Skip to main content
Erschienen in:

Open Access 09.09.2021 | case report

Immune-related hepatitis in a patient with hepatocellular carcinoma treated with nivolumab

verfasst von: Bernhard Scheiner, MD, Matthias Pinter, MD PhD

Erschienen in: memo - Magazine of European Medical Oncology | Ausgabe 1/2022

download
DOWNLOAD
print
DRUCKEN
insite
SUCHEN

Summary

We present a case of a male patient with advanced hepatocellular carcinoma who developed hepatic and dermatological immune-related adverse events during treatment with the immune checkpoint inhibitor nivolumab. We discuss relevant aspects regarding the management of immune-related hepatic adverse events, including the incidence and onset of the event, the requirement for immune-modulating medication, resuming of immunotherapy, and the association between the occurrence of immune-related adverse events and the outcome.
Hinweise

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Case presentation

A 61-year-old male patient with alcoholic liver cirrhosis and a history of transjugular intrahepatic portosystemic shunt (TIPS) placement for refractory ascites underwent surveillance for hepatocellular carcinoma (HCC) with ultrasound at 6‑month intervals at our institution. When ultrasound showed a new onset of portal vein thrombosis, the patient was referred for a computed tomography (CT) scan. The CT scan revealed a 6-cm tumor with portal vein invasion, several smaller hypodense liver lesions, and no clear evidence of extrahepatic metastases. Biopsy finally confirmed the diagnosis of moderately differentiated HCC. The tumor marker alpha-fetoprotein was within the normal range at this time. Based on a well-preserved liver function (Child–Pugh class A), a performance status of 0 (asymptomatic), and vascular tumor invasion, the patients was classified as having advanced-stage HCC (Barcelona Clinic Liver Cancer [BCLC] stage C).
After multidisciplinary team discussion, systemic treatment was recommended and the immune checkpoint inhibitor (ICI) nivolumab at a dose of 240 mg every 2 weeks was initiated. After the second cycle, a grade 3 increase in transaminases was noted (Fig. 1). The patient was asymptomatic and had no signs of liver decompensation. Given the rapid increase, immune-related hepatitis (irHepatitis) was suspected. Nivolumab was paused and prednisolone was initiated with an intravenous bolus of 0.75 mg/kg followed by a maintenance dose of 50 mg daily. After 1 week, the transaminase levels decreased significantly and prednisolone was tapered over a 4-week course. However, after discontinuation of prednisolone, an increase in transaminases was noted again and prednisolone was reinitiated at a dose of 50 mg daily for 2 weeks and then tapered over a course of 3 weeks. The transaminase levels eventually returned to normal values and nivolumab treatment was finally resumed around 3 months after initiation of steroids. Despite the 3‑month interruption of nivolumab treatment, the patients achieved stable disease on follow-up imaging and remained stable for 2.5 years. He never developed an episode of irHepatitis again during this period.
However, approximately 1 year after the start of nivolumab treatment, the patient developed scaly, psoriasiform skin lesions on the upper and lower extremities (Fig. 2). After histological evaluation, the diagnosis of an immune-mediated verrucous lichen ruber was made. Given that the lichen was complicated by recurrent skin infections, the patient repeatedly received antibiotic treatment and nivolumab treatment was interrupted several times. The skin lesions were treated with topical steroids and photochemotherapy (PUVA).
Around 3 years after initiation, nivolumab was discontinued due to tumor progression. Thereafter, the patient received several lines of systemic therapy, including sorafenib, lenvatinib, cabozantinib, and regorafenib, and died roughly 1 year later due to further tumor progression.

Discussion

Several systemic therapies are approved for the treatment of patients with HCC, including sorafenib and lenvatinib in first-line treatment, and regorafenib, cabozantinib, and ramucirumab in patients pretreated with sorafenib. Immunotherapy has been added to the treatment armamentarium only recently [1]. The immune checkpoint inhibitors nivolumab, pembrolizumab, and the combination of nivolumab plus ipilimumab have been conditionally approved based on promising data from phase II trials in the United States (but not in Europe; [1, 2]). The combination of atezolizumab and bevacizumab improved overall survival and progression-free survival over sorafenib in a phase III trial [3], and represents the new reference standard in systemic front-line therapy of HCC [1].
Immune-related adverse events of immune checkpoint inhibitors can affect several organs, including the liver. Immune-related hepatic adverse events usually occur within 4–12 weeks of immunotherapy initiation. They affect approximately 5–10% of patients treated with monotherapy, but are much more frequent upon combination of ICIs (15–30%). During diagnostic work-up, differential diagnoses (i.e., intrahepatic tumor progression, hepatotoxic medication, acute viral infection or flares in patients with chronic viral hepatitis, alcohol abuse, thrombotic events or benign biliary obstructions) need to be excluded [47]. Notably, in patients developing an increase in liver enzymes during ICI treatment, immune-related hepatic adverse events were diagnosed in only 16% of cases, while around half of the patients had tumor progression [8].
In our patient, a grade 3 increase in transaminase levels developed 4 weeks after nivolumab initiation. Given the rapid onset and the low likelihood of other potential causes, we suspected irHepatitis. The good response to steroid treatment eventually confirmed the diagnosis. The adverse event was resolved around 3 months after steroid initiation. This is well in line with previous reports on the management of immune-related hepatic adverse events in patients with HCC receiving nivolumab [9]. Of 37 patients experiencing hepatic adverse events, seven (19%) required systemic corticosteroids and only one patient (3%) required additional mycophenolic acid. Resolution of the event occurred in all seven patients (100%) requiring immune-modulating medication after a median time of 19.4 weeks [9].
According to current recommendations, PD-(L)1-targeted ICIs can be resumed in cases of grade 3 irHepatitis while permanent discontinuation is recommended in patients experiencing grade 4 irHepatitis [4]. In our patient, nivolumab was resumed when steroids were discontinued and transaminases returned to baseline values. Even though our patient received nivolumab for more than 2 years, he never developed an episode of irHepatitis again. However, the further course of treatment was complicated by lichen ruber, a known but rather rare dermatological adverse event during ICI treatment, [10] that occurred approximately 1 year after nivolumab initiation.
The occurrence of immune-related adverse events may be associated with improved outcomes in cancer patients treated with ICIs [1113], and this association could be even more pronounced in patients with multisystem immune-related adverse events [14]. Our patient, who experienced two immune-related adverse events, failed to respond to treatment but achieved stable disease for over 2 years, which can be considered treatment success.

Conclusion

Immune-related hepatic adverse events usually occur early after ICI initiation, sometimes require systemic corticosteroids, but rarely additional immune-modulating medication, and mostly resolve within several weeks of initiation of immunomodulators [4, 9].

Conflict of interest

B. Scheiner received travel support from AbbVie, Ipsen and Gilead. M. Pinter is an investigator for Bayer, BMS, and Lilly; he received speaker honoraria from Bayer, BMS, Eisai, and MSD; he is a consultant for Bayer, BMS, Ipsen, Eisai, Lilly, and MSD, and he received travel support from Bayer and BMS.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://​creativecommons.​org/​licenses/​by/​4.​0/​.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Unsere Produktempfehlungen

Abo für kostenpflichtige Inhalte

Literatur
2.
Zurück zum Zitat Pinter M, Jain RK, Duda DG. The current landscape of immune checkpoint blockade in hepatocellular carcinoma: a review. JAMA Oncol. 2021;7:113–23.CrossRef Pinter M, Jain RK, Duda DG. The current landscape of immune checkpoint blockade in hepatocellular carcinoma: a review. JAMA Oncol. 2021;7:113–23.CrossRef
3.
Zurück zum Zitat Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382:1894–905.CrossRef Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382:1894–905.CrossRef
4.
Zurück zum Zitat Sangro B, Chan SL, Meyer T, et al. Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma. J Hepatol. 2020;72:320–41.CrossRef Sangro B, Chan SL, Meyer T, et al. Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma. J Hepatol. 2020;72:320–41.CrossRef
5.
Zurück zum Zitat Haanen J, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28:iv119–iv42.CrossRef Haanen J, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28:iv119–iv42.CrossRef
6.
Zurück zum Zitat Boutros C, Tarhini A, Routier E, et al. Safety profiles of anti-CTLA‑4 and anti-PD‑1 antibodies alone and in combination. Nat Rev Clin Oncol. 2016;13:473–86.CrossRef Boutros C, Tarhini A, Routier E, et al. Safety profiles of anti-CTLA‑4 and anti-PD‑1 antibodies alone and in combination. Nat Rev Clin Oncol. 2016;13:473–86.CrossRef
7.
Zurück zum Zitat Hassel JC, Heinzerling L, Aberle J, et al. Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): evaluation and management of adverse drug reactions. Cancer Treat Rev. 2017;57:36–49.CrossRef Hassel JC, Heinzerling L, Aberle J, et al. Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): evaluation and management of adverse drug reactions. Cancer Treat Rev. 2017;57:36–49.CrossRef
8.
Zurück zum Zitat Cunningham M, Iafolla M, Kanjanapan Y, et al. PS-139-Liver enzyme elevations and hepatotoxicity in patients treated with checkpoint inhibitor immunotherapy. J Hepatol. 2019;70(1):e89.CrossRef Cunningham M, Iafolla M, Kanjanapan Y, et al. PS-139-Liver enzyme elevations and hepatotoxicity in patients treated with checkpoint inhibitor immunotherapy. J Hepatol. 2019;70(1):e89.CrossRef
9.
Zurück zum Zitat Julien K, Leung HT, Fuertes C, et al. Nivolumab in advanced hepatocellular carcinoma: safety profile and select treatment-related adverse events from the checkmate 040 study. Oncologist. 2020;25:e1532–e40.CrossRef Julien K, Leung HT, Fuertes C, et al. Nivolumab in advanced hepatocellular carcinoma: safety profile and select treatment-related adverse events from the checkmate 040 study. Oncologist. 2020;25:e1532–e40.CrossRef
11.
Zurück zum Zitat Haratani K, Hayashi H, Chiba Y, et al. Association of immune-related adverse events with nivolumab efficacy in non-small-cell lung cancer. JAMA Oncol. 2018;4:374–8.CrossRef Haratani K, Hayashi H, Chiba Y, et al. Association of immune-related adverse events with nivolumab efficacy in non-small-cell lung cancer. JAMA Oncol. 2018;4:374–8.CrossRef
12.
Zurück zum Zitat Maher VE, Fernandes LL, Weinstock C, et al. Analysis of the association between adverse events and outcome in patients receiving a programmed death protein 1 or programmed death ligand 1 antibody. J Clin Oncol. 2019;37:2730–7.CrossRef Maher VE, Fernandes LL, Weinstock C, et al. Analysis of the association between adverse events and outcome in patients receiving a programmed death protein 1 or programmed death ligand 1 antibody. J Clin Oncol. 2019;37:2730–7.CrossRef
13.
Zurück zum Zitat Das S, Johnson DB. Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors. J Immunother Cancer. 2019;7:306.CrossRef Das S, Johnson DB. Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors. J Immunother Cancer. 2019;7:306.CrossRef
14.
Zurück zum Zitat Shankar B, Zhang J, Naqash AR, et al. Multisystem immune-related adverse events associated with immune checkpoint inhibitors for treatment of non-small cell lung cancer. JAMA Oncol. 2020;6:1952–6.CrossRef Shankar B, Zhang J, Naqash AR, et al. Multisystem immune-related adverse events associated with immune checkpoint inhibitors for treatment of non-small cell lung cancer. JAMA Oncol. 2020;6:1952–6.CrossRef
Metadaten
Titel
Immune-related hepatitis in a patient with hepatocellular carcinoma treated with nivolumab
verfasst von
Bernhard Scheiner, MD
Matthias Pinter, MD PhD
Publikationsdatum
09.09.2021
Verlag
Springer Vienna
Erschienen in
memo - Magazine of European Medical Oncology / Ausgabe 1/2022
Print ISSN: 1865-5041
Elektronische ISSN: 1865-5076
DOI
https://doi.org/10.1007/s12254-021-00747-9

Weitere Artikel der Ausgabe 1/2022

memo - Magazine of European Medical Oncology 1/2022 Zur Ausgabe