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. 2021 Nov 12;13(22):5665.
doi: 10.3390/cancers13225665.

Hepatotoxicity in Patients with Hepatocellular Carcinoma on Treatment with Immune Checkpoint Inhibitors

Nicola Personeni  1   2 , Tiziana Pressiani  2 , Antonio D'Alessio  1 , Maria Giuseppina Prete  1 , Silvia Bozzarelli  2 , Luigi Terracciano  1   3 , Arianna Dal Buono  1   4 , Antonio Capogreco  1   4 , Alessio Aghemo  1   4 , Ana Lleo  1   4 , Romano Fabio Lutman  5 , Massimo Roncalli  1   3 , Laura Giordano  2 , Armando Santoro  1   2 , Luca Di Tommaso  1   3 , Lorenza Rimassa  1   2
Affiliations

Hepatotoxicity in Patients with Hepatocellular Carcinoma on Treatment with Immune Checkpoint Inhibitors

Nicola Personeni et al. Cancers (Basel). .

Abstract

Risk factors for hepatic immune-related adverse events (HIRAEs) in patients with advanced/unresectable hepatocellular carcinoma (HCC) treated with immune checkpoint inhibitors (ICIs) are unclear. We investigated: (i) clinical and morpho-pathological predictors of HIRAEs in 27 pretreatment tumor specimens, including surrogate biomarkers of the HCC immune class (based on intratumoral tertiary lymphoid structures, and glutamine synthase, CD3, and CD79 expression); and (ii) the relationship between HIRAE onset and subsequent treatment outcomes. Fifty-eight patients were included-20 (34%) received ICIs alone, and 38 (66%) received ICIs plus targeted agents as first- or further-line treatment. After a median time of 0.9 months (range, 0.4-2.7), nine patients (15.5%) developed grade ≥ 3 hepatitis, which was significantly associated with higher baseline ALT levels (p = 0.037), and an infectious HCC etiology (p = 0.023). ICIs were safely resumed in six out of nine patients. Time to treatment failure (TTF) was not significantly different in patients developing grade ≥ 3 hepatitis vs. lower grades (3.25 vs. 3.91 months, respectively; p = 0.81). Biomarker surrogates for the HCC immune class were not detected in patients developing grade ≥ 3 hepatitis. Grade ≥ 3 hepatitis has a benign course that does not preclude safe ICI reintroduction, without any detrimental effect on TTF.

Keywords: hepatocellular carcinoma; hepatotoxicity; immune checkpoint inhibitors.

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Conflict of interest statement

N.P. reports receiving consulting fees from Amgen, Merck Serono, Servier; lectures fees from AbbVie, Gilead, Lilly, Sanofi; travel expenses from Amgen, ArQule; and institutional research funding from Basilea, Merck Serono, Servier. L.R. reports receiving consulting fees from Amgen, ArQule, AstraZeneca, Basilea, Bayer, BMS, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi, Servier, Taiho Oncology, and Zymeworks; lecture fees from AbbVie, Amgen, Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Ser-ono, Roche, and Sanofi; travel expenses from Ipsen; and institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, and Zymeworks.

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