title: Association between severe toxicity of nilotinib and UGT1A1 polymorphisms in Japanese patients with chronic myelogenous leukemia.
abstract: BACKGROUND
  Nilotinib is a BCR-ABL kinase inhibitor approved for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia (CML). The UDP-glucuronosyltransferase 1A1 (UGT1A1) polymorphism UGT1A1*28 (*28)/*28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib. Beside *28, UGT1A1*6 (*6) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan, metabolized by UGT1A1. We retrospectively investigated the association between severe toxicity of nilotinib and UGT1A1 polymorphisms (*6 and*28) in Japanese patients with CML.
  
  
  METHODS
  Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of UGT1A1 polymorphisms with severe nilotinib-related toxicity. Genotyping analyses were determined for *6 and *28.
  
  
  RESULTS
  All 3 patients with the *6/*6 or *6/*28 genotype had severe toxicity, including QT interval prolongation (grade 3), elevated lipase levels (grade 3) plus hyperbilirubinemia (grade 2), and anemia (grade 3) plus hepatic cyst hemorrhage (grade 2) in 1 patient each. Among the 5 patients with the *6/*1 or *1/*1 genotype, 1 had elevated lipase levels (grade 3) and another had severe pain in the lower extremities (grade 3).
  
  
  CONCLUSIONS
  These findings suggest that UGT1A1 polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients.
authors.affiliation: Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Shibata
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Minami
authors.forename: Ayako
authors.initials: A
authors.lastname: Mitsuma
authors.forename: Sachi
authors.initials: S
authors.lastname: Morita
authors.forename: Megumi
authors.initials: M
authors.lastname: Inada-Inoue
authors.forename: Tomoyo
authors.initials: T
authors.lastname: Oguri
authors.forename: Tomoya
authors.initials: T
authors.lastname: Shimokata
authors.forename: Mihoko
authors.initials: M
authors.lastname: Sugishita
authors.forename: Tomoki
authors.initials: T
authors.lastname: Naoe
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ando
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects*; D066126:Cardiotoxicity; D004562:Electrocardiography; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D006932:Hyperbilirubinemia / Q000139:chemically induced; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011743:Pyrimidines / Q000009:adverse effects*; D000099148:UGT1A1 Enzyme
chemical_list: D000970:Antineoplastic Agents; D014453:Glucuronosyltransferase; D011743:Pyrimidines; D000099148:UGT1A1 Enzyme; C498826:nilotinib