Retrospective Cohort Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 21, 2017; 23(11): 2023-2028
Published online Mar 21, 2017. doi: 10.3748/wjg.v23.i11.2023
Colonic ulcerations may predict steroid-refractory course in patients with ipilimumab-mediated enterocolitis
Animesh Jain, Evan J Lipson, William H Sharfman, Steven R Brant, Mark G Lazarev
Animesh Jain, Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of North Carolina Chapel Hill, Chapel Hill, NC 27599-7080, United States
Evan J Lipson, William H Sharfman, Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, United States
Steven R Brant, Mark G Lazarev, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States
Author contributions: Jain A, Lipson EJ and Lazarev MG conceived the study and initial study design; Sharfman W contributed to study design; Lipson EJ and Sharfman WH contributed the patient cohort; Brant SR assisted with data analysis and interpretation; Jain A wrote the primary draft of the manuscript; all authors contributed to data analysis/interpretation, and drafting/revising the manuscript, and have approved the final version of this manuscript, including the authorship list.
Institutional review board statement: The study was approved by the Institutional Review Board of the Johns Hopkins University.
Informed consent statement: Informed consent was not obtained from patients given that this was a retrospective cohort study with low likelihood of identifiable patient information - only anonymized data are presented. The study was approved by our Institutional Review Board as being exempt from informed consent requirements based on the nature and design of the study.
Conflict-of-interest statement: Jain A and Lazarev MG have no declarations. Lipson EJ has served as a consultant for Bristol-Myers Squibb, EMD, Serono, Merck and Novartis; He has received research funding from Genentech and AstraZeneca. Sharfman WH has served as a consultant for Merck, Genentech, and Castle Biosciences, and he has received research funding from Bristol-Myers Squibb, Glaxo Smith Kline, and Novartis. Brant SR has served as an advisory board member for Asana Medical Inc., and he has received research funding from Johnson and Johnson.
Data sharing statement: The original anonymous dataset is available on request from the corresponding author at AnimeshJ@med.unc.edu.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Animesh Jain, MD, Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of North Carolina Chapel Hill, 130 Mason Farm Road, Campus Box 7080, Chapel Hill, NC 27599-7080, United States. animeshj@med.unc.edu
Telephone: +1-919-9668946 Fax: +1-919-9661036
Received: November 21, 2016
Peer-review started: November 23, 2016
First decision: December 19, 2016
Revised: January 6, 2017
Accepted: March 2, 2017
Article in press: March 2, 2017
Published online: March 21, 2017
Processing time: 118 Days and 14.8 Hours
Abstract
AIM

To investigate management of patients who develop ipilimumab-mediated enterocolitis, including association of endoscopic findings with steroid-refractory symptoms and utility of infliximab as second-line therapy.

METHODS

We retrospectively reviewed all patients at our center with metastatic melanoma who were treated with ipilimumab between March 2011 and May 2014. All patients received a standard regimen of intravenous ipilimumab 3 mg/kg every 3 wk for four doses or until therapy was stopped due to toxicity or disease progression. Basic demographic and clinical data were collected on all patients. For patients who developed grade 2 or worse diarrhea (increase of 4 bowel movements per day), additional data were collected regarding details of gastrointestinal symptoms, endoscopic findings and treatment course. Descriptive statistics were used.

RESULTS

A total of 114 patients were treated with ipilimumab during the study period and all were included. Sixteen patients (14%) developed ≥ grade 2 diarrhea. All patients were treated with high-dose corticosteroids (1-2 mg/kg prednisone daily or equivalent). Nine of 16 patients (56%) had ongoing diarrhea despite high-dose steroids. Steroid-refractory patients received one dose of intravenous infliximab at 5 mg/kg, and all but one had brisk resolution of diarrhea. Fourteen of the patients underwent either colonoscopy or sigmoidoscopy with variable endoscopic findings, ranging from mild erythema to colonic ulcers. Among 8 patients with ulcers demonstrated by sigmoidoscopy or colonoscopy, 7 patients (88%) developed steroid-refractory symptoms requiring infliximab. With a median follow-up of 264 d, no major adverse events associated with prednisone or infliximab were reported.

CONCLUSION

In patients with ipilimumab-mediated enterocolitis, the presence of colonic ulcers on endoscopy was associated with a steroid-refractory course.

Keywords: Ipilimumab; Melanoma; Enterocolitis; Colitis; Infliximab; Corticosteroid; Colonic ulcer

Core tip: Immune-mediated enterocolitis is a common toxicity of ipilimumab therapy for melanoma. Infliximab is often needed as a second line therapy in steroid refractory cases. Our findings suggest that colonic ulcers seen on lower gastrointestinal endoscopy may predict a steroid refractory disease course. This would support a role for endoscopy in select cases, and suggest that early initiation of infliximab therapy may be appropriate in patients with colonic ulceration. These results require further exploration in larger patient cohorts.