MOLECULAR AND CLINICAL ONCOLOGY 14: 65, 2021 Efficacy and safety of Infliximab for steroid‑resistant immune‑related adverse events: A retrospective study YUKIO KADOKAWA1, MARI TAKAGI1, TOMOE YOSHIDA1, AKITOSHI TATSUMI2, KEIKO FUJITA1, TAKAKO INOUE3, SHUICHI OHE4, YASUTOMO NAKAI5, SACHIKO YAMAMOTO6, TOMOYUKI OTSUKA7, RYU ISHIHARA6, TAIKI ISEI4, TORU KUMAGAI3, KAZUO NISHIMURA5 and FUMIO IMAMURA7 1Department of Pharmacy, Osaka International Cancer Institute, Osaka Prefectural Hospital Organization, Osaka 541‑8567; 2Education and Research Center for Clinical Pharmacy, Kobe Pharmaceutical University, Kobe, Hyogo 658‑8558; Departments of 3Respiratory Medicine, 4Dermatologic Oncology, 5Urology, 6Gastroenterology and 7Medical Oncology, Osaka International Cancer Institute, Osaka Prefectural Hospital Organization, Osaka 541‑8567, Japan Received April 6, 2020; Accepted January 12, 2021 DOI: 10.3892/mco.2021.2227 Abstract. The present study investigated outcomes of grade 0 after a median of 18 (range, 9‑32) days. No AEs were infliximab (IFX) treatment among 8 Japanese patients with attributable to IFX. Additionally, anti‑cytomegalovirus (CMV) various types of cancer (4 with malignant melanoma, 3 with and antibacterial agents were administered in parallel given lung cancer and 1 with renal cancer) who developed severe the presence of CMV and Clostridium difficile (CD) infections steroid‑resistant immune‑related adverse events (irAEs) in in all patients, except in 1 exhibiting a marked IFX response association with immune checkpoint inhibitors (ICIs) to after one dose. The combination of highly immunosuppressive determine its efficacy and safety. Information, including IFX and high‑dose systemic steroid administration over a long patient background, treatment progress, examination data and period presumably predisposed the patients to opportunistic imaging data, was collected retrospectively from electronic enteric infections. Accordingly, early initiation of IFX medical records. Adverse reactions were evaluated using treatment in conjunction with systemic steroid therapy should the Common Terminology Criteria for Adverse Events be considered for severe diarrhea/colitis and other irAEs. version 4.0. Specific ICIs used were anti‑PD‑1, anti‑PD‑L1 However, the possibility for CMV and CD infections should and anti‑CTLA‑4 antibody preparations in 7, 2 and 5 patients, be recognized, and for these the treatment strategy may need respectively. Specific irAEs included grade 3 diarrhea/colitis to be modified at an early stage. in 7 patients and disseminated intravascular coagulation and myocarditis attributed to autoimmune activation in 1 patient. Introduction The median duration between systemic steroid and IFX treatments was 9 (range, 2‑39) days. A total of 3 patients Immune checkpoint inhibitors (ICIs) are promising drugs responded to IFX, 1 of whom responded after one dose and that can potentiate the immune system of cancer patients for 2 responded after two doses. Respective diseases improved to disease treatment. ICIs block endogenous factors, such as cytotoxic T‑lymphocyte antigen‑4 (CTLA‑4) and programmed cell death‑1 (PD‑1), thereby enhancing the antitumor effect. ICIs, such as nivolumab (Nivo), have reportedly extended the Correspondence to: Mr. Yukio Kadokawa, Department of patient overall survival in cases of different types of cancer Pharmacy, Osaka International Cancer Institute, Osaka Prefectural and have been approved in several countries. Meanwhile, Hospital Organization, 3‑1‑69 Otemae, Chuo‑ku, Osaka 541‑8567, Immune‑related adverse events (irAEs), which often occur Japan in association with immune checkpoint inhibitor (ICI) treat‑ E‑mail: [email protected] ment, require early detection and appropriate management considering their potentially fatal outcomes. Among irAEs, Abbreviations: CD, Clostridium difficile; ICI, immune checkpoint diarrhea/colitis occurs particularly frequently, and serious inhibitor; IFX, infliximab; irAEs, immune‑related adverse events; CMV, cytomegalovirus; CTLA‑4, T‑lymphocyte antigen‑4; PD‑1, complications, such as intestinal perforation, may follow programmed cell death‑1; PD‑L1, programmed cell death‑ligand 1; unless timely and appropriate treatment is provided (1). The PSL, prednisolone; IPI, ipilimumab; Nivo, nivolumab; CRT, American Society of Clinical Oncology guideline includes chemoradiation therapy; TNF‑α, tumor necrosis factor‑α; CyA, an organ system‑based management algorithm showing cyclosporine recommended management procedures for various irAEs according to grade (2). In line with this, steroid therapy with Key words: infliximab, immune‑related adverse event, immune approximately 1 mg/kg/day prednisolone (PSL) equivalent is checkpoint inhibitor, diarrhea/colitis, steroid resistance immediately initiated for grade 3 diarrhea/colitis. However, when symptoms do not improve, infliximab (IFX) treat‑ ment, generally at a dose of 5 mg/kg/day according to the 2 KADOKAWA et al: IFX FOR STEROID‑RESISTANT irAEs administration for ulcerative colitis (3‑11), has been recom‑ Results mended. Single‑dose IFX administration has often been selected as an irAE treatment, with additional doses admin‑ Background and irAE treatment details. Patient background istered only when no improvements occur after the first dose. and irAE treatment details are summarized in Table I. Six male Perez‑Ruiz et al (12) have demonstrated that the inhibition of and two female patients, with a median (range) age and body tumor necrosis factor‑α (TNF‑α) after ICI administration may weight of 66 (58‑74) years and 60.0 (38.0‑85.1) kg, respec‑ prevent the occurrence of severe colitis. IFX, approved in 1999 tively, were included in this study. Four patients presented in the United States and in 2003 in Japan, is an anti‑TNF‑α with malignant melanoma, three with lung cancer, and one antibody drug that binds to and neutralizes the action of with kidney cancer. Specific ICIs used included anti‑PD‑1, TNF‑α, which plays a key role in the development and exac‑ anti‑PD‑L1, and anti‑CTLA‑4 antibody preparations in seven, erbation of rheumatoid arthritis. While transient headache and two, and five patients, respectively. nausea can occur as short‑term adverse reactions to IFX, these irAE treatment was switched from steroids to IFX since symptoms are mild. However, it is imperative to pre‑emptively systemic steroid treatment was ineffective for grade ≥3 diar‑ identify symptoms of medium‑ and long‑term adverse reac‑ rhea/colitis (case nos. 1‑7) or for disseminated intravascular tions such as infectious diseases, demyelinating diseases, coagulation and myocarditis resulting from activated autoim‑ aplastic anemia, malignant tumors, autoimmune diseases, and munity (case no. 8). Grade 3 diarrhea/colitis occurred at a heart failure, among which infectious diseases are of partic‑ median (range) of 119 (5‑1,011) days after the first ICI dose or ular concern. Several case reports have described successful at a median (range) of 15.5 (5‑75) days after the last ICI dose. treatment of steroid‑resistant ICI‑induced diarrhea/colitis with Grade 3 hepatitis preceded diarrhea/colitis in one case IFX in patients receiving ipilimumab (IPI), an anti‑cytotoxic (case no. 4). T‑lymphocyte antigen‑4 (CTLA‑4) antibody preparation (3‑6), Three patients who responded to IFX satisfied the defined as well as anti‑programmed cell death‑1 (PD‑1) antibody or resolution (case nos. 1, 5 and 8). Accordingly, responses to anti‑programmed cell death‑ligand 1 (PD‑L1) antibody prepa‑ IFX occurred after one dose in case no. 1 and after two doses rations (7‑11). However, we were unable to identify any report in case nos. 5 and 8 (in case no. 5, an accessory third dose systematically dealing with the required number of IFX doses was administered, but the defined resolution was satisfied or the time to switch to after treatment. after two IFX doses). Although the treatment was transiently Therefore, this study investigated the outcomes of IFX effective in one case (case no. 2), irAEs relapsed. Two patients treatment among Japanese cancer patients who developed did not respond to IFX (case nos. 3 and 4), while two patients severe steroid‑resistant irAEs induced by various ICIs and (case nos. 6 and 7) underwent rapid deterioration of their examined its efficacy and safety for severe steroid‑resistant general condition after IFX treatment initiation and died irAEs. before the IFX effect was noted. The cause of death was irAE diarrhea and multi‑organ failure in case no. 6 and respiratory Materials and methods failure due to multiple lung metastases and pulmonary conges‑ tion in case no. 7. No causal relationships were observed Patients. Among nine Japanese patients with cancer who between IFX treatment and deaths. The median (range) underwent IFX treatment for ICI‑induced steroid‑resistant number of days between systemic steroid treatment and IFX irAEs at the Osaka International Cancer Institute (hereinafter initiation was 9 (2‑39) days. In three IFX responders, resolu‑ referred to as the ‘Institution’) between January 2018 and tion to grade 0 required a median (range) of 18 (9‑32) days June 2019, eight whose electronic medical records contained after IFX treatment initiation. No AEs were attributable the necessary treatment information were included; one patient to IFX. No patients developed cytomegalovirus (CMV) or who participated in a clinical trial was excluded. Clostridium difficile (CD) infection when grade 3 irAEs We obtained ‘consent to the publication of a paper related