Nivolumab Induces Sustained Liver Injury in a Patient with Malignant Melanoma

Matsubara, Tokuhiro; Nishida, Tsutomu; Higaki, Yu; Tomita, Ryo; Shimakoshi, Hiromi; Shimoda, Akiyoshi; Osugi, Naoto; Sugimoto, Aya; Takahashi, Kei; Nakamatsu, Dai; Mukai, Kaori; Yamamoto, Masashi; Fukui, Koji; Adachi, Shiro; Inada, Masami

doi:10.2169/internalmedicine.9851-17

Cited by 29 publications

(13 citation statements)

References 18 publications

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“…Another patient taking nivolumab after carboplatin and gemcitabine suffered from fulminant hepatic failure [21]. In 2018, a patient with malignant melanoma underwent 17 cycles of nivolumab before developing grade 4 ALT elevation [22]. After steroids, his ALT did not recover to normal 3 Case Reports in Oncological Medicine range, even after 5 months.…”

Section: Discussionmentioning

confidence: 99%

Fulminant Hepatic Failure after Chemosaturation with Percutaneous Hepatic Perfusion and Nivolumab in a Patient with Metastatic Uveal Melanoma

Teal

Yorio

2021

Case Reports in Oncological Medicine

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Immune checkpoint inhibitors, such as nivolumab, a programmed death receptor-1 (PD-1) inhibitor, have dramatically improved the treatment of advanced melanomas. Chemosaturation with percutaneous hepatic perfusion (PHP) delivers chemotherapy in high doses directly to the liver and is a potentially effective treatment modality in metastatic uveal melanoma with liver metastases. Its safety and effectiveness have not been studied in patients also receiving immunotherapy. A 46-year-old male with a history of uveal melanoma of the right eye was found to have liver metastases. He was treated with PHP using high-dose melphalan for 6 months with a partial response followed by progression. Two months after his last PHP treatment, the patient was started on nivolumab. After two doses of nivolumab, the patient developed severe hepatitis that progressed to fulminant hepatic failure and death despite treatment with high-dose corticosteroids and mycophenolate mofetil. Nivolumab and other immune checkpoint inhibitors have been effective in treating advanced melanoma and extending life. However, there are serious immune adverse events that can occur. While hepatitis after taking nivolumab has been documented, fulminant hepatic failure is rare. We believe that prior PHP treatment contributed to the severity of the hepatitis and, ultimately, fulminant hepatic failure. To our knowledge, this is the only case of fulminant hepatic failure secondary to a checkpoint inhibitor with preceding PHP. Specific precautions should be made in patients who have been exposed to PHP in the past, and further studies should be done to assess the safety of using checkpoint inhibitors after PHP.

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Section: Discussionmentioning

confidence: 99%

Fulminant Hepatic Failure after Chemosaturation with Percutaneous Hepatic Perfusion and Nivolumab in a Patient with Metastatic Uveal Melanoma

Teal

Yorio

2021

Case Reports in Oncological Medicine

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“…Five patients treated with nivolumab, similar to ipilimumab, had immune‐mediated liver injury that, after further investigation, was considered to be distinct from AIH . A sustained liver injury marked by grade 4 ALT elevation has been reported to be refractory to steroid therapy, but the hepatocellular pattern of injury resolved about 5 months after discontinuation of nivolumab . Another patient with worsening liver enzymes after nivolumab treatment for metastatic melanoma had a liver biopsy showing focal ductopenia and periductal fibrosis consistent with a pattern of biliary injury, so treatment was stopped .…”

Section: Tumor Necrosis Factor Alpha Inhibitorsmentioning

confidence: 99%

Biologic and Checkpoint Inhibitor‐Induced Liver Injury: A Systematic Literature Review

2020

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Biologics are among the most commonly prescribed medications for several chronic inflammatory diseases. Tumor necrosis factor alpha inhibitors, more so than other agents, have been observed to cause drug-induced liver injury. Additionally, because the approval and popularity of checkpoint inhibitors have grown, similar patterns of liver injury have been documented, with a majority of cases describing immune-mediated hepatitis. Although the exact mechanism of injury is unknown, various host and medication characteristics play a role in the outcome of the molecular cascade invoked by biologics. Prognosis is usually favorable with cessation of the offending agent, but cases of acute liver failure requiring liver transplantation have also been observed. Therefore, algorithms have been created to assist clinicians in treating drug-induced autoimmune hepatitis, mostly with corticosteroids. Additionally, case reports have documented successfully rechallenging patients with a different biologic without recurrence of liver injury, but data are limited. Further investigation is warranted regarding the potential for cross-reactivity and mechanism of injury to develop guidelines to aid clinicians in further management of these patients. (Hepatology Communications 2020;4:172-184).

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“…51 In a theoretical context, acetylcysteine may have a role in the recovery of hepatic damage while ursodeoxycholic acid may have a role in immune-mediated cholestasis. 59 In order to sort the above-mentioned immunosuppressive options, a proposed therapeutic algorithm for severe (≥grade 3) ir-hepatitis, resistant to steroids, is presented in figure 2, including the differences among oncology experts' societies. Large immunotherapy trials are not designed to respond with details about how the ICPIsinduced toxicities are treated, keeping precise records of administered immunosuppressants (eg, dose, sequence, etc).…”

Section: Open Accessmentioning

confidence: 99%

“… 51 In a theoretical context, acetylcysteine may have a role in the recovery of hepatic damage while ursodeoxycholic acid may have a role in immune-mediated cholestasis. 59 …”

Section: Clinical Considerationsmentioning

confidence: 99%

When steroids are not enough in immune-related hepatitis: current clinical challenges discussed on the basis of a case report

Ziogas

Gkoufa

Diamantopoulos

et al. 2020

J Immunother Cancer

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Unleashing adaptive immunity via immune checkpoint inhibitors (ICPIs) in many cancer types led to durable antitumor responses and prolonged survivals and also added some new immune-related adverse events (irAEs) to the ‘old-fashioned’ safety profile of chemotherapy. Among bowel and endocrine irAEs, immune-mediated hepatotoxicity/hepatitis is a less common and far less well-studied toxicity, which, however, could develop into a serious complication, especially when it becomes persistent or refractory to steroids. Its incidence, onset and severity vary widely, depending on the type of underlying treated cancer, the class, the dosage and the duration of immunotherapy as well as the way of its administration (as a single agent or in combination with other ICPI or chemotherapy). In this study, we present a patient with metastatic melanoma who developed severe steroid-resistant ir-hepatitis after treatment with ipilimumab and required triple concurrent immunosuppression with prednisolone, mycofenolate mofetil and tacrolimus in order for his liver toxicity to be resolved. Intrigued by this case, we focused further on melanoma, as the disease-paradigm of immunotherapy in cancer, reviewed the reported incidence of hepatotoxicity among phase III ICPIs-containing trials on melanoma and discussed the main clinical considerations regarding the diagnosis and the management of persistent/steroid-refractory ir-hepatitis. As more clinical experience is gradually gained on this challenging topic, better answers are provided to questions about the appropriate diagnostic workup, the necessity of liver biopsy, the available immunosuppressive options beyond corticosteroids (their combinations and/or their sequence) as well as the correct decision on withdrawing or resuming immunotherapy. Nonetheless, a thorough multidisciplinary discussion is still required to individualize the overall approach in each case after failure of steroids.

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Nivolumab Induces Sustained Liver Injury in a Patient with Malignant Melanoma

Cited by 29 publications

References 18 publications

Fulminant Hepatic Failure after Chemosaturation with Percutaneous Hepatic Perfusion and Nivolumab in a Patient with Metastatic Uveal Melanoma

Fulminant Hepatic Failure after Chemosaturation with Percutaneous Hepatic Perfusion and Nivolumab in a Patient with Metastatic Uveal Melanoma

Biologic and Checkpoint Inhibitor‐Induced Liver Injury: A Systematic Literature Review

When steroids are not enough in immune-related hepatitis: current clinical challenges discussed on the basis of a case report

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