Irreversible hepatotoxicity after administration of trabectedin to a pleiomorphic sarcoma patient with a rare ABCC2 polymorphism: a case report

• Published in: Pharmacogenomics Vol. 14; no. 12; p. 1389
• Main Authors: Laurenty, Anne-Pascale, Thomas, Fabienne, Chatelut, Etienne, Bétrian, Sarah, Le Guellec, Chantal, Hennebelle, Isabelle, Le Guellec, Sophie, Chevreau, Christine
• Format: Journal Article
• Language: English
• Published: England 01-09-2013
• Subjects: Aged; Antineoplastic Agents, Alkylating - administration & dosage; Antineoplastic Agents, Alkylating - toxicity; Chemical and Drug Induced Liver Injury - diagnosis; Chemical and Drug Induced Liver Injury - genetics; Chemical and Drug Induced Liver Injury - pathology; Dioxoles - administration & dosage; Dioxoles - toxicity; Genotype; Humans; Liver - drug effects; Male; Multidrug Resistance-Associated Proteins - genetics; Multidrug Resistance-Associated Proteins - metabolism; Polymorphism, Genetic; Sarcoma - drug therapy; Sarcoma - metabolism; Sarcoma - pathology; Tetrahydroisoquinolines - administration & dosage; Tetrahydroisoquinolines - toxicity
• ISSN: 1744-8042
• DOI: 10.2217/pgs.13.124

We describe here the case of a 60-year old male patient treated for an extensive local progression of a pleiomorphic sarcoma on the right tibial crest with second-line trabectedin. Two cycles were administrated before a major liver toxicity was retrieved, with both cytolytic and cholestatic hepatitis quickly associated with irreversible jaundice. The radiological, histological, chemistry and pharmacogenetic investigations led us to diagnose chronic hepatobiliary toxicity with portal fibrosis, cholangiolitis damages and chronic hepatopathy. The patient had a deficient variant genotype of ABCC2 (c.-24TT, c.4488CT and c.4544GA), which has been suggested to play a role in excretion of toxic metabolites of trabectedin. This case report is, to our knowledge, the first description of trabectedin's irreversible liver toxicity in a human patient. Supported by a thorough review of the literature, this hepatitis is thought to have resulted from a multihit process involving genetic variants of ABC proteins and comedication.