APDS (activated PI3Kδ syndrome), also known as PASLI (p110δ-activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency) is a rare primary immunodeficiency caused by pathogenic variants in PIK3CD or PIK3R1, leading to PI3Kδ signalling hyperactivity. Clinical characteristics of APDS are lymphoproliferation, auto-immunity, immunodeficiency, and increased risk of lymphoma. Current treatment options include stem cell transplantation, immunoglobulin replacement therapy, and empirical treatment such as immunomodulatory, antibiotic, and antiviral therapy for symptom relief. Leniolisib is a small-molecule inhibitor of hyperactive PI3Kδ signalling1.
Dr Koneti Rao (National Institute of Health, MD, USA) presented results from a phase 3, placebo-controlled, randomised clinical trial (NCT02435173) that evaluated the efficacy and safety of leniolisib in patients with APDS2. A total of 31 patients were 2:1 randomised to leniolisib (twice daily for 12 weeks) or placebo. Primary outcomes measures were change from baseline in percentage of naïve B cells out of total B cells, and diameters in the index lesions (lymph nodes). Additional observations included changes in spleen size and cytopenia.
Leniolisib significantly increased the mean percentage of naïve B cells over time (from 40% at baseline to 65% at day 85), whereas no change was observed in the placebo arm (P=0.0006). Lymphadenopathy was significantly reduced in the leniolisib arm. In addition, leniolisib significantly decreased splenomegaly from baseline: -13.5 cm2 (2D diameter) and -186.3 cm3 (3D diameter), whereas no changes were observed in the placebo arm. Cytopenia improved in 82% of patients receiving leniolisib, compared with 60% of patients receiving placebo.
Leniolisib was well tolerated, and no serious adverse events related to the study treatment were observed. However, leniolisib resulted in a transient neutropenia (nadir on day 15). Based on these results, Dr Rao concluded that “leniolisib is safe, increases naïve B cells, decreases lymphadenopathy, decreases spleen size, and improves cytopenia.”
1. Rao VK, et al. Blood 2017;130:2307–2316.
2. Rao VK, et al. Hematological outcomes from a phase 3, placebo-controlled, randomized clinical trial of PI3K delta inhibitor leniolisib in patients with activated PI3K delta syndrome (APDS/PASLI). Abstract LB2369. EHA2022 Hybrid Congress, 09–12 June.