title: Ancestry and pharmacogenetics of antileukemic drug toxicity.
abstract: Treatment-related toxicity in acute lymphoblastic leukemia (ALL) can not only be life threatening but may also affect relapse risk. In 240 patients, we determined whether toxicities were related to 16 polymorphisms in genes linked to the pharmacodynamics of ALL chemotherapy, adjusting for age, race (self-reported or via ancestry-informative markers), sex, and disease risk group (lower- vs higher-risk therapy). Toxicities (gastrointestinal, infectious, hepatic, and neurologic) were assessed in each treatment phase. During the induction phase, when drugs subject to the steroid/cytochrome P4503A pathway predominated, genotypes in that pathway were important: vitamin D receptor (odds ratio [OR], 6.85 [95% confidence interval [CI], 1.73-27.0]) and cytochrome P4503A5 (OR, 4.61 [95% CI, 1.11-19.2]) polymorphisms were related to gastrointestinal toxicity and infection, respectively. During the consolidation phase, when antifolates predominated, the reduced folate carrier polymorphism predicted gastrointestinal toxicity (OR, 10.4 [95% CI, 1.35-80.4]) as it also did during continuation (OR, 2.01 [95% CI, 1.06-4.11]). In all 3 treatment phases, a glucuronosyltransferase polymorphism predicted hyperbilirubinemia (P = .017, P < .001, and P < .001) and methotrexate clearance (P = .028), which was also independently associated with hyperbilirubinemia (P = .026). The genotype-phenotype associations were similar whether analyses were adjusted by self-reported race or ancestry-informative genetic markers. Germ-line polymorphisms are significant determinants of toxicity of antileukemic therapy.
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN 38105-2794, USA.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kishi
authors.forename: Cheng
authors.initials: C
authors.lastname: Cheng
authors.forename: Deborah
authors.initials: D
authors.lastname: French
authors.forename: Deqing
authors.initials: D
authors.lastname: Pei
authors.forename: Soma
authors.initials: S
authors.lastname: Das
authors.forename: Edwin H
authors.initials: EH
authors.lastname: Cook
authors.forename: Nobuko
authors.initials: N
authors.lastname: Hijiya
authors.forename: Carmelo
authors.initials: C
authors.lastname: Rizzari
authors.forename: Gary L
authors.initials: GL
authors.lastname: Rosner
authors.forename: Tony
authors.initials: T
authors.lastname: Frudakis
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000145:classification; D002648:Child; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000208:ethnology / Q000235:genetics; D005838:Genotype; D006801:Humans; D008727:Methotrexate / Q000009:adverse effects / Q000627:therapeutic use; D008954:Models, Biological; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D044469:Racial Groups; D012074:Remission Induction
chemical_list: D000970:Antineoplastic Agents; D008727:Methotrexate