Severe enterocolitis associated with phosphatidylinositol 3-kinase delta inhibitors: A multicentre cohort study

Abstract

Introduction: Phosphatidylinositol 3-kinase-δ (PI3Kδ) inhibitors have been approved for treatment of patients with chronic lymphocytic leukemia and non-Hodgkin's lymphomas and may lead to enterocolitis.

Patients and methods: This is a multicenter, retrospective cohort study. Consecutive patients treated with PI3Kδ inhibitors who developed severe enterocolitis.

Results: Between 2014 and 2023, 31 out of 133 (23 %) patients exposed to PI3Kδ inhibitors had severe enterocolitis. Among them, 71 % required hospitalization, 64 % experienced weight loss and 39 % of patients had acute kidney injury. Endoscopic lesions were mild in 15/19 patients while four patients had shallow ulcers. Histopathological examination of colonic biopsies was abnormal in all cases. The most common lesions were neutrophilic cryptitis, crypt abscesses, crypt epithelial cell apoptosis and crypt architectural abnormalities. PI3Kδ inhibitors were discontinued in 24 cases (77 %). At day 30, clinical remission was achieved in 0/7 patients who continued PI3Kδ-inhibitor and in all patients who discontinued PI3Kδ-inhibitor (p < 0.001) with no benefit of adding prednisone or budesonide to treatment discontinuation. Relapse of diarrhea occurred in four out of seven (57 %) patients who resumed half-dosed PI3Kδ inhibitor.

Conclusion: Severe enterocolitis associated with PI3Kδ inhibitors is frequent and respond to drug withholding. Steroids do not seem to provide additional benefits. Rechallenge is often accompanied by a relapse.

Keywords: Enterocolitis; Gastrointestinal toxicity; PI3Kδ inhibitor.