Clinical features of immune-mediated hepatotoxicity induced by immune checkpoint inhibitors in patients with cancers

Abstract

Purpose

The risk factors and clinical characteristics of ICI-induced immune-mediated hepatotoxicity (IMH) are not fully understood. Thus, the present study sought to clarify the clinical features of IMH.

Methods

All patients treated with ICIs between September 2014 and April 2019 at our institution were included. Clinical data were retrospectively collected from medical records. The frequency of grade ≥ 2 liver damage, clinical characteristics, and risk factors for developing IMH were examined.

Results

Overall, 250 patients (median age 71 years; range 30–87 years; 202 males and 48 females) were included in the analyses. Forty-five patients had elevated transaminase levels (> threefold the upper limit of normal). Of these, 21 were considered to have IMH. The remaining 24 patients had other causes of elevated transaminase levels. Steroids were administered to 13/21 patients with IMH. Although all patients exhibited improvement, IMH was not associated with the anticancer efficacy of the ICIs or OS. A multivariable analysis revealed that IMH was significantly associated with malignant melanoma (odds ratio [OR] 11.6; 95% confidence interval [CI] 3.5–38.0; P = 0.0002) and ipilimumab–nivolumab combination therapy (OR 61.2; 95% CI 7.9–1275.3; P < 0.0001).

Conclusion

Immune-mediated hepatotoxicity occurred in 9.5% of patients treated with ICIs. Appropriate therapeutic interventions are important to avoid affecting the patient’s prognosis, and accurate diagnosis of IMH is essential for this purpose. The frequency of IMH varied according to the type of cancer and the drug used, and was significantly higher in patients with malignant melanoma and in patients given ipilimumab–nivolumab combination therapy.

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Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Abbreviations

ALT:

Alanine aminotransferase

ANA:

Antinuclear antibody

AST:

Aspartate aminotransferase

CI:

Confidence interval

CTCAE:

Common terminology criteria for adverse events

CTLA-4:

Cytotoxic T lymphocyte-associated molecule-4

DCR:

Disease control rate

ECOG PS:

Eastern Cooperative Oncology Group performance status

Hb:

Hemoglobin

ICI:

Immune checkpoint inhibitor

IMH:

Immune-mediated hepatotoxicity

INR:

International normalized ratio

irAE:

Immune-related adverse reaction

MM:

Malignant melanoma

MMF:

Mycophenolate mofetil

NSCLC:

Non-small cell lung cancer

OR:

Odds ratio

OS:

Overall survival

PD-1:

Programmed cell death receptor-1

PD-L1:

Programmed cell death ligand-1

RECIST:

Response evaluation criteria in solid tumors

RCC:

Renal cell carcinoma

RR:

Response rate

UDCA:

Ursodeoxycholic acid

ULN:

Upper limit of the institutional normal

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Acknowledgements

We thank Stallard Scientific Editing (https://www.stallardediting.com) for editing a draft of this manuscript.

Funding

Not applicable.

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Authors

Contributions

Study conception and design were performed AY, YY and YU. Material preparation and data collection were performed by AY, EY, YH, HH, RY and NA. Analysis was performed by AY. The first draft of the manuscript was written by AY and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Yoshihiko Yano.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval and consent to participate

The study was carried out in accordance with the Declaration of Helsinki and was approved by the institutional review board of the Kobe University Graduate School of Medicine and by the institutional review boards of the participating hospitals (no. B200118). The need to collect informed consent from the patients was waived because this was a retrospective study. Information about this study was published in our institute, and patients could ask for their data to be withdrawn from the analysis.

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Yamamoto, A., Yano, Y., Ueda, Y. et al. Clinical features of immune-mediated hepatotoxicity induced by immune checkpoint inhibitors in patients with cancers. J Cancer Res Clin Oncol (2020). https://doi.org/10.1007/s00432-020-03448-8

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Keywords

  • Immune checkpoint inhibitors
  • Immune-related adverse events
  • Liver injury
  • Immune-mediated hepatotoxicity
  • Risk factors