Lymphoma in Patients with Activated Phosphoinositide 3-kinase δ Syndrome Enrolled in Targeted PI3Kδ Inhibitor (Leniolisib) Clinical Trial

Hyperactivation of phosphoinositide 3-kinase δ (PI3Kδ) due to gain-of-function variants in catalytic domain gene PIK3CD or loss-of-regulatory-function variants in PIK3R1 leads to activated PI3Kδ syndrome (APDS1/APDS2). APDS manifests as immunodeficiency, cytopenia, lymphoproliferation, and increased risk of lymphoma. Leniolisib, a selective PI3Kδ inhibitor, addresses hyperactive signaling, but long-term data on the risk of subsequent lymphoma development are not available. We present two cases of lymphoma in patients with APDS1 and APDS2, respectively, while on leniolisib. The first case is a 20-year-old Saudi female with APDS1 (NM_005026.5(PIK3CD), c.1574A>G, p.Glu525Gly) and a maternal history of lymphoma who experienced recurrent infections, splenomegaly, and EBV+ lymphoproliferative disease. She initially received mycophenolate mofetil and sirolimus before enrolling in a leniolisib Phase III trial (NCT02435173) in March 2020. After 85 days in the placebo arm, she transitioned to leniolisib during open-label extension. Adherence challenges, including customs-related issues, complicated her treatment. In June 2022, she developed stage IV CHL and received ABVD chemotherapy. Following remission, she underwent haploidentical stem cell transplantation but died from sepsis and acute respiratory failure in June 2023. The second case is a 25-year-old male with APDS2 (NM_181523.3(PIK3R1), c.1425+1G>T, del434-475) and chronic colitis who presented with massive hematochezia and small bowel obstruction from lymphocyte aggregation in December 2020. He enrolled in the leniolisib trial in March 2021 and transitioned to the commercial drug after Day 115, following FDA approval. In June 2024, he had a sigmoidoscopy for recurrent hematochezia with biopsy demonstrating crypt destructive colitis with cryptitis and crypt abscesses. In September 2024, he developed retroperitoneal lymphadenopathy, recurrent hematochezia, and weight loss. Biopsy revealed CD20+MUM1+EBV-DLBCL. He died from hemorrhagic shock and septicemia before lymphoma treatment could begin. These cases represent the first reported instances of lymphoma in APDS patients enrolled in the leniolisib Phase III trial. Diligent treatment adherence and lifelong lymphoma surveillance are critical. The emergence of resistance mechanisms in APDS, including co-optation of non-PI3K pathways like FAS-FASL defects, may contribute. Comprehensive genetic sequencing of germline and somatic tumor tissue may uncover alternate mechanisms of lymphomagenesis. Therapeutic strategies targeting more than one signaling pathway in APDS patients might improve prognosis.