title: Imatinib-induced hyperbilirubinemia with UGT1A1 (*28) promoter polymorphism: first case series in patients with gastrointestinal stromal tumor.
abstract: Imatinib, an orally administered protein-tyrosine kinase inhibitor (TKI) is indicated for the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST). Severe hepatotoxicity associated with imatinib is rare, and relationship to polymorphism of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) expression and related frequency of hyperbilirubinemia or toxicity are not well known. We present a case series patients who developed hyperbilirubinemia while on oral administration imatinib for treatment of GIST. Genetic testing for polymorphism of UGT1A1 showed the first patient to be homozygous for the UGT1A1 TA7 (*28) polymorphism and the second patient heterozygous for the UGT1A1 TA1 (*28) polymorphism. The first patient had to stop imatinib due to severe and persistent hyperbilirubenemia peaking >3 despite reducing imatininb to only 100 mg every other day while the second patient improved at this dose. Our case series represent the first data associating UGT1A1 polymorphism and imatinib in patients being treated for GIST. Given the prevalence of Gilbert's syndrome and the increasing use of imatinib, we encourage physicians to be aware of this possible toxicity as hepatotoxicity can be fatal if not managed in a timely fashion. This association is also timely due to recent FDA requirement for testing UGT1A1 polymorphism for nilotinib, another TKI.
authors.affiliation: Division of Hematology/Oncology and Experimental Therapeutics, Tufts Cancer Center- Tufts Medical Center, Boston, MA, USA (Muhammad Wasif Saif, Melissa Hennessey Smith, Antonia Maloney), USA.
authors.forename: Muhammad Wasif
authors.initials: MW
authors.lastname: Saif
authors.affiliation: Division of Hematology/Oncology and Experimental Therapeutics, Tufts Cancer Center- Tufts Medical Center, Boston, MA, USA (Muhammad Wasif Saif, Melissa Hennessey Smith, Antonia Maloney), USA.
authors.forename: Melissa Hennessey
authors.initials: MH
authors.lastname: Smith
authors.affiliation: Division of Hematology/Oncology and Experimental Therapeutics, Tufts Cancer Center- Tufts Medical Center, Boston, MA, USA (Muhammad Wasif Saif, Melissa Hennessey Smith, Antonia Maloney), USA.
authors.forename: Antonia
authors.initials: A
authors.lastname: Maloney
authors.affiliation: Mayo Clinic Cancer Center, Rochester, MN (Robert B. Diasio), USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Diasio
keywords: Gilbert’s syndrome; Imatinib; UGT1A1 polymorphism; chronic myeloid leukemia; hyperbilirubinemia