Ipilimumab and immune-mediated adverse events: a case report of anti-CTLA4 induced ileitis

A 54 years old woman with previous history of malignant cutaneus melanoma came to our attention in April 2013. In 2009 she had undergone surgery after the detection of a nodular mass located in the right iliac fossa. Pathology specimens were consistent with pigmented nodular melanoma, with vertical growth, Clark level III, Breslow tickeness of 9 mm. The excision margins were negative. Right inguinal sentinel lymph node was positive but a subsequent dissection excluded further lymphnodal involvement (stage IIIB: pT4a, pN1a, pMx). A staging Fluorodeoxyglucose-PET (FDG-PET) showed no local or distant disease. Then patient started a follow up program until January 2012, when a CT scan showed multiple bilateral lung metastases and a FDG-PET scan revealed pathological uptake in the right iliac fossa and lumbar vertebra L3. Mutational analysis of BRAF V600E was carried out with the detection of exon 15 mutation. The patient started a first line treatment with Dabrafenib (150 mg orally twice daily) from May 2012 to February 2013. The FDG-PET scan performed in October 2012 proved a complete metabolic response in right iliac fossa and a partial response at L3 level; moreover, the CT scan demonstrated a reduction in number and size of lung metastases. In January 2013 a new FDG-PET scan showed progressive disease in lung and bones (D11, L3, 4th right rib and pelvis) and appearance of liver metastases. Subsequently patient started a second line treatment with Ipilimumab (3 mg/kg every 3 weeks planned for a total of 4 doses). On June 2013 two days after the third cycle of Ipilimumab she was admitted to our oncology unit reporting fever (body temperature >38.5°C) without shiver, Grade 2 asthenia and nausea and Grade 1 diarrhea. The blood cultures performed were negative for bacterial growth. Administration of intravenous Metilprednisolone 2 mg/Kg die was started with clinical benefit but without a complete resolution of fever. Considering the significant clinical benefit obtained, patient was dismissed with prescription of oral prednisone 1 mg/kg daily. Given previous toxicity and according to the drug schedule, the 4th dose of ipilimumab was delayed until the toxicities returned to Grade 0 or 1. After two weeks, in July 2013 the patient was admitted again to our oncology unit for persisting and deteriorating Grade 3 asthenia, Grade 2 nausea and vomiting, Grade 3 diarrhea and dehydratation, despite of oral corticosteroid treatment.

Physical examination proved a poor hydration of skin and mucosal membranes, a diffuse abdominal pain, in particular in the right iliac fossa; blood examination revealed anemia (Hemoglobin- Hgb- 9.60 g/dL) and hypoalbuminemia (1.74 g/dL). During the hospital stay fluids, corticosteroids (metilprednisolone 2 mg/Kg die) and albumin were administered with partial resolution of symptoms. Few days later, clinical conditions worsened, because of the development of gastrointestinal (GI) hemorrhage, severe anemia (Hgb 5.20 g/dL), thrombocytopenia (platelets 52.00 ×10^3/uL) and coagulation impairment (INR 1.58). Red blood cells, platelet and plasma were transfused with poor benefit. A CT scan of the abdomen was performed in order to exclude an immune-mediated colitis (described in literature as a possible side effect occurring during ipilimumab treatment [1,2]) since no comorbidities such as intestinal bowel disease or hematological disorder were referred at the moment of hospital admission. Radiological imaging showed colic mucosal hyperemia and submucosal edema (Figure 1).

In consideration of CT findings, a total colonscopy was performed detecting red blood in rectal ampulla and sigmoid colon, without mucosal alterations and a hyperemic and edematous colic mucosa with extensive loss of substance. Terminal ileum biopsies confirmed the presence of superficial loss of substance, and an intense inflammatory infiltrate rich of lymphocytes and granulocytes with sporadic cryptic abscesses extending up to the muscolaris mucosae tonaca. Since gastrointestinal (GI) bleeding did not stop with medical therapy, the patient underwent surgery. A subtotal colectomy with resection of the last tract of terminal ileum was performed, with the small bowel appearing necrotic and perforated in several points for at least 40 cm of length (Figure 2). Pathology report showed extensive superficial ulceration and full-thickness inflammatory infiltrate rich of lymphocytes, granulocytes and eosinophils, associated with acute sierosytis and vessels rupture (Figure 3). None of these findings were observed in the colic tract, where it has been found normal colic mucosa and glands without inflammatory infiltrate or ulceration (Figure 4). The patient continued steroid therapy with metilprednisolone 2 mg/Kg iv die, and no further episodes of diarrhea or GI bleeding were reporter after surgery. A post-operative CT scan showed disease progression in all sites previously detected and appearance of diffuse peritoneal carcinomatosis. In consideration of these findings, the patients was addressed to a palliative care program.

Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.