Hepatotoxicity
In clinical trials of
belinostat in patients with PTCL, the rates of serum enzyme elevations during therapy were usually less than 5%, and were above 5 times the ULN in only 1% to 2% of patients. A single instance of severe acute liver injury leading to death from liver failure was reported in an open label trial of belinostat monotherapy in 120 patients with PTCL. The liver injury arose after 10 cycles of treatment and progressed despite drug discontinuation. Specific details were not provided. Thus, belinostat is considered to be a cause of acute liver injury but the timing of onset, associated features, clinical course and outcome have not been well defined.
Likelihood score: D (possible cause of clinically apparent liver injury).
Mechanism of Injury
The reason why belinostat causes serum enzyme elevations is not known, but may be a direct toxicity to hepatocytes caused by inhibition of histone deacetylase or other enzyme activities. Belinostat is metabolized in the liver by UGT1A1 and the cytochrome P450 isozymes CYP 2A6, 2C9 and 3A4, so that it may cause drug-drug interactions, and hepatotoxicity could be the result of production of a toxic or immunogenic intermediate. Finally, belinostat is a sulfonamide hydroxyamide and severe acute liver injury from belinostat might be the result of a sulfonamide-like hepatic reaction.
Outcome and Management
Serum enzyme elevations are uncommon during belinostat therapy and are rarely dose limiting. Belinostat should not be used with other agents with hepatotoxic potential. Furthermore, regular monitoring of liver tests with each course of therapy is recommended, with more frequent monitoring if serum aminotransferase values rise. Belinostat should be held if ALT or AST values rise above 5 times the ULN. Elevations of more than 20 times the ULN or appearance of jaundice or symptoms of liver injury should trigger permanent discontinuation. There is no known cross sensitivity to hepatic injury among the different histone deacetylase inhibitors. Because belinostat is a sulfonamide derivative, it should be used with caution in patients with a history of sulfa allergy.
