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

SIMPLE SUMMARY: Targeted therapies are becoming more widespread in the treatment of indolent B-cell malignancies, as has been the case for chronic lymphocytic leukemias and small B-cell non-Hodgkin lymphomas. Due to the severity of these diseases, several drugs have received fast track approval since 2014 including the BTK inhibitor ibrutinib, the Bcl2 inhibitor venetoclax and various P13 kinase inhibitors. Of the Pi3 kinase inhibitors, idelalisib was the first of this class to be approved, followed by the second-generation drugs copanlisib, duvelisib and umbralisib. However, the last of these agents have now been withdrawn, partly due to severe gastrointestinal side effects. We herein describe these gastrointestinal effects, as reported in clinical trials, and then review real-world data for these targeted inhibitors using world-wide pharmacovigilance evidence. Our own single-center experience of 15 patients with an indolent B-cell malignancy, from with six biopsies were derived, has helped us to describe the incidence and severity of Pi3 kinase-induced colitis. Histological analysis of these cases yielded clues toward an immunopathological hypothesis. We finally speculate on future directions in relation to managing this severe toxicity and thereby optimizing the safe use of these drugs. 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.