Acta Scientific Gastrointestinal Disorders Volume 2 Issue 1 March 2019

Case Report

Margaux Geier1*, Sylvie GouvaEnterocolitis1 and Bertrand Due Geier to Nivolumab2 Treated by Infliximab 1Oncology Department, University Hospital of Brest, France 2Gastroenterology Department, University Hospital of Brest, France *Corresponding Author:

Received: MargauxPublished: Geier, Oncology Department, University Hospital of Brest, France.

February 19, 2019; February 28, 2019

Abstract

Immune checkpoint inhibitors are monoclonal antibodies that target CTLA-4 and PD-1. They have proven efficient, either as monotherapy or in combination in several cancer types, resulting in an increase in the incidence of relates side effects. In this report, we describe a case of a patient with lung cancer treated with nivolumab presenting diarrhea and abdominal pain. Colonoscopy was performed revealing pancolitis mimicking ulcerative colitis [UC]. Treatment was in accordance with UC therapy which resulted in beneficial outcomes. Severe acute colitis is among the commonest form of gastrointestinal immune-related adverse events due to immune check point Keywordsinhibitors. :Gastroenterologists will be increasingly faced with these patients.

Immune-Checkpoint Inhibitors; Colitis; Nivolumab

Introduction pattern, erosions type Mayo 2 inflammatory index throughout the

Immune checkpoint inhibitors [ICPI], such as ipilimumab entire colorectum, the ileum appearing healthy. Histopathologic [anti-cytotoxic T-lymphocyte antigen-4 [CTLA-4] antibody] and examination of biopsy specimen showed active colitis involving nivolumab or pembrolizumab [anti-programmed cell death infiltration of neutrophils, eosinophils, plasma cells with crypt protein-1 [PD-1] antibodies], improve survival in several cancer abscesses. types. Since inhibition of CTLA-4 or PD-1 leads to non-selective Base on these findings, we diagnosed the patient as having activation of the immune system, immuno-related adverse nivolumab-induced colitis. The patient was initially treated with event [irAE] may affect the skin [rash, vitiligo, exacerbation of corticosteroids in accordance with international recommendations psoriasis], glands endocrine [pituitary insufficiency, thyroidis], for treatment of IPCI-induced enterocolitis [4,5], including kidney, joints, liver [immune-hepatitis] and intestine [1]. Support intravenous administration of methylprednisolone 1000mg/d undesirable effects of cancer immunotherapy is the subject of for 3 days, followed by oral prednisolone (60mg/d) for 2 weeks. ESMO recommandations [2]. Observation However, the steroid therapy was ineffective. We therefore started intravenous administration of infliximab (5mg/kg), with resulted in resolution of symptoms after the third perfusion and continuation A 53-year old woman with non-small cell lung cancer stage IV of prednisolone (10mg/d). was treated with nivolumab with twice a month infusion 3mg/kg. After the eigth infusion of nivolumab, she manifested abdominal After one year the cancer was in remission, but the patient had Clostridium difficile cramps and bloody diarrhea. Bacterial cause for diarrhea was sometimes bloody diarrhea [grade1] and the recto sigmoidoscopy ruled out by means of stool cultures and toxin showed net improvement with reddish and edematous mucosa tests. Nivolumab was discontinued after onset of grade 3 diarrhea [Mayo 1 index]. The patient was treated symptomatically with [3]. The laboratory test results were as follows: white blood cell mesalazine orally (4g/d) in the long term. She needed also L count 11370/μL, hemoglobin level 9,1 g/dL, albumin level 3,9g/ thyroxin, hydrocortisone and mineralocorticoids for thyroidis and dL and C-reactive protein level 63mg/L. Colonoscopy showed hypohysitis. reddish, edematous mucosa, exsudate, sequential loss of vascular

Citation: ., et al. “ Acta Scientific Gastrointestinal Disorders

Margaux Geier Enterocolitis Due to Nivolumab Treated by Infliximab". 2.1 (2019): 14-16. Enterocolitis Due to Nivolumab Treated by Infliximab

Discussion 15

0,8 to 2mg/kg and 24 hours medicosurgical monitoring. We make Diarrhea and colitis have been previously documented as the point between d3 and d7. The answerers corticosteroids gastrointestinal tract-related side effects of ICPI. Although PD-1/ intravenous go to oral corticosteroids, with a gradual decrease over PD-L1 inhibitors produce fewer side effects than CTLA-4 inhibitors 8 to 12 weeks. One-third to two-thirds of patients do not respond and gastrointestinal toxicity anti-PD-1 is less known [6,7]. A recent to corticosteroids intravenous or relapse during dose reduction of series shows that it is much rarer than the observed toxicity corticoids per os. They come under treatment by infliximab 5mg/ with anti-CTLA-4 [8]: it is estimated that 1,5% of patients have kg indeed 10m/kg. A few patients may require a second injection, enterocolitis induced by anti-PD-1. One half of the patients who one to two weeks after the first [4]. this disease were suspects to have gastrointestinal toxicity to anti-PD-1 had In a recent study on 254 melanoma patients with irAE, 29 [11,4%] [8]. patients received infliximab therapy and high-dose corticosteroids The main differential diagnosis is tumor-related digestive [17]. Among these 29 patients, 21 patients responsed to infliximab tract: peritoneal carcinomatosis, metastase of lung cancer. but 8 [27,6%] did not respond and received prolonged courses of Gastrointestinal toxicity anti-PD-1 can make different clinical corticosteroids. arrays: acute colitis similar to those observed with anti-CTLA-4, There is very little data available on the effects and safety of microscopic colitis [lymphocytic or collagenous], inflammation of infliximab treatment in this context and on the potential effects of the upper digestive tract, pseudo obstruction [9]. corticosteroids in combination with infliximab on the anti-tumor Three out of four patients respond to corticosteroids [10]. efficay of ICPI therapy [18]. In a retrospective study on ipilimumab- However, the moderate duration of symptoms is 90 days, relapses treated melanoma patients who had developed diarrhea, there was to arrest and/or decrease doses of corticoids are common [9]. no significant difference in the median overall survival time between Mesalazine could represent first -line treatment intention in mild those treated with infliximab or not [10]. There is an ongoing proctitis [11]. Corticoids enable a sustainable remission in a two debate whether irAE and/or the severity of irAE is associated out of three patients [12,13]. Second treatment intention, after with better cancer-specific outcomes, and whether treatment with primary failure or loss of response to corticoids, like our patient, immunosuppressive agents potentially counteracts the anti-tumor obtain the remission is the infliximab. One or two injections are enough generally to effect of ICPI therapy. There are several studies supporting these the cancer [14]. Infliximab does not seem to aggravate concepts [10,19] but also those refuing them [5,17]. [10]. Some patients have to be operated on a colectomy It is not surprising that anti-CTLA-4 are the cause of enterocolitis. because of complications [abscesses, toxic maceration, perforation]. In fact, the germinal mutations of the CTLA-4 are at the origin of A recent serie shows that partial colectomies are associated with et al. inflammatory diseases which can reach the lung, the brain, but also inflammation of the colon, causing postoperative complications the intestine, in the majority of the cases [20,21]. Regulatory T cells [13]. Berggvist., report on seven patients with ICPI-induced FOXP3+ of the intestine are generated locally from precursors that enterocolitis, which were either corticosteroid-dependant and/ animal and human studies have demonstrated a express receptors specific to microbota antigens [22]. Several recent or partially refractory, managed successfully with vedolizumab [23,24] [25,26] infusions [15]. They consider suitable for vedolizumab treatment link between ICPI therapy response, gut microbiota composition patient with steroid dependant and/or partially refractory mild to and intestinal inflammation. moderate enterocolitis and without irAE. In contrast, patient with Conclusion severe gut inflammation that demands urgent measures should be considered for other therapies such as infliximab, mycophenate mofetil [16] or, as last resort, colectomy. There are several new ICPI agents being subjected to clinical evaluation in numerous types of malignancies resulting in an The duration of intestinal inflammation is not known precisely. increase in the incidence of related side effects, and subsequently Several patients had a colonoscopy of control several months after the prevalence of ICPI induced-enterocolitis may be expected to the first symptoms [13]. Endoscopic and/or histological lesions increase. were observed in about one in two patients. It is important to develop evidence-based optimized immune We schematize the behavior to hold in the presence of nivolumab- mediated-adverse effects management algorithms, taking the induced colitis as follows: stop of anti-PD-1, methylprenisolone long term cancer-treatment strategy and the overall survival into account.

Citation: ., et al. “ Acta Scientific Gastrointestinal Disorders

Margaux Geier Enterocolitis Due to Nivolumab Treated by Infliximab". 2.1 (2019): 14-16. Enterocolitis Due to Nivolumab Treated by Infliximab

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MartheyJournal L., of Crohn’s. “Cancer and immunotherapy Colitis with anti-CTLA-4 monoclonal antibodies induces an inflammatory bowel dis- Volume 2 Issue 1 March 2019 14. ease”. et al 10 (2016): 395-401. © All rights arereserved by Margaux Geier., et al. Clinical Gastroenterology and Hepatology Yanai S., . “Nivolumab-induced colitis treated by Inflix- imab”. 15 (2017): e80-e81.

Citation: ., et al. “ Acta Scientific Gastrointestinal Disorders

Margaux Geier Enterocolitis Due to Nivolumab Treated by Infliximab". 2.1 (2019): 14-16.