Hepatic sinusoidal obstruction syndrome associated with nivolumab: an uncommon adverse event related to immune checkpoint inhibitors

Riveiro‐Barciela, Mar; González-Sans, Didac; Marmolejo, David; Salcedo, Maite; Muñoz‐Couselo, Eva

doi:10.15403/jgld-3207

Cited by 13 publications

(9 citation statements)

References 3 publications

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“…Hepatic sinusoidal obstruction syndrome leading to PHT was already noticed after nivolumab treatment, as well as a rapid progression to liver fibrosis after atezolizumab. One can hypothesize that it was probably the case for our patient even if we did not perform liver biopsy to study the underlying liver parenchyma 19,20 . Moreover, the appreciation of the size of the EV is left to the appreciation of the operator and it can be difficult to accurately distinguish EV of grades 1 and 2.…”

Section: Discussionmentioning

confidence: 95%

A history of variceal bleeding is associated with further bleeding under atezolizumab–bevacizumab in patients with HCC

Larrey

Campion

Evain

et al. 2022

Liver International

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Background Atezolizumab–bevacizumab is the new standard for advanced hepatocellular carcinoma (HCC) but its impact on portal hypertension (PHT) is unknown. We aimed to identify predictive factors of acute variceal bleeding (AVB) and to monitor PHT parameters under treatment. Methods We conducted a prospective study including all cirrhotic patients treated with atezolizumab–bevacizumab since 2020. We performed monitoring of PHT using upper endoscopy at inclusion and at 6 months and hepatic venous pressure gradient (HVPG) at inclusion, 3 and 6 months after the beginning of treatment. We also included a retrospective series of patients treated with sorafenib. Time‐to‐events data were estimated by Kaplan–Meier with the log‐rank test, along with Cox models. Results Forty‐three patients treated with atezolizumab–bevacizumab were included (male 79.1%, Child‐Pugh A 86%). At baseline, 48.8% were treated with curative anticoagulation, 16.3% already experienced AVB and 25.6% had large oesophageal varices (EV). Sorafenib group characteristics were similar. Vascular invasion was present in 60.5% and median was HVPG 8.5 mm Hg. No significant modification in HVPG and EV size was observed at 6 months in the whole cohort but also when considering vascular invasion and radiological response. 14% presented AVB within a median time of occurrence of 3 months, without bleeding‐related death. In multivariate analysis, history of AVB (HR = 10.58, p = .03) was associated with AVB. AVB incidence was higher in atezolizumab–bevacizumab compared to sorafenib group (21% vs. 5% at 1 year, p = .02). Conclusions Atezolizumab–bevacizumab treatment was associated with a higher risk of AVB compared to sorafenib. A history of AVB was associated with AVB during follow‐up, which questions the use of bevacizumab in this setting.

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Section: Discussionmentioning

confidence: 95%

A history of variceal bleeding is associated with further bleeding under atezolizumab–bevacizumab in patients with HCC

Larrey

Campion

Evain

et al. 2022

Liver International

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“…The venoocclusive disease, in these cases, could be explained by the infiltration of T-cells in the hepatocytes, causing obstruction of the terminal hepatic venules and leading to symptoms of portal hypertension. Although it is a rare cause of ascites, in general, these cases highlight the need for a complete panel of investigations for patients undertaking ICI treatment [64,65].…”

Section: Discussionmentioning

confidence: 99%

“…A histopathological study on the liver of a pembrolizumab treated patient revealed liver injury with predominantly biliary damage [62], and another clinicopathological study showed patterns of granulomatous hepatitis, sclerosing cholangitis or lymphocytic duct injury, adding to the spectrum of ICI induced liver injury, besides hepatitis [63]. Additionally, other uncommon side effects emerged, with only two case reports published, of hepatic sinusoidal obstruction syndrome related to nivolumab treatment [64,65], and a case of vanishing bile duct syndrome potentially related to pembrolizumab [66].…”

Section: Liver Toxicitymentioning

confidence: 99%

Digestive Toxicities Secondary to Immune Checkpoint Inhibition Therapy – Reports of Rare Events. A Systematic Review

Radulescu

Crişan

Grapa

et al. 2021

JGLD

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Background and Aims: While immune checkpoint inhibitors therapy (ICI) is exceedingly effective, these drugs are associated with various immune-related adverse effects. As gastrointestinal, hepatic or pancreatic toxicity becomes more common, various reports of rare adverse effects have emerged, leading to a significant clinical and prognostic impact. We aimed to provide a systematic review of mainly case-reports on rare events, to help physicians to make an accurate and fast diagnosis. Methods: We performed a systematic review of the literature, using established MeSH terms: “immune checkpoint inhibitors”, “gastrointestinal tract”, “gastrointestinal diseases”, “liver”, “pancreas”, “nivolumab”, “ipilimumab”, the subheadings “adverse effects”, “toxicity” and the supplementary concepts “pembrolizumab”, “tremelimumab”, “atezolizumab”, “avelumab”, “durvalumab”, with defined inclusion criteria. Results: From 419 manuscripts initially selected, 74 reports of rare adverse events were included in our review. Special cases of neutrophilic gastritis, hemorrhagic gastritis, or even perforations were described at upper digestive tract. Different types of colitis were found secondary to ICI such as pseudomembranous, granulomatous, collagenous and microscopic colitis or even inflammatory bowel disease. In terms of liver toxicity, we found rare reports of cholangitis, granulomatous hepatitis, lipodystrophy and hepatic sinusoidal obstruction syndrome. Pancreas toxicity was rarely reported as severe pancreatitis, exocrine failure and diabetes mellitus. Conclusion: Although a complete check-up of every organ at every routine visit may not be practical, focus on symptoms, targeted laboratory and imaging testing may reveal rare organ damage. Raising awareness of the uncommon toxicities related to the immunotherapy is essential, as some rare events can lead to fatal outcomes.

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“…Thus, promoting inflammation in a setting of diseases where chronic inflammation plays a major role could be also detrimental. Last, but not least, hepatic sinusoidal obstruction syndrome leading to PHT was also noticed after nivolumab treatment, and one can hypothesize that this is also the case with other immunotherapies 91 . Hence, further studies are needed to evaluate the impact of the new combination Atezolizumab and Bevacizumab in real life, especially in patients with more severe PHT status.…”

Section: Portal Hypertension and The New Combination Bevacizumab And Atezolizumabmentioning

confidence: 95%

“…Last, but not least, hepatic sinusoidal obstruction syndrome leading to PHT was also noticed after nivolumab treatment, and one can hypothesize that this is also the case with other immunotherapies. 91 Hence, further studies are needed to evaluate the impact of the new combination Atezolizumab and Bevacizumab in real life, especially in patients with more severe PHT status. Until then, one can only recommend strict screening and monitoring of PHT, by regular endoscopies, and optimal prophylaxis of AVB.…”

Section: P Ortal Hyperten S I On and The Ne W Comb Inati On B E Vacizumab And Ate Zolizumabmentioning

confidence: 99%

Portal hypertension and hepatocellular carcinoma: Des liaisons dangereuses…

Allaire

Rudler

Thabut

2021

Liver International

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Background and Aims Portal hypertension (PHT) and hepatocellular carcinoma (HCC) are major complication of cirrhosis which significantly contribute to morbidity and mortality. In this review, we aim to describe the consequences of both angiogenesis and inflammation in the pathogenesis of PHT and HCC, but also the difficulty to propose adapted treatment when PHT and HCC coexist in the same patients. Methods Studies for review in this article were retrieved from the PubMed database using literature published in English until March 2021. Results Portal hypertension occurs secondary to an increase of intrahepatic vascular resistances, the opening of portosystemic collateral vessels and the formation of neovessels, related to vascular endothelial growth factor (VEGF). Recently, bacterial translocation‐mediated inflammation was also identified as a major contributor to PHT. Interestingly, VEGF and chronic inflammation also contribute to HCC occurrence. As PHT and HCC often coexist in the same patient, management of PHT and its related complications as well as HCC treatment appear more complex. Indeed, PHT‐related complications such as significant ascites may hamper the access to HCC treatment and the presence of HCC is also independently associated with poor prognosis in patients with acute variceal bleeding related to PHT. Due to their respective mechanism of action, the combination of Atezolizumab and Bevacizumab for advanced HCC may impact the level of PHT and its related complications and to date, no real‐life data are available. Conslusions Appropriate evaluation and treatment of PHT remains a major issue in order to improve the outcome of HCC patients.

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Hepatic sinusoidal obstruction syndrome associated with nivolumab: an uncommon adverse event related to immune checkpoint inhibitors

Cited by 13 publications

References 3 publications

A history of variceal bleeding is associated with further bleeding under atezolizumab–bevacizumab in patients with HCC

A history of variceal bleeding is associated with further bleeding under atezolizumab–bevacizumab in patients with HCC

Digestive Toxicities Secondary to Immune Checkpoint Inhibition Therapy – Reports of Rare Events. A Systematic Review

Portal hypertension and hepatocellular carcinoma: Des liaisons dangereuses…

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