Association of Chronic Immune-Mediated Diarrhea and Colitis With Favorable Cancer Response

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  • 1 Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, PR China;
  • | 2 Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas;
  • | 3 Department of Internal Medicine, University of Missouri, Kansas City, Missouri;
  • | 4 Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China;
  • | 5 Department of Biosciences, Rice University, Houston, Texas;
  • | 6 Department of Biostatistics,
  • | 7 Department of Genitourinary Medical Oncology,
  • | 8 Department of Melanoma Medical Oncology, and
  • | 9 Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas; and
  • | 10 Department of Medicine, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Background: Immune-mediated diarrhea and colitis (IMDC) is a common immune-related adverse effect related to immune checkpoint inhibitors. We aimed to identify risk factors for chronic IMDC and its prognostic value in cancer outcomes. Methods: We retrospectively collected data on patients with a diagnosis of IMDC between January 2018 and October 2019 and grouped them based on disease duration into acute (≤3 months) and chronic (>3 months) categories. A logistic regression model and the Kaplan-Meier method with log-rank tests were used for biostatistical analysis. Results: In our sample of 88 patients, 43 were in the chronic group and 45 were in the acute group. Genitourinary cancer and melanoma accounted for 70% of malignancies. PD-1/L1 monotherapy (52%) was the more frequently used regimen. We showed that chronic IMDC was associated with proton pump inhibitor use (odds ratio [OR], 3.96; P=.026), long duration of IMDC symptoms (OR, 1.05; P<.001) and hospitalization (OR, 1.07; P=.043), a histologic feature of chronic active colitis (OR, 4.8; P=.025) or microscopic colitis (OR, 5.0; P=.045), and delayed introduction of selective immunosuppressive therapy (infliximab/vedolizumab; OR, 1.06; P=.047). Chronic IMDC also reflected a better cancer response to immune checkpoint inhibitors (30% vs 51%; P=.002) and was accompanied by improved overall survival (P=.035). Similarly, higher doses of selective immunosuppressive therapy were associated with better overall survival (P=.018). Conclusions: Chronic IMDC can develop among patients with a more aggressive disease course and chronic features on colon histology. It likely reflects a prolonged immune checkpoint inhibitor effect and is associated with better cancer outcome and overall survival.

Submitted June 25, 2020; final revision received August 11, 2020; accepted for publication August 31, 2020.

Published online December 14, 2020.

Author contributions: Study concept and design: Thomas, Y. Wang. Data collection: Zou. Conduct and interpretation of analysis: Zou. Project design: Abu-Sbeih, Ma, Peng. Interpretation of results: Thomas, Y. Wang. Preservation of data accuracy and integrity at all stages: Thomas, Y. Wang. Biostatistical analysis: Qiao. Manuscript preparation: Thomas, Y. Wang, Zou. Critical revision: Abu-Sbeih, Ma, Peng, J. Wang, Shah, Glitza Oliva, Piha-Paul, Thompson, Zhang.

Disclosures: Dr. Piha-Paul has disclosed that she receives grant/research support (through her institution) from AbbVie, Inc.; ABM Therapeutics, Inc.; Acepodia, Inc; Alkermes; Aminex Therapeutics; Amphivena Therapeutics, Inc.; BioMarin Pharmaceutical, Inc; Boehringer Ingelheim; Bristol-Myers Squibb; Cerulean Pharma, Inc.; Chugai Pharmaceutical Co., Ltd; Curis, Inc.; Daichi Sanko; Eli Lilly; ENB Therapeutics; Five Prime Therapeutics; Gene Quantum; Genmab A/S; GlaxoSmithKline; Helix BioPharma Corp.; Incyte Corporation; Jacobio Pharmaceuticals Co., Ltd.; Medimmune, LLC.; Medivation, Inc.; Merck Sharp & Dohme Corp.; Novartis Pharmaceuticals; Pieris Pharmaceuticals, Inc.; Pfizer; Principia Biopharma, Inc.; Puma Biotechnology, Inc.; Rapt Therapeutics, Inc.; Seattle Genetics; Silverback Therapeutics; Taiho Oncology; Tesaro, Inc.; and TransThera Bio. The remaining authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: Dr. Piha-Paul is the recipient of an NCI/NIH Core Grant (P30CA016672 – CCSG shared resources).

Disclaimers: Ethics approval for this study was granted by The University of Texas MD Anderson Cancer Center Institutional Review Board (PA18-0472). Patient consent was waived for this study. The datasets used and analyzed in this study are available from the corresponding author upon reasonable request.

Correspondence: Yinghong Wang, MD, PhD, Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Unit 1466, 1515 Holcombe Boulevard, Houston, TX 77030. Email: ywang59@mdanderson.org

Supplementary Materials

    • Supplemental Materials (PDF 190 KB)
  • 1.

    Darvin P, Toor SM, Sasidharan Nair V, et al.. Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med 2018;50:111.

    • Search Google Scholar
    • Export Citation
  • 2.

    Bayle A, Khettab M, Lucibello F, et al.. Immunogenicity and safety of influenza vaccination in cancer patients receiving checkpoint inhibitors targeting PD-1 or PD-L1. Ann Oncol 2020;31:959961.

    • Search Google Scholar
    • Export Citation
  • 3.

    Abril-Rodriguez G, Ribas A. SnapShot: immune checkpoint inhibitors. Cancer Cell 2017;31:848848.e1.

  • 4.

    Marin-Acevedo JA, Soyano AE, Dholaria B, et al.. Cancer immunotherapy beyond immune checkpoint inhibitors. J Hematol Oncol 2018;11:8.

  • 5.

    Singh BP, Marshall JL, He AR. Workup and management of immune-mediated colitis in patients treated with immune checkpoint inhibitors. Oncologist 2020;25:197202.

    • Search Google Scholar
    • Export Citation
  • 6.

    Bellaguarda E, Hanauer S. Checkpoint inhibitor-induced colitis. Am J Gastroenterol 2020;115:202210.

  • 7.

    Abu-Sbeih H, Ali FS, Naqash AR, et al.. Resumption of immune checkpoint inhibitor therapy after immune-mediated colitis. J Clin Oncol 2019;37:27382745.

    • Search Google Scholar
    • Export Citation
  • 8.

    Abu-Sbeih H, Ali FS, Wang Y. Immune-checkpoint inhibitors induced diarrhea and colitis: a review of incidence, pathogenesis and management. Curr Opin Gastroenterol 2020;36:2532.

    • Search Google Scholar
    • Export Citation
  • 9.

    Abu-Sbeih H, Ali FS, Wang X, et al.. Early introduction of selective immunosuppressive therapy associated with favorable clinical outcomes in patients with immune checkpoint inhibitor-induced colitis. J Immunother Cancer 2019;7:93.

    • Search Google Scholar
    • Export Citation
  • 10.

    Som A, Mandaliya R, Alsaadi D, et al.. Immune checkpoint inhibitor-induced colitis: a comprehensive review. World J Clin Cases 2019;7:405418.

    • Search Google Scholar
    • Export Citation
  • 11.

    Wang Y, Abu-Sbeih H, Mao E, et al.. Endoscopic and histologic features of immune checkpoint inhibitor-related colitis. Inflamm Bowel Dis 2018;24:16951705.

    • Search Google Scholar
    • Export Citation
  • 12.

    Wang Y, Abu-Sbeih H, Mao E, et al.. Immune-checkpoint inhibitor-induced diarrhea and colitis in patients with advanced malignancies: retrospective review at MD Anderson. J Immunother Cancer 2018;6:37.

    • Search Google Scholar
    • Export Citation
  • 13.

    Abu-Sbeih H, Ali FS, Qiao W, et al.. Immune checkpoint inhibitor-induced colitis as a predictor of survival in metastatic melanoma. Cancer Immunol Immunother 2019;68:553561.

    • Search Google Scholar
    • Export Citation
  • 14.

    Wang Y, Wiesnoski DH, Helmink BA, et al.. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat Med 2018;24:18041808.

    • Search Google Scholar
    • Export Citation
  • 15.

    Abu-Sbeih H, Tang T, Ali FS, et al.. The impact of immune checkpoint inhibitor-related adverse events and their immunosuppressive treatment on patients’ outcomes. J Immunother Precis Oncol 2018;1:718.

    • Search Google Scholar
    • Export Citation
  • 16.

    Fujii Y, Nishikawa Y, Nomura M, et al.. Readministration of nivolumab after persistent immune-related colitis in a patient with recurrent melanoma. Intern Med 2018;57:11731176.

    • Search Google Scholar
    • Export Citation
  • 17.

    Johnson DH, Zobniw CM, Trinh VA, et al.. Infliximab associated with faster symptom resolution compared with corticosteroids alone for the management of immune-related enterocolitis. J Immunother Cancer 2018;6:103.

    • Search Google Scholar
    • Export Citation
  • 18.

    Abu-Sbeih H, Ali FS, Alsaadi D, et al.. Outcomes of vedolizumab therapy in patients with immune checkpoint inhibitor-induced colitis: a multi-center study. J Immunother Cancer 2018;6:142.

    • Search Google Scholar
    • Export Citation
  • 19.

    van den Heuvel TR, Wintjens DS, Jeuring SF, et al.. Inflammatory bowel disease, cancer and medication: cancer risk in the Dutch population-based IBDSL cohort. Int J Cancer 2016;139:12701280.

    • Search Google Scholar
    • Export Citation
  • 20.

    Axelrad JE, Lichtiger S, Yajnik V. Inflammatory bowel disease and cancer: the role of inflammation, immunosuppression, and cancer treatment. World J Gastroenterol 2016;22:47944801.

    • Search Google Scholar
    • Export Citation
  • 21.

    Taleban S, Elquza E, Gower-Rousseau C, et al.. Cancer and inflammatory bowel disease in the elderly. Dig Liver Dis 2016;48:11051111.

  • 22.

    Scott SC, Pennell NA. Early use of systemic corticosteroids in patients with advanced NSCLC treated with nivolumab. J Thorac Oncol 2018;13:17711775.

    • Search Google Scholar
    • Export Citation
  • 23.

    Esfahani K, Miller WH Jr. Reversal of autoimmune toxicity and loss of tumor response by interleukin-17 blockade. N Engl J Med 2017;376:19891991.

    • Search Google Scholar
    • Export Citation
  • 24.

    Verheijden RJ, May AM, Blank CU, et al.. Association of anti-TNF with decreased survival in steroid refractory ipilimumab and anti-PD1-treated patients in the Dutch Melanoma Treatment Registry. Clin Cancer Res 2020;26:22682274.

    • Search Google Scholar
    • Export Citation
  • 25.

    Horvat TZ, Adel NG, Dang TO, et al.. Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol 2015;33:31933198.

    • Search Google Scholar
    • Export Citation
  • 26.

    Arriola E, Wheater M, Karydis I, et al.. Infliximab for IPILIMUMAB-related colitis—letter. Clin Cancer Res 2015;21:56425643.

  • 27.

    The University of Texas MD Anderson Cancer Center. Evaluation and management of suspected immune-mediated colitis/diarrhea. Accessed September 10, 2020. Available at: https://www.mdanderson.org/content/dam/mdanderson/documents/for-physicians/algorithms/clinical-management/clin-management-immune-mediated-colitis-web-algorithm.pdf

  • 28.

    Abu-Sbeih H, Faleck DM, Ricciuti B, et al.. Immune checkpoint inhibitor therapy in patients with preexisting inflammatory bowel disease. J Clin Oncol 2020;38:576583.

    • Search Google Scholar
    • Export Citation
  • 29.

    Abu-Sbeih H, Ali FS, Luo W, et al.. Importance of endoscopic and histological evaluation in the management of immune checkpoint inhibitor-induced colitis. J Immunother Cancer 2018;6:95.

    • Search Google Scholar
    • Export Citation
  • 30.

    Choi K, Abu-Sbeih H, Samdani R, et al.. Can immune checkpoint inhibitors induce microscopic colitis or a brand new entity? Inflamm Bowel Dis 2019;25:385393.

    • Search Google Scholar
    • Export Citation
  • 31.

    Freedberg DE, Toussaint NC, Chen SP, et al.. Proton pump inhibitors alter specific taxa in the human gastrointestinal microbiome: a crossover trial. Gastroenterology 2015;149:883885.e9.

    • Search Google Scholar
    • Export Citation
  • 32.

    Ducarmon QR, Zwittink RD, Hornung BVH, et al.. Gut microbiota and colonization resistance against bacterial enteric infection. Microbiology and molecular biology reviews. Microbiol Mol Biol Rev 2019;83:e0000700009.

    • Search Google Scholar
    • Export Citation
  • 33.

    Bonderup OK, Nielsen GL, Dall M, et al.. Significant association between the use of different proton pump inhibitors and microscopic colitis: a nationwide Danish case-control study. Aliment Pharmacol Ther 2018;48:618625.

    • Search Google Scholar
    • Export Citation
  • 34.

    Verhaegh BP, de Vries F, Masclee AA, et al.. High risk of drug-induced microscopic colitis with concomitant use of NSAIDs and proton pump inhibitors. Aliment Pharmacol Ther 2016;43:10041013.

    • Search Google Scholar
    • Export Citation
  • 35.

    Rogers MAM, Aronoff DM. The influence of non-steroidal anti-inflammatory drugs on the gut microbiome. Clin Microbiol Infect 2016;22:178.e1178.e9.

    • Search Google Scholar
    • Export Citation
  • 36.

    Becattini S, Taur Y, Pamer EG. Antibiotic-induced changes in the intestinal microbiota and disease. Trends Mol Med 2016;22:458478.

  • 37.

    Abu-Sbeih H, Herrera LN, Tang T, et al.. Impact of antibiotic therapy on the development and response to treatment of immune checkpoint inhibitor-mediated diarrhea and colitis. J Immunother Cancer 2019;7:242.

    • Search Google Scholar
    • Export Citation
  • 38.

    Chaput N, Lepage P, Coutzac C, et al.. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol 2017;28:13681379.

    • Search Google Scholar
    • Export Citation
  • 39.

    Matson V, Fessler J, Bao R, et al.. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018;359:104108.

    • Search Google Scholar
    • Export Citation
  • 40.

    Routy B, Le Chatelier E, Derosa L, et al.. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018;359:9197.

    • Search Google Scholar
    • Export Citation
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