Efficacy and safety of Infliximab for steroid‑resistant immune‑related adverse events: A retrospective study

Kadokawa,Yukio; Takagi,Mari; Yoshida,Tomoe; Tatsumi,Akitoshi; Fujita,Keiko; Inoue,Takako; Ohe,Shuichi; Nakai,Yasutomo; Yamamoto,Sachiko; Otsuka,Tomoyuki; Ishihara,Ryu; Isei,Taiki; Kumagai,Toru; Nishimura,Kazuo; Imamura,Fumio

doi:10.3892/mco.2021.2227

Efficacy and safety of Infliximab for steroid‑resistant immune‑related adverse events: A retrospective study

Authors:
- Yukio Kadokawa
- Mari Takagi
- Tomoe Yoshida
- Akitoshi Tatsumi
- Keiko Fujita
- Takako Inoue
- Shuichi Ohe
- Yasutomo Nakai
- Sachiko Yamamoto
- Tomoyuki Otsuka
- Ryu Ishihara
- Taiki Isei
- Toru Kumagai
- Kazuo Nishimura
- Fumio Imamura
View Affiliations

Affiliations: Department of Pharmacy, Osaka International Cancer Institute, Osaka Prefectural Hospital Organization, Osaka 541‑8567, Japan, Education and Research Center for Clinical Pharmacy, Kobe Pharmaceutical University, Kobe, Hyogo 658‑8558, Japan, Department of Respiratory Medicine, Osaka International Cancer Institute, Osaka Prefectural Hospital Organization, Osaka 541‑8567, Japan, Department of Dermatologic Oncology, Osaka International Cancer Institute, Osaka Prefectural Hospital Organization, Osaka 541‑8567, Japan, Department of Urology, Osaka International Cancer Institute, Osaka Prefectural Hospital Organization, Osaka 541‑8567, Japan, Department of Gastroenterology, Osaka International Cancer Institute, Osaka Prefectural Hospital Organization, Osaka 541‑8567, Japan, Department of Medical Oncology, Osaka International Cancer Institute, Osaka Prefectural Hospital Organization, Osaka 541‑8567, Japan
Published online on: February 8, 2021 https://doi.org/10.3892/mco.2021.2227
Article Number: 65
Copyright: © Kadokawa et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The present study investigated outcomes of infliximab (IFX) treatment among 8 Japanese patients with various types of cancer (4 with malignant melanoma, 3 with lung cancer and 1 with renal cancer) who developed severe steroid‑resistant immune‑related adverse events (irAEs) in association with immune checkpoint inhibitors (ICIs) to determine its efficacy and safety. Information, including patient background, treatment progress, examination data and imaging data, was collected retrospectively from electronic medical records. Adverse reactions were evaluated using the Common Terminology Criteria for Adverse Events version 4.0. Specific ICIs used were anti‑PD‑1, anti‑PD‑L1 and anti‑CTLA‑4 antibody preparations in 7, 2 and 5 patients, respectively. Specific irAEs included grade 3 diarrhea/colitis in 7 patients and disseminated intravascular coagulation and myocarditis attributed to autoimmune activation in 1 patient. The median duration between systemic steroid and IFX treatments was 9 (range, 2‑39) days. A total of 3 patients responded to IFX, 1 of whom responded after one dose and 2 responded after two doses. Respective diseases improved to grade 0 after a median of 18 (range, 9‑32) days. No AEs were attributable to IFX. Additionally, anti‑cytomegalovirus (CMV) and antibacterial agents were administered in parallel given the presence of CMV and Clostridium difficile (CD) infections in all patients, except in 1 exhibiting a marked IFX response after one dose. The combination of highly immunosuppressive IFX and high‑dose systemic steroid administration over a long period presumably predisposed the patients to opportunistic enteric infections. Accordingly, early initiation of IFX treatment in conjunction with systemic steroid therapy should be considered for severe diarrhea/colitis and other irAEs. However, the possibility for CMV and CD infections should be recognized, and for these the treatment strategy may need to be modified at an early stage.

View Figures

View References

1	Soularue E, Lepage P, Colombel JF, Coutzac C, Faleck D, Marthey L, Collins M, Chaput N, Robert C and Carbonnel F: Enterocolitis due to immune checkpoint inhibitors: A systematic review. Gut. 67:2056–2067. 2018.PubMed/NCBI View Article : Google Scholar
2	Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, Chau I, Ernstoff MS, Gardner JM, Ginex P, et al: Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy. J Clin Oncol. 36:1714–1768. 2018.PubMed/NCBI View Article : Google Scholar
3	Minor DR, Chin K and Kashani-Sabet M: Infliximab in the treatment of anti-CTLA4 antibody (Ipilimumab) induced immune-related colitis. Cancer Biother Radiopharm. 24:321–325. 2009.PubMed/NCBI View Article : Google Scholar
4	Beck KE, Blansfield JA, Tran KQ, Feldman AL, Hughes MS, Royal RE, Kammula US, Topalian SL, Sherry RM, Kleiner D, et al: Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol. 24:2283–2289. 2006.PubMed/NCBI View Article : Google Scholar
5	Hillock NT, Heard S, Kichenadasse G, Hill CL and Andrews J: Infliximab for ipilimumab-induced colitis: A series of 13 patients. Asia Pac J Clin Oncol. 13:e284–e290. 2017.PubMed/NCBI View Article : Google Scholar
6	Pagès C, Gornet JM, Monsel G, Allez M, Bertheau P, Bagot M, Lebbé C and Viguier M: Ipilimumab-Induced acute severe colitis treated by infliximab. Melanoma Res. 23:227–230. 2013.PubMed/NCBI View Article : Google Scholar
7	Geier M, Gouva S and Geier B: Enterocolitis due to nivolumab treated by infliximab. ASGIS. 2:14–16. 2019.
8	Yanai S, Nakamura S and Matsumoto T: Nivolumab-induced colitis treated by infliximab. Clin Gastroenterol Hepatol. 15:e80–e81. 2017.PubMed/NCBI View Article : Google Scholar
9	Nassri AB, Muenyi V, Al-Khasawneh A, De Souza Ribeiro B, Scolapio JS, Malespin M and de Melo SW Jr: Ipilimumab and nivolumab induced steroid-refractory colitis treated with infliximab: A case report. World J Gastroint Pharmacol Ther. 10:29–24. 2019.PubMed/NCBI View Article : Google Scholar
10	Delasos L, Desai A, Lia NL, Kethireddy N and Ray C: A case of immunotherapy-induced colitis complicated by perforation and treated with infliximab postoperatively. Case Rep Oncol Med. 2019(9069354)2019.PubMed/NCBI View Article : Google Scholar
11	Johnson DH, Zobniw CM, Trinh VA, Ma J, Bassett RL Jr, Abdel-Wahab N, Anderson J, Davis JE, Joseph J, Uemura M, et al: Infliximab associated with faster symptom resolution compared with corticosteroids alone for the management of immune-related enterocolitis. J Immunother Cancer. 6(103)2018.PubMed/NCBI View Article : Google Scholar
12	Perez-Ruiz E, Minute L, Otano I, Alvarez M, Ochoa MC, Belsue V, de Andrea C, Rodriguez-Ruiz ME, Perez-Gracia JL, Marquez-Rodas I, et al: Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy. Nature. 569:428–432. 2019.PubMed/NCBI View Article : Google Scholar
13	Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 363:711–723. 2010.PubMed/NCBI View Article : Google Scholar
14	Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grobb JJ, et al: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 364:2517–2526. 2011.PubMed/NCBI View Article : Google Scholar
15	Gupta A, De Felice KM, Loftus EV Jr and Khanna S: Systematic review: Colitis associated with anti-CTLA-4 therapy. Aliment Pharmacol Ther. 42:406–417. 2015.PubMed/NCBI View Article : Google Scholar
16	Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, Weber JS, Joshua AM, Hwu WJ, Gangadhar TC, et al: Anti-Programmed-Death-Receptor-1 treatment with pembrolizumab in Ipilimumab-refractory advanced melanoma: A randomised dose-comparison cohort of a phase 1 trial. Lancet. 384:1109–1117. 2014.PubMed/NCBI View Article : Google Scholar
17	Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, et al: Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 369:134–144. 2013.PubMed/NCBI View Article : Google Scholar
18	Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, et al: Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 16:375–384. 2015.PubMed/NCBI View Article : Google Scholar
19	Rizvi NA, Mazières J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, Horn L, Lena H, Minenza E, Mennecier B, et al: Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): A phase 2, single-arm trial. Lancet Oncol. 16:257–265. 2015.PubMed/NCBI View Article : Google Scholar
20	Berman D, Parker SM, Siegel J, Chasalow SD, Weber J, Galbraith S, Targan SR and Wang HL: Blockade of cytotoxic T-lymphocyte antigen-4 by ipilimumab results in dysregulation of gastrointestinal immunity in patients with advanced melanoma. Cancer Immun. 24:10–11. 2010.PubMed/NCBI
21	Liu J, Blake SJ, Harjunpää H, Fairfax KA, Yong MC, Allen S, Kohrt HE, Takeda K, Smyth MJ and Teng MW: Assessing immune-related adverse events of efficacious combination immunotherapies in preclinical models of cancer. Cancer Res. 76:5288–5301. 2016.PubMed/NCBI View Article : Google Scholar
22	Weber JS, Kähler KC and Hauschild A: Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 30:2691–2697. 2012.PubMed/NCBI View Article : Google Scholar
23	Franklin C, Rooms I, Fiedler M, Reis H, Milsch L, Herz S, Livingstone E, Zimmer L, Schmid KW, Dittmer U, et al: Cytomegalovirus reactivation in patients with refractory checkpoint inhibitor-induced colitis. Eur J Cancer. 86:248–256. 2017.PubMed/NCBI View Article : Google Scholar
24	Kuo JR, Davis AD, Rodriguez EA, Vela MF, Heigh RI, Salomao MA and Gurudu SR: Severe diarrhea in the setting of immune checkpoint inhibitors. Case Rep Gastroenterol. 12:704–708. 2018.PubMed/NCBI View Article : Google Scholar
25	Iyoda T, Kurita N, Takada A, Watanabe H and Ando M: Resolution of infliximab-refractory nivolumab-induced acute severe enterocolitis after cyclosporine treatment in a patient with non-small cell lung cancer. Am J Case Rep. 27:360–364. 2018.PubMed/NCBI View Article : Google Scholar
26	Bergqvist V, Hertervig E, Gedeon P, Kopljar M, Griph H, Kinhult S, Carneiro A and Marsal J: Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis. Cancer Immunol Immunother. 66:581–592. 2017.PubMed/NCBI View Article : Google Scholar
27	Postow MA, Sidlow R and Hellmann MD: Immune-Related adverse events associated with immune checkpoint blockade. N Engl J Med. 378:158–168. 2018.PubMed/NCBI View Article : Google Scholar