Ipilimumab Induced Enterocolitis - A Novel Cause of Diarrhea

Abstract

Purpose: A 64 year-old man presented for evaluation of watery, non-bloody diarrhea. He was having up to ten bowel movements per day with multiple episodes of emesis. He was participating in a clinical trial comparing ipilimumab versus placebo for treatment of hormone refractory metastatic prostate cancer and had just completed his fourth infusion. On examination he was dehydrated, so he was admitted to the hospital for intravenous hydration. Enteric pathogen analysis including Clostridium difficile polymerase chain reaction was negative. The patient underwent a flexible sigmoidoscopy that demonstrated scattered focal erythema and erosions. Random colonic biopsies showed focal active colitis characterized by patchy infiltration of crypts by polymorphonuclear leukocytes. No increase in intraepithelial lymphocytes or granulomas was observed. Cytomegalovirus immunostaining was negative. His diarrhea improved with a five day course of methylprednisolone 125 mg daily and he was discharged home to complete a six week prednisone taper. Follow-up imaging one month later showed marked improvement in metastatic disease burden as well as prostate specific antigen levels. Ipilimumab is a cytotoxic T-lymphocyte-associated antigen 4 antibody that allows immune disinhibition of T cells leading to targeted tumor regression. It was recently approved for treatment of metastatic melanoma and is currently being evaluated for both prostate and lung cancer. Immune-mediated toxicities may represent a marker for treatment efficacy, as in the present case. Immune-mediated toxicity is most prevalent in the gastrointestinal tract with a reported incidence of enterocolitis in up to 21% of patients undergoing treatment. The cumulative dose administered does not appear to predict the risk for developing ipilimumab induced enterocolitis. The clinical hallmark of ipilimumab induced enterocolitis is profound watery diarrhea that may also present with abdominal pain, nausea, vomiting, and/or fever. Diagnosis is confirmed via endoscopic evaluation, which demonstrates colonic erythema, ulceration, and potentially gastritis and/or duodenitis. Histopathological findings include acute colonic neutrophilic and/or lymphocytic infiltrates. Oral corticosteroids can be used for treatment of mild cases (<6 bowel movements per day). Severe cases (>7 bowel movements per day) however, may require hospitalization with administration of high-dose intravenous steroids followed by an oral taper. Refractory cases have been successfully managed by administering one dose of infliximab (5 mg/kg). Timely diagnosis and treatment is critical to avoid unnecessary premature discontinuation of therapy or complications such as colonic perforation.