Ipilimumab Enterocolitis: An Unusual Case of Colonic Perforation and Death

Abstract

Ipilimumab, a humanized monoclonal antibody to anti-cytotoxic T-lymphocyte associated antigen 4 (CTLA-4), is approved for treatment of melanoma and undergoing clinical trials for other malignancies. Immunological adverse effects due to T cell activation and proliferation have been described. Gastrointestinal side effects include abdominal pain, rectal bleeding, and diarrhea. While there have been reports of enterocolitis, we report an unusual case of multiple colonic perforations occurring three weeks after ipilimumab administration. A 63-year-old male with hormone-refractory metastatic prostate cancer received ipilimumab in a phase II clinical trial. Three weeks following ipilimumab administration, he developed fever, abdominal pain and bloody bowel movements. Stool studies were negative. Abdominal CT revealed pancolitis. Sigmoidoscopy showed mucosal friability with biopsies demonstrating focal active colitis without chronicity, ischemic injury or viral infection. Steroids and mesalamine were administered for suspected ipilimumab enterocolitis. Bowel movements improved and he was discharged on prednisone. One week later, he was re-admitted with abdominal pain and persistent diarrhea. Labs were notable for a leukocytosis and negative stool studies. He received intravenous steroids with improvement. Following a sigmoidoscopy to assess his status prior to discharge, he developed worsening abdominal pain. Abdominal CT revealed free intra-peritoneal air. He underwent a subtotal colectomy with end ileostomy and debridement. The surgical specimen was notable for ischemia, necrosis with multiple perforations proximal to the sigmoid colon. His post-operative course was complicated by venous thrombosis, aspiration pneumonia, retroperitoneal hematoma and persistent peritonitis. He was transitioned to home hospice. While gastrointestinal side effects of ipilimumab has been reported in 28-30% of patients, severe enterocolitis rarely occurs. We report an unusual case of a fatality resulting from progressive enterocolitis complicated by colonic perforations occurring after a single dose of ipilimumab. The suggested mechanism for colitis is immune cell infiltration, autoreactive antibodies and inflammatory cytokines. Resolution of enterocolitis typically occurs after steroid administration. However, physicians must be aware of the potential progression of ipilimumab-induced enterocolitis, steroids masking symptoms and the possibility of colonic perforation and death.Figure 1Figure 2Figure 3