Hepatotoxicity an uncommon side effect of immune-checkpoint-inhibitor treatment

Last Updated: 2019-12-30

By Will Boggs MD

NEW YORK (Reuters Health) - Hepatotoxicity resulting from treatment with immune-checkpoint inhibitors is uncommon, but it leads to permanent treatment discontinuation in most patients who develop it, according to a retrospective study.

"From a clinical standpoint, immune-mediated hepatotoxicity seems manageable," Dr. Ethan D. Miller of MD Anderson Cancer Center, in Houston, Texas, told Reuters Health by email. "The question then is how we can anticipate which patients may develop hepatotoxicity and how we can consistently recognize it as early as possible and refine its management to minimize its impact on cancer treatment."

Immune-checkpoint inhibitors (ICIs) are effective against a wide range of advanced malignancies, but up to 30% of patients treated with ICIs develop hepatotoxicity.

Dr. Miller and colleagues investigated the incidence of liver injury and its clinical features and outcomes in their retrospective study of more than 5,700 ICI recipients.

Overall, 100 patients (2%) had ALT elevations greater than five times the upper limit of normal and constituted this study group: 25 had received anti-CTLA-4, 46 had received anti-PD-1/PD-L1 and 29 had received combination therapy.

The incidence of hepatotoxicity was significantly higher with combination therapy (9.2%) than with monotherapy (1.7% for anti-CTLA-4 and 1.1% for anti-PD-1/PD-L1), the researchers report in The American Journal of Gastroenterology.

Hepatotoxicity emerged after a median latency of 59 days or three ICI infusions, at which time ICI treatment was suspended.

Treatment was discontinued permanently in 69 patients and withheld temporarily in 31 patients. Among the 31 patients who were rechallenged with ICIs, only eight exhibited recurrent hepatotoxicity (all eight of whom initially had grade-3 hepatotoxicity); ICIs were stopped permanently in these eight patients.

Overall, 67 patients received steroid therapy, and 10 of these patients exhibited recurrence of hepatotoxicity after the steroid taper. Three patients received mycophenolate mofetil in response to worsening ALT despite steroids, after which ALT declined to grade 1 or lower.

The median time from the onset of hepatotoxicity to improvement to grade 1 or lower was significantly longer for those who received steroids (23 days) than for those who did not (14 days).

Among the 36 patients who died from any cause, seven had persistently elevated ALT and two had liver failure at the time of death.

"Immune-mediated hepatotoxicity seems to be recognized early and on its own does not appear to be a major cause of morbidity and mortality among checkpoint-inhibitor recipients," Dr. Miller said. "It may be more common among those receiving combinations of checkpoint inhibitors than single agent therapy, but it is not necessarily more severe among recipients of combination therapy."

"Another major point is that among those rechallenged, recurrence of hepatotoxicity only occurred in the minority," he said. "This raises the possibility that oncologists might consider rechallenge in a higher proportion of patients in the future."

"The low proportion of patients experiencing recurrent hepatotoxicity suggests that immune-mediated hepatotoxicity is different from other types of drug-induced liver injury, where rechallenge is generally avoided due to the high likelihood of liver injury," Dr. Miller added. "There is an opportunity to better characterize immune-mediated hepatotoxicity."

The study had no financial support. Several authors report ties to drugmakers.

SOURCE: https://bit.ly/2ZE3iNN The American Journal of Gastroenterology, online November 27, 2019.