Hepatic sinusoidal obstruction syndrome induced by nivolumab in advanced melanoma: a case report
Authors: E. Charvet, C. Lheure, C. Isnard, N. Franck, N. Kramkimel, A. Vallet-Pichard, A. Dohan, B. Terris, S. Aractingi, N. Dupin, S. Guégan
Journal: Annals of Oncology (2020)

Immune checkpoint inhibitors (ICIs) such as anti-programmed cell death protein 1 (PD-1) antibodies have significantly improved prognosis in advanced melanoma with a low rate of adverse events.1Larkin J. Chiarion-Sileni V. Gonzalez R. et al.Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.N Engl J Med. 2015; 373: 23-34Crossref PubMed Scopus (5110) Google Scholar Hepatic sinusoidal obstruction syndrome (SOS) is a rare disease characterized by small hepatic vessels damage leading to partial or complete occlusion of small hepatic veins.2DeLeve L.D. Shulman H.M. McDonald G.B. Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease).Semin Liver Dis. 2002; 22: 027-042Crossref PubMed Scopus (543) Google Scholar We here report the first case of hepatic SOS induced by an ICI. A 66-year-old woman was treated surgically for an ulcerated amelanotic vulvar melanoma of 3.5 mm Breslow thickness without any BRAF/NRAS/C-KIT mutations. Two years later, she presented with three pelvic lymph node and soft tissue metastases. Nivolumab was started, resulting in disease stability. Fourteen months after anti-PD-1 initiation, she presented with an 8% weight increase, diffuse edema of the face and lower limbs, and abdominal pain and swelling. Blood tests displayed a five-fold increase in alanine and aspartate aminotransferase levels, a two-fold increase in alkaline phosphatase and gamma-glutamyl transpeptidase levels, normal bilirubin, ferritin, prothrombin time, and platelet count. Laboratory values showed low albumin level (30 g/l), mild elevation of C-reactive protein (6.5 mg/l: normal <5). Serologic tests for human immunodeficiency virus, hepatitis B virus, and hepatitis C virus were negative with undetectable hepatitis B virus DNA and hepatitis C virus RNA levels. Both anti-hepatitis E virus and anti-hepatitis A virus immunoglobulin G were positive. Serologic tests for parasites, the QuantiFERON assay, and liver autoantibodies were negative. Abdominal paracentesis diagnosed sterile chylous ascites with a protein level of 16 g/l, a triglyceride rate of 11 mmol/l, and no melanoma tumor cells (Figure 1A). The computed tomography scan revealed ascites, moderate pleural effusions and hepatomegaly with a heterogeneous enhancement of the liver at portal phase (mosaic appearance), and patency of portal and hepatic veins without any focal nodular lesions suggestive of liver metastases (Figure 1B). Cavography and hepatic and cardiac Doppler ultrasounds were normal. The hepatic pressure gradient was increased to 14 mmHg suggesting mild portal hypertension. The liver biopsy showed non-fibrous portal areas but moderate sinusoidal dilatation with perisinusoidal fibrosis and centrilobular veins partially occluded by fibrous tissue (Figure 1C–E). Such lesions were consistent with SOS. Immunotherapy was discontinued because of its possible causation; repeated paracenteses and diuretics resulted in a favorable outcome. The patient died of melanoma progression 6 months after nivolumab discontinuation. Hepatic SOS, also known as veno-occlusive disease, is an obliterative venulitis of the terminal hepatic venules histologically characterized by sinusoidal dilatation, hepatocyte necrosis, and obliterated hepatic venules. It may occur in the context of allograft bone marrow transplantation3Shulman H.M. McDonald G.B. Matthews D. et al.An analysis of hepatic venocclusive disease and centrilobular hepatic degeneration following bone marrow transplantation.Gastroenterology. 1980; 79: 1178-1191Abstract Full Text PDF PubMed Scopus (254) Google Scholar or colorectal carcinoma with liver metastases following cytoreductive chemotherapy, or in patients taking pyrrolizidine alkaloid-containing herbal remedies. Cases of SOS induced by the immunotoxin gemtuzumab ozogamicin, an anti-CD33 monoclonal antibody coupled to an antibiotic inducing the release of free radicals, have also been reported in allografted hematological malignancies.4Rajvanshi P. Shulman H.M. Sievers E.L. McDonald G.B. Hepatic sinusoidal obstruction after gemtuzumab ozogamicin (Mylotarg) therapy.Blood. 2002; 99: 2310-2314Crossref PubMed Scopus (194) Google Scholar Our patient had no other known cause of hepatic SOS, no metastatic liver involvement, but had been treated with nivolumab for 14 months at the onset of SOS. The most frequent grade 3 and 4 adverse reactions reported with ICIs include rash, colitis, hepatitis, and endocrinopathy.5Weber J. Mandala M. Del Vecchio M. et al.Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma.N Engl J Med. 2017; 377: 1824-1835Crossref PubMed Scopus (1346) Google Scholar This is the first reported case of SOS induced by an ICI. None declared