Medline ® Abstracts for References 38-40

Ipilimumab (anti-CTLA-4 antibody) is a new tool for the treatment of metastatic melanoma patients that has led to an improvement in survival rates worldwide. New types of toxicities have been described with ipilimumab called 'immune-related adverse events' or irAEs. Here, we report an acute and steroid resistant case of ipilimumab-induced colitis treated with infliximab in a melanoma stage IV AJCC patient. The patient presented with acute grade 3 diarrhea after the second perfusion of ipilimumab. After the administration of intravenous steroids, the patient continued to have grade 2 diarrhea with erythematous mucous with several ulceration sites on rectosigmoidoscopy. Infliximab perfusion (5 mg/kg) was performed and resulted in resolution of symptoms within 2 days with complete healing was observed by rectal sigmoidoscopy on day 7. After failure of two further lines of chemotherapy, the patient died 10 months after the diagnosis of stage IVM1C melanoma. Treatment algorithms exist for the management of these digestive adverse events; however, some points remain unclear. No predictive marker for the occurrence of this digestive toxicity has been validated to date. Modes of administration of steroids and dosage are not clearly defined, except in cases of acute abdomen; surgery is difficult to propose for patients with a poor prognosis. Infliximab is another option for the treatment of steroid-resistant ipilimumab-induced colitis but its use in metastatic melanoma raises questions of its possible impact on the evolution of cancer. We reviewed at least 19 cases published of infliximab administration for ipilimumab-mediated colitis. Unfortunately, tolerance and cancer evolution have scarcely been reported. Thus, because more patients are being treated with CTLA-4 blockade, management of ipilimumab-induced colitis requires further studies.

The anti-CTLA4 antibody, ipilimumab, has shown clinical activity against melanoma. Diarrhea due to immune-related colitis is the most frequent serious toxicity and, if untreated, may lead to intestinal perforation. Diarrhea treatment guidelines were developed based on clinical experience in over 2000 patients treated with ipilimumab, and these safety guidelines recommend systemic steroids as the first choice for the treatment of severe diarrhea. In this article, we present an alternative approach to the control of immune-related colitis by using the antitumor necrosis factor antibody, infliximab. Patients with metastatic melanoma received ipilimumab 10 mg/kg every 3 weeks for 4 doses, then every 3 months. Those who developed grade 2 diarrhea were treated with infliximab 5 mg/kg weeks 0 and 2 with mesalamine and loperamide. Steroids were given only for refractory cases requiring hospitalization. Of the first 3 cases of ipilimumab-induced diarrhea, 2 proved refractory and required hospitalization, but 1 recovered quickly without systemic steroids. We then added hydrocortisone enemas daily to the above regimen, and the next 3 patients recovered from grade 2 ipilimumab-induced colitis without difficulty. Treatment with infliximab, mesalamine, and hydrocortisone enemas may produce a rapid improvement in ipilimumab-induced colitis and avoid the administration of systemic steroids.

OBJECTIVE: To report a case of ipilimumab-associated life-threatening diarrhea responding quickly to a single dose of infliximab.

CASE SUMMARY: A 67-year-old man presented 3 weeks after his second dose of ipilimumab with severe diarrhea, acute kidney injury, and hypotension. After 2 days of high-dose corticosteroids and supportive care, he continued to have 2.8 L of stool output per day (grade 4 National Cancer Institute Common Terminology Criteria for Adverse Events). The patient was transferred to the medical intensive care unit requiring endotracheal intubation because of concerns of worsening mental status, metabolic acidosis, and increased work of breathing, with a serum bicarbonate concentration of<5 mmol/L. Despite aggressive fluid resuscitation and a sodium bicarbonate infusion, he remained hypotensive and hyponatremic with persistent premature ventricular contractions. On the evening of day 3, infliximab (5 mg/kg) was given, resulting in a rapid decrease in diarrhea. After 48 hours, the acidosis was corrected and electrolytes, renal function, and fluid status were improving. At discharge, diarrhea, acute kidney injury, and acidosis had resolved, and he was discharged on a slow steroid taper.

DISCUSSION: Autoimmune colitis is a described immune-related adverse event of ipilimumab. Prompt recognition, initiation of steroids, and supportive therapy are key to the management of diarrhea. Infliximab should be considered early in steroid-nonresponsive or life-threatening diarrhea.

CONCLUSION: Infliximab is a life-saving intervention in patients with ipilimumab-induced diarrhea.