Management of Gastro-Intestinal Toxicity of the Pi3 Kinase Inhibitor: Optimizing Future Dosing Strategies

Abstract

The phosphatidylinositol 3-kinase (PI3K) pathway plays a key role in cancer progression and in host immunity. Idelalisib was the first of this class to be approved with the second-generation Pi3 kinase inhibitors copanlisib, duvelisib and umbralisib, subsequently being approved in the United States. Real-world data are lacking, however, in relation to the incidence and toxicity of Pi3 kinase inhibitor-induced colitis. We here review, in the first instance, the general landscape of the Pi3K inhibitors in the context of hematological malignancies, with a focus on the adverse gastrointestinal side effects reported by various clinical trials. We further review the available worldwide pharmacovigilance data in relation to these drugs. Finally, we describe our own real-world experience with idelalisib-induced colitis management in our center and in a national setting.

Keywords: adverse drug reaction; colitis; idelalisib; pharmacovigilance; phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor.

Figure 1

Histological patterns of the idelalisib-induced colitis in the study patients. (A,B) Mild crypt distortion without any other anomaly (case 1). (C,D) Acute inflammatory changes, crypt abscess, IBD/ulcerative colitis-like (cases 3 and 5). (E,F) Withering crypt, fibrosis of the lamina propria, chronic ischemic-like lesion (case 4). (G,H) Apoptotic predominant aspect, GVH-like (cases 2 and 6). (A,E) ×25; (C,G) ×100; (B,F) ×200; (D,H) ×400.