Concurrent ipilimumab and CMV colitis refractory to oral steroids

Immune checkpoint inhibitors, including anti-cytotoxic T-lymphocyte antigen 4 (antiCTLA4) and anti-programmed cell death protein-1 (anti-PD-1) antibodies, have demonstrated clinical and survival bene­ts in a variety of malignancies, which has led to an expansion in their role in oncology. In melanoma, the anti-CTLA-4 antibody, ipilimumab, has demonstrated a survival bene­t in patients with advanced metastatic melanoma and in patients with resectable disease with lymph node involvement.1,2 Ipilimumab exerts its e„ect by binding CTLA-4 on conventional and regulatory T cells, thus blocking inhibitory signals on T cells, which leads to an antitumor response.3 †e increased immune response counteracts the immune-evading mechanisms of the tumor. With increased use of these agents, immune-related adverse events (irAEs) have become more prevalent. †e most common irAEs secondary to ipilimumab are skin rash, colitis/diarrhea, hepatitis, pneumonitis, and various endocrinopathies.4 In a phase 3 trial of adjuvant ipilimumab in patients with resected stage III melanoma, grade 3 or 4 adverse events occurred in 54.1% of participants in the ipilimumab arm, the most common being diarrhea and colitis (9.8% and 6.8%, respectively).2 Recognition and management of irAEs has led to the implementation of treatment guidelines.4,5 Management of irAEs includes checkpoint inhibitor discontinuation and reversal of the immune response by institution of immunosuppression with corticosteroids. Here we present the case of a patient with stage IIIB, BRAF V600E-positive melanoma, who developed colitis refractory to standard therapy after treatment with ipilimumab and whose clinical course was complicated by cytomegalovirus (CMV) reactivation and bowel perforation. Case presentation and summary A 40-year-old white woman with stage IIIB BRAF V600E-positive melanoma presented with diarrhea refractory to high-dose prednisone (1 mg/kg BID). She had recently undergone wide local excision and sentinel node biopsy and received her inaugural dose of ipilimumab (10 mg/kg). †e patient ­rst presented with loose, watery stools that had begun 8 days after she had received her ­rst dose of adjuvant ipilimumab. She was admitted to the hospital, and intravenous methylprednisolone was initiated along with empiric cipro™oxacin (400 mg, IVPB Q12h) and metronidazole (500 mg, IVPB Q8h) as infectious causes were concurrently ruled out. During this initial admission, the patient’s stool was negative for Clostridium di cile toxin, ova, and parasites, as well as enteric pathogens by culture. After infectious causes were excluded, she was diagnosed with ipilimumab-induced colitis. Antibiotics were discontinued, and the patient ultimately noted improvement in her symptoms. On hospital day 7, she was experiencing only 2 bowel movements a day and was discharged on 80 mg of prednisone twice daily. After discharge the patient noted persistence of her symptoms. At her follow-up, 9 days after discharge, the patient noted continued symptoms of low-grade diarrhea. She failed a trial of steroid tapering due to exacerbation of her abdominal pain and frequency of diarrhea. Further investigation was negative for C. di toxin and a computed-tomography scan was consistent with continuing colitis. †e patient’s symptoms continued to worsen, with recurrence of grade 3 diarrhea, and she was ultimately readmitted 17 days after her earlier discharge (36 days after her ­rst ipilimumab dosing). On re-admission, the patient was again given intravenous methylprednisolone and experienced