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Immune checkpoint inhibitor-induced hepatitis injury: risk factors, outcomes, and impact on survival

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Abstract

Purpose

Immune checkpoint inhibitors (ICIs) are associated with a unique set of immune-related adverse events (irAEs). Few studies have evaluated the risk factors and outcomes of patients who develop ICI-induced hepatitis (ICIH).

Methods

We utilized an institutional database of patients with advanced cancers treated with ICI to identify patients with ICIH. irAEs were graded using the Common Terminology Criteria for Adverse Events v4. Overall survival (OS) was calculated from the date of ICI to death from any cause or the date of the last follow-up. OS with 95% confidence intervals were estimated using the Kaplan–Meier method and stratified by the occurrence of ICIH.

Results

We identified 1096 patients treated with ICI. The most common ICIs were PD1/L1 (n = 774) and CTLA-4 inhibitors (n = 195). ICIH occurred among 64 (6%) patients: severity was < grade 3 in 30 and ≥ grade 3 in 24 patients (3.1% overall). Median time to ICIH was 63 days. ICIH was more frequent in women (p = 0.038), in patients treated with combination ICIs (p < 0.001), and when given as first-line therapy (p = 0.018). Occurrence of ICIH was associated with significantly longer OS, median 37.0 months (95% CI 21.4, NR) compared to 11.3 months (95% CI 10, 13, p < 0.001); there was no difference in OS between patients with ≥ grade 3 ICIH vs grade 1–2.

Conclusions

Female sex, combination immunotherapy, and the first line of immunotherapy were associated with ICIH. Patients with ICIH had improved clinical survival compared to those that did not develop ICIH. There is a need for prospective further studies to confirm our findings.

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Acknowledgements

This project utilized REDCap database software which was supported by The Ohio State University Center for Clinical and Translational Science grant support (National Center for Advancing Translational Sciences, Grant UL1TR002733). Dr. Owen is supported by the LUNGevity Career Development Award. Dr. Presley is supported by the NIA: R03AG064374. Dr. Tinoco is supported by K12 CA133250. We thank the Biostatistics Shared Resource at The Ohio State University Comprehensive Cancer Center, Columbus, OH for statistical planning, analysis, and reporting (P30CA016058).

Funding

This study was supported by the National Institutes of Health (P30CA016058 and K12 CA133250).

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Author notes

  1. Abdul Miah and Gabriel Tinoco contributed equally to this work.

Authors and Affiliations

  1. Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, 1810 Cannon Drive, Suite 1240C, Columbus, OH, 43210, USA

    Abdul Miah, Gabriel Tinoco, Andrew Johns, Sandip Patel, Mingjia Li, Madison Grogan, Gabrielle Lopez, Marium Husain, Rebecca Hoyd, Alexa Meara, Erin M. Bertino, Kari Kendra, Daniel Spakowicz, Gregory A. Otterson, Carolyn J. Presley & Dwight H. Owen

  2. Department of Biomedical Informatics and Center for Biostatistics, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA

    Songzhu Zhao & Lai Wei

  3. Division of Gastroenterology Hepatology and Nutrition, The Ohio State University, Columbus, OH, USA

    Khalid Mumtaz

  4. Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA

    Alexa Meara

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  1. Abdul Miah
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Contributions

AM, SZ, LW, CP, GO and DO: contributed to the study conception and study design. Material preparation, data collection and interpretation of data were performed by all authors. Statistical analysis was conducted by SZ and LW. The first draft of the manuscript was written by AM and DO. All authors read the manuscript, revised it critically, and approve the final manuscript, tables and figures.

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Correspondence to Gabriel Tinoco.

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Miah, A., Tinoco, G., Zhao, S. et al. Immune checkpoint inhibitor-induced hepatitis injury: risk factors, outcomes, and impact on survival. J Cancer Res Clin Oncol 149, 2235–2242 (2023). https://doi.org/10.1007/s00432-022-04340-3

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