Evaluation of liver enzyme elevations and hepatotoxicity in patients treated with checkpoint inhibitor immunotherapy.

<h4>Background and aims</h4>Immune checkpoint inhibitors (ICI) are increasingly used in cancer therapy. Elevated liver enzymes frequently occur in patients treated with ICI but evaluation is poorly described. We sought to better understand causes of liver enzyme elevation, investigation...

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Autores principales:	Morven Cunningham, Marco Iafolla, Yada Kanjanapan, Orlando Cerocchi, Marcus Butler, Lillian L Siu, Philippe L Bedard, Kendra Ross, Bettina Hansen, Anna Spreafico, Jordan J Feld
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7836004569814b22aad22e6c8e90288a
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spelling	oai:doaj.org-article:7836004569814b22aad22e6c8e90288a2021-12-02T20:10:43ZEvaluation of liver enzyme elevations and hepatotoxicity in patients treated with checkpoint inhibitor immunotherapy.1932-620310.1371/journal.pone.0253070https://doaj.org/article/7836004569814b22aad22e6c8e90288a2021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0253070https://doaj.org/toc/1932-6203<h4>Background and aims</h4>Immune checkpoint inhibitors (ICI) are increasingly used in cancer therapy. Elevated liver enzymes frequently occur in patients treated with ICI but evaluation is poorly described. We sought to better understand causes of liver enzyme elevation, investigation and management.<h4>Methods</h4>Patients treated with anti-PD-1, PDL-1 or CTLA-4 therapy in Phase I/II clinical trials between August 2012 and December 2018 were included. Clinical records of patients with significant liver enzyme elevations were retrospectively reviewed.<h4>Results</h4>Of 470 ICI-treated patients, liver enzyme elevation occurred in 102 (21.6%), attributed to disease progression (56; 54.9%), other drugs/toxins (7; 6.9%), other causes (22; 21.6%) and ICI immunotoxicity (17; 16.7%; 3.6% of total cohort). Immunotoxicity was associated with higher peak ALT than other causes of enzyme elevation (N = 17; M = 217, 95% CI 145-324 for immunotoxicity, N = 103; M = 74, 95% CI 59-92 for other causes; ratio of means 0.34, 95% CI 0.19-0.60, p = <0.001) and higher ALT:AST ratio (M = 1.27, 95% CI 0.78-2.06 for immunotoxicity, M = 0.69, 95% CI 0.59-0.80 for other causes, ratio of means 0.54, 95% CI 0.36-0.82, p = 0.004). Immunotoxicity was more often seen in patients with prior CPI exposure (41.2% of immunotoxicity vs 15.9% of patients without, p = 0.01), anti-CTLA-4 -containing ICI treatments (29.4% of immunotoxicity vs 6.8% of patients without, p = <0.001) and other organ immunotoxicity (76.5% of immunotoxicity vs 19.2% of patients without, p = <0.001). Cause for enzyme elevation was established in most patients after non-invasive investigation. Liver biopsy was reserved for four patients with atypical treatment response.<h4>Conclusions</h4>Liver enzyme elevation is common in patients receiving ICI, but often has a cause other than immunotoxicity. A biochemical signature with higher ALT and ALT/AST ratio, a history of prior ICI exposure and other organ immunotoxicities may help to identify patients at a higher likelihood of immunotoxicity. Liver biopsy can be safely deferred in most patients. We propose an approach to diagnostic evaluation in patients with liver enzyme elevations following ICI exposure.Morven CunninghamMarco IafollaYada KanjanapanOrlando CerocchiMarcus ButlerLillian L SiuPhilippe L BedardKendra RossBettina HansenAnna SpreaficoJordan J FeldPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 6, p e0253070 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Morven Cunningham Marco Iafolla Yada Kanjanapan Orlando Cerocchi Marcus Butler Lillian L Siu Philippe L Bedard Kendra Ross Bettina Hansen Anna Spreafico Jordan J Feld Evaluation of liver enzyme elevations and hepatotoxicity in patients treated with checkpoint inhibitor immunotherapy.
description	<h4>Background and aims</h4>Immune checkpoint inhibitors (ICI) are increasingly used in cancer therapy. Elevated liver enzymes frequently occur in patients treated with ICI but evaluation is poorly described. We sought to better understand causes of liver enzyme elevation, investigation and management.<h4>Methods</h4>Patients treated with anti-PD-1, PDL-1 or CTLA-4 therapy in Phase I/II clinical trials between August 2012 and December 2018 were included. Clinical records of patients with significant liver enzyme elevations were retrospectively reviewed.<h4>Results</h4>Of 470 ICI-treated patients, liver enzyme elevation occurred in 102 (21.6%), attributed to disease progression (56; 54.9%), other drugs/toxins (7; 6.9%), other causes (22; 21.6%) and ICI immunotoxicity (17; 16.7%; 3.6% of total cohort). Immunotoxicity was associated with higher peak ALT than other causes of enzyme elevation (N = 17; M = 217, 95% CI 145-324 for immunotoxicity, N = 103; M = 74, 95% CI 59-92 for other causes; ratio of means 0.34, 95% CI 0.19-0.60, p = <0.001) and higher ALT:AST ratio (M = 1.27, 95% CI 0.78-2.06 for immunotoxicity, M = 0.69, 95% CI 0.59-0.80 for other causes, ratio of means 0.54, 95% CI 0.36-0.82, p = 0.004). Immunotoxicity was more often seen in patients with prior CPI exposure (41.2% of immunotoxicity vs 15.9% of patients without, p = 0.01), anti-CTLA-4 -containing ICI treatments (29.4% of immunotoxicity vs 6.8% of patients without, p = <0.001) and other organ immunotoxicity (76.5% of immunotoxicity vs 19.2% of patients without, p = <0.001). Cause for enzyme elevation was established in most patients after non-invasive investigation. Liver biopsy was reserved for four patients with atypical treatment response.<h4>Conclusions</h4>Liver enzyme elevation is common in patients receiving ICI, but often has a cause other than immunotoxicity. A biochemical signature with higher ALT and ALT/AST ratio, a history of prior ICI exposure and other organ immunotoxicities may help to identify patients at a higher likelihood of immunotoxicity. Liver biopsy can be safely deferred in most patients. We propose an approach to diagnostic evaluation in patients with liver enzyme elevations following ICI exposure.
format	article
author	Morven Cunningham Marco Iafolla Yada Kanjanapan Orlando Cerocchi Marcus Butler Lillian L Siu Philippe L Bedard Kendra Ross Bettina Hansen Anna Spreafico Jordan J Feld
author_facet	Morven Cunningham Marco Iafolla Yada Kanjanapan Orlando Cerocchi Marcus Butler Lillian L Siu Philippe L Bedard Kendra Ross Bettina Hansen Anna Spreafico Jordan J Feld
author_sort	Morven Cunningham
title	Evaluation of liver enzyme elevations and hepatotoxicity in patients treated with checkpoint inhibitor immunotherapy.
title_short	Evaluation of liver enzyme elevations and hepatotoxicity in patients treated with checkpoint inhibitor immunotherapy.
title_full	Evaluation of liver enzyme elevations and hepatotoxicity in patients treated with checkpoint inhibitor immunotherapy.
title_fullStr	Evaluation of liver enzyme elevations and hepatotoxicity in patients treated with checkpoint inhibitor immunotherapy.
title_full_unstemmed	Evaluation of liver enzyme elevations and hepatotoxicity in patients treated with checkpoint inhibitor immunotherapy.
title_sort	evaluation of liver enzyme elevations and hepatotoxicity in patients treated with checkpoint inhibitor immunotherapy.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/7836004569814b22aad22e6c8e90288a
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Evaluation of liver enzyme elevations and hepatotoxicity in patients treated with checkpoint inhibitor immunotherapy.

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