment was 1.4 years (range 0.5–2.5 years). Leniolisib was well tolerated by most patients. Treatment was temporarily interrupted in 4 patients due to separate occurrences of rash and headache (patient 1), septic arthritis following a knee injury related to a fall (patient 2), worsening CMV colitis (Patient 5), or febrile neutropenia and spontaneous bacterial peritonitis with multiple bacteremias (patient 6). Patient 6 discontinued leniolisib related to difficult-to-control hyperglycemia and relapse of neutropenia. Favorable treatment responses were observed, including reductions in splenomegaly and/or lymphadenopathy (3/6), improvement in cytopenias (5/5), and imaging and/or functional improvement in ILD (2/4). Decreases in IgM, reductions of transitional B cells, and reductions in CD21low B cells were reported in some patients. Five patients self-reported feeling better. Conclusions Experience suggests that PI3K inhibition may offer clinical benefit to CVID and other primary immunodeficiency patients suffering from complications of immune dysregulation. Two phase 2 clinical trials to formally evaluate safety and tolerability in CVID and other patients with clinical manifestations of immune dysregulation are underway in the USA, England, and Spain.