NCCN Guidelines Insights: Management of Immunotherapy-Related Toxicities, Version 1.2020

Featured Updates to the NCCN Guidelines

View More View Less
  • 1 Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance;
  • 2 University of Michigan Rogel Cancer Center;
  • 3 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins;
  • 4 Moffitt Cancer Center;
  • 5 Dana-Farber/Brigham and Women’s Cancer Center;
  • 6 City of Hope National Medical Center;
  • 7 O’Neal Comprehensive Cancer Center at UAB;
  • 8 Yale Cancer Center/Smilow Cancer Hospital;
  • 9 Patient Advocate;
  • 10 Roswell Park Comprehensive Cancer Center;
  • 11 Massachusetts General Hospital Cancer Center;
  • 12 The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute;
  • 13 Fred & Pamela Buffett Cancer Center;
  • 14 Abramson Cancer Center at the University of Pennsylvania;
  • 15 Huntsman Cancer Institute at the University of Utah;
  • 16 Robert H. Lurie Comprehensive Cancer Center of Northwestern University;
  • 17 Fox Chase Cancer Center;
  • 18 Vanderbilt-Ingram Cancer Center;
  • 19 UC San Diego Moores Cancer Center;
  • 20 Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute;
  • 21 Stanford Cancer Institute;
  • 22 Mayo Clinic Cancer Center;
  • 23 Memorial Sloan Kettering Cancer Center;
  • 24 Duke Cancer Institute;
  • 25 The University of Texas MD Anderson Cancer Center;
  • 26 University of Colorado Cancer Center; and
  • 27 National Comprehensive Cancer Network.
Restricted access

The NCCN Guidelines for Management of Immunotherapy-Related Toxicities provide interdisciplinary guidance on the management of immune-related adverse events (irAEs) resulting from cancer immunotherapy. These NCCN Guidelines Insights describe symptoms that may be caused by an irAE and should trigger further investigation, and summarize the NCCN Management of Immunotherapy-Related Toxicities Panel discussions for the 2020 update to the guidelines regarding immune checkpoint inhibitor–related diarrhea/colitis and cardiovascular irAEs.

  • 1.

    Keytruda (pembrolizumab) for injection, for intravenous use [prescribing information]. Whitehouse Station, NJ: Merck & Co, Inc.; 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125514s065lbl.pdf. Accessed September 1, 2019.

  • 2.

    Opdivo (nivolumab) injection, for intravenous use [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125554s075lbl.pdf. Accessed September 1, 2019.

  • 3.

    Tecentriq (atezolizumab) injection, for intravenous use [prescribing information]. South San Francisco, CA: Genentech, Inc.; 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761034s021lbl.pdf. Accessed December 1, 2019.

  • 4.

    Bavencio (avelumab) injection, for intravenous use [prescribing information]. Rockland, MA: EMD Serono, Inc; 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761049s006lbl.pdf. Accessed May 1, 2019.

  • 5.

    Yervoy (ipilimumab) injection, for intravenous use [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125377s104lbl.pdf. Accessed September 1, 2019.

  • 6.

    Imfinzi (durvalumab) injection, for intravenous use [prescribing information]. Cambridge, England: AstraZeneca UK Limited; 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761069s013lbl.pdf. Accessed July 2019.

  • 7.

    Seidel JA, Otsuka A, Kabashima K. Anti-PD-1 and anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy, and limitations. Front Oncol 2018;8:86.

  • 8.

    Libtayo (cemiplimab) injection, for intravenous use [prescribing Information]. Tarrytown, NY: Regeneron Pharmaceuticals, Inc.; 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761097s001lbl.pdf. Accessed Mar 2019.

  • 9.

    Lam LH, Lin SD, Sun J. Pharmacokinetics and pharmacodynamics of immunotherapy. In: Patel SP, Kurzrock R, eds. Early Phase Cancer Immunotherapy. Manhattan, NY: Springer International Publishing, 2018:2967.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Gangadhar TC, Vonderheide RH. Mitigating the toxic effects of anticancer immunotherapy. Nat Rev Clin Oncol 2014;11:9199.

  • 11.

    Kong YC, Flynn JC. Opportunistic autoimmune disorders potentiated by immune-checkpoint inhibitors anti-CTLA-4 and anti-PD-1. Front Immunol 2014;5:206.

  • 12.

    Ledezma B, Heng A. Real-world impact of education: treating patients with ipilimumab in a community practice setting. Cancer Manag Res 2013;6:514.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Maude SL, Barrett D, Teachey DT, . Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J 2014;20:119122.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Kumar V, Chaudhary N, Garg M, . Current diagnosis and management of immune related adverse events (irAEs) induced by immune checkpoint inhibitor therapy. Front Pharmacol 2017;8:49.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Puzanov I, Diab A, Abdallah K, . Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer 2017;5:95.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Boutros C, Tarhini A, Routier E, . Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol 2016;13:473486.

  • 17.

    Robert C, Long GV, Brady B, . Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015;372:320330.

  • 18.

    Ferris RL, Blumenschein G Jr, Fayette J, . Nivolumab vs investigator’s choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression. Oral Oncol 2018;81:4551.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Hodi FS, Chiarion-Sileni V, Gonzalez R, . Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol 2018;19:14801492.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Topalian SL, Hodi FS, Brahmer JR, . Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:24432454.

  • 21.

    Agrawal S, Feng Y, Roy A, . Nivolumab dose selection: challenges, opportunities, and lessons learned for cancer immunotherapy. J Immunother Cancer 2016;4:72.

  • 22.

    Hamid O, Robert C, Daud A, . Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Ann Oncol 2019;30:582588.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Hamid O, Puzanov I, Dummer R, . Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer 2017;86:3745.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Schachter J, Ribas A, Long GV, . Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet 2017;390:18531862.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 2018;378:158168.

  • 26.

    Weber JS, Postow M, Lao CD, . Management of adverse events following treatment with anti-programmed death-1 agents. Oncologist 2016;21:12301240.

  • 27.

    Ryder M, Callahan M, Postow MA, . Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution. Endocr Relat Cancer 2014;21:371381.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    González-Rodríguez E, Rodríguez-Abreu D. Immune checkpoint inhibitors: review and management of endocrine adverse events. Oncologist 2016;21:804816.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Ganatra S, Neilan TG. Immune checkpoint inhibitor-associated myocarditis. Oncologist 2018;23:879886.

  • 30.

    Kadota H, Gono T, Shirai Y, . Immune checkpoint inhibitor-induced myositis: a case report and literature review. Curr Rheumatol Rep 2019;21:10.

  • 31.

    Anquetil C, Salem JE, Lebrun-Vignes B, . Immune checkpoint inhibitor-associated myositis. Circulation 2018;138:743745.

  • 32.

    Touat M, Maisonobe T, Knauss S, . Immune checkpoint inhibitor-related myositis and myocarditis in patients with cancer. Neurology 2018;91:e985994.

  • 33.

    Wang DY, Salem JE, Cohen JV, . Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol 2018;4:17211728.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.

    Moslehi JJ, Salem JE, Sosman JA, . Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet 2018;391:933.

  • 35.

    Weber JS, Dummer R, de Pril V, . Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma. Cancer 2013;119:16751682.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

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

  • 37.

    Gupta A, De Felice KM, Loftus EV Jr, . Systematic review: colitis associated with anti-CTLA-4 therapy. Aliment Pharmacol Ther 2015;42:406417.

  • 38.

    Pernot S, Ramtohul T, Taieb J. Checkpoint inhibitors and gastrointestinal immune-related adverse events. Curr Opin Oncol 2016;28:264268.

  • 39.

    Tandon P, Bourassa-Blanchette S, Bishay K, . The risk of diarrhea and colitis in patients with advanced melanoma undergoing immune checkpoint inhibitor therapy: a systematic review and meta-analysis. J Immunother 2018;41:101108.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40.

    Wang DY, Ye F, Zhao S, . Incidence of immune checkpoint inhibitor-related colitis in solid tumor patients: a systematic review and meta-analysis. OncoImmunology 2017;6:e1344805.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41.

    National Cancer Institute, Division of Cancer Treatment & Diagnosis. Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Bethesda, MD: US Department of Health and Human Services; 2017. Available at: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50. Accessed December 1, 2019.

  • 42.

    Brahmer JR, Lacchetti C, Schneider BJ, . Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2018;36:17141768.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 43.

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

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44.

    Dai C, Jiang M, Sun MJ, . Fecal lactoferrin for assessment of inflammatory bowel disease activity: a systematic review and meta-analysis [published online April 15, 2019]. J Clin Gastroenterol, doi: 10.1097/MCG.0000000000001212

    • Search Google Scholar
    • Export Citation
  • 45.

    Wang Y, Pei F, Wang X, . Diagnostic accuracy of fecal lactoferrin for inflammatory bowel disease: a meta-analysis. Int J Clin Exp Pathol 2015;8:1231912332.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46.

    Geukes Foppen MH, Rozeman EA, van Wilpe S, . Immune checkpoint inhibition-related colitis: symptoms, endoscopic features, histology and response to management. ESMO Open 2018;3:e000278.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 47.

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

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48.

    Jain A, Lipson EJ, Sharfman WH, . Colonic ulcerations may predict steroid-refractory course in patients with ipilimumab-mediated enterocolitis. World J Gastroenterol 2017;23:20232028.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49.

    Sfikakis PP. The first decade of biologic TNF antagonists in clinical practice: lessons learned, unresolved issues and future directions. Curr Dir Autoimmun 2010;11:180210.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50.

    Reimold AM. TNFalpha as therapeutic target: new drugs, more applications. Curr Drug Targets Inflamm Allergy 2002;1:377392.

  • 51.

    Wolfe RM, Ang DC. Biologic therapies for autoimmune and connective tissue diseases. Immunol Allergy Clin North Am 2017;37:283299.

  • 52.

    Friedman CF, Proverbs-Singh TA, Postow MA. Treatment of the immune-related adverse effects of immune checkpoint inhibitors: a review. JAMA Oncol 2016;2:13461353.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53.

    Pagès C, Gornet JM, Monsel G, . Ipilimumab-induced acute severe colitis treated by infliximab. Melanoma Res 2013;23:227230.

  • 54.

    Merrill SP, Reynolds P, Kalra A, . Early administration of infliximab for severe ipilimumab-related diarrhea in a critically ill patient. Ann Pharmacother 2014;48:806810.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 55.

    Entyvio (vedolizumab) for injection, for intravenous use [prescribing information]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125476s024lbl.pdf. Accessed May 2019.

  • 56.

    Bergqvist V, Hertervig E, Gedeon P, . Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis. Cancer Immunol Immunother 2017;66:581592.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 57.

    Diana P, Mankongpaisarnrung C, Atkins MB, . Emerging role of vedolizumab in managing refractory immune checkpoint inhibitor-induced enteritis. ACG Case Rep J 2018;5:e17.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 58.

    Hsieh AH, Ferman M, Brown MP, Andrews JM. Vedolizumab: a novel treatment of ipilimumab-induced colitis. BMJ Case Rep 2016;2016:bcr2016216641.

  • 59.

    Abu-Sbeih H, Ali FS, Wang X, . 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.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 60.

    Wang Y, Wiesnoski DH, Helmink BA, . Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis [errata appears in Nat Med 2019;25:188]. Nat Med 2018;24:18041808.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 61.

    Heinzerling L, Ott PA, Hodi FS, . Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy. J Immunother Cancer 2016;4:50.

  • 62.

    Mahmood SS, Fradley MG, Cohen JV, . Myocarditis in patients treated with immune checkpoint inhibitors. J Am Coll Cardiol 2018;71:17551764.

  • 63.

    Johnson DB, Balko JM, Compton ML, . Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med 2016;375:17491755.

  • 64.

    Yun S, Vincelette ND, Mansour I, . Late onset ipilimumab-induced pericarditis and pericardial effusion: a rare but life threatening complication. Case Rep Oncol Med 2015;2015:794842.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 65.

    Esfahani K, Buhlaiga N, Thébault P, . Alemtuzumab for immune-related myocarditis due to PD-1 therapy. N Engl J Med 2019;380:23752376.

  • 66.

    Varricchi G, Marone G, Mercurio V, . Immune checkpoint inhibitors and cardiac toxicity: an emerging issue. Curr Med Chem 2018;25:13271339.

  • 67.

    Agrawal N, Khunger A, Vachhani P, . Cardiac toxicity associated with immune checkpoint inhibitors: case series and review of the literature. Case Rep Oncol 2019;12:260276.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 68.

    Norwood TG, Westbrook BC, Johnson DB, . Smoldering myocarditis following immune checkpoint blockade. J Immunother Cancer 2017;5:91.

  • 69.

    Tajmir-Riahi A, Bergmann T, Schmid M, . Life-threatening autoimmune cardiomyopathy reproducibly induced in a patient by checkpoint inhibitor therapy. J Immunother 2018;41:3538.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 70.

    Aquaro GD, Perfetti M, Camastra G, . Cardiac MR with late gadolinium enhancement in acute myocarditis with preserved systolic function: ITAMY study. J Am Coll Cardiol 2017;70:19771987.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 71.

    Tay RY, Blackley E, McLean C, . Successful use of equine anti-thymocyte globulin (ATGAM) for fulminant myocarditis secondary to nivolumab therapy. Br J Cancer 2017;117:921924.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 72.

    Jain V, Bahia J, Mohebtash M, . Cardiovascular complications associated with novel cancer immunotherapies. Curr Treat Options Cardiovasc Med 2017;19:36.

  • 73.

    Kobashigawa J, Crespo-Leiro MG, Ensminger SM, . Report from a consensus conference on antibody-mediated rejection in heart transplantation. J Heart Lung Transplant 2011;30:252269.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 74.

    Frigeri M, Meyer P, Banfi C, . Immune checkpoint inhibitor-associated myocarditis: a new challenge for cardiologists. Can J Cardiol 2018;34:92.e192.e3.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 75.

    Rodriguez ER, Skojec DV, Tan CD, . Antibody-mediated rejection in human cardiac allografts: evaluation of immunoglobulins and complement activation products C4d and C3d as markers. Am J Transplant 2005;5:27782785.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 76.

    Kobashigawa JA, Miller LW, Russell SD, . Tacrolimus with mycophenolate mofetil (MMF) or sirolimus vs. cyclosporine with MMF in cardiac transplant patients: 1-year report. Am J Transplant 2006;6:13771386.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 77.

    Kwon HJ, Coté TR, Cuffe MS, . Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Ann Intern Med 2003;138:807811.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 78.

    Salem JE, Allenbach Y, Vozy A, . Abatacept for severe immune checkpoint inhibitor-associated myocarditis. N Engl J Med 2019;380:23772379.

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 8517 8517 686
PDF Downloads 3546 3546 235
EPUB Downloads 0 0 0