title: Profiling of drug-metabolizing enzymes/transporters in CD33+ acute myeloid leukemia patients treated with Gemtuzumab-Ozogamicin and Fludarabine, Cytarabine and Idarubicin.
abstract: Genetic heterogeneity in drug-metabolizing enzyme/transporter (DMET) genes affects specific drug-related cancer phenotypes. To investigate the relationships between genetic variation and response to treatment in acute myeloid leukemia (AML), we genotyped 1931 variants on DMET genes in 94 CD33-positive AML patients enrolled in a phase III multicenter clinical trial combining Gemtuzumab-Ozogamicin (GO) with Fludarabine-Cytarabine-Idarubicin (FLAI) regimen, with the DMET Plus platform. Two ADH1A variants showed statistically significant differences (odds ratio (OR)=5.68, P=0.0006; OR=5.35, P=0.0009) in allele frequencies between patients in complete/partial remission and patients without response, two substitutions on CYP2E1 (OR=0.13, P=0.001; OR=0.09, P=0.003) and one on SLCO1B1 (OR=4.68, P=0.002) were found to differently influence liver toxicity, and two nucleotide changes on SULTB1 and SLC22A12 genes correlated with response to GO (OR=0.24, P=0.0009; OR=2.75, P=0.0029). Genetic variants were thus found for the first time to be potentially associated with differential response and toxicity in AML patients treated with a combination of GO-FLAI regimen.
authors.affiliation: Department of Hematology and Oncological Sciences 'L. and A. Seràgnoli' S.Orsola Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Iacobucci
authors.forename: A
authors.initials: A
authors.lastname: Lonetti
authors.forename: A
authors.initials: A
authors.lastname: Candoni
authors.forename: M
authors.initials: M
authors.lastname: Sazzini
authors.forename: C
authors.initials: C
authors.lastname: Papayannidis
authors.forename: S
authors.initials: S
authors.lastname: Formica
authors.forename: E
authors.initials: E
authors.lastname: Ottaviani
authors.forename: A
authors.initials: A
authors.lastname: Ferrari
authors.forename: A
authors.initials: A
authors.lastname: Michelutti
authors.forename: E
authors.initials: E
authors.lastname: Simeone
authors.forename: A
authors.initials: A
authors.lastname: Astolfi
authors.forename: M C
authors.initials: MC
authors.lastname: Abbenante
authors.forename: S
authors.initials: S
authors.lastname: Parisi
authors.forename: F
authors.initials: F
authors.lastname: Cattina
authors.forename: M
authors.initials: M
authors.lastname: Malagola
authors.forename: D
authors.initials: D
authors.lastname: Russo
authors.forename: D
authors.initials: D
authors.lastname: Damiani
authors.forename: F
authors.initials: F
authors.lastname: Gherlinzoni
authors.forename: M
authors.initials: M
authors.lastname: Gottardi
authors.forename: M
authors.initials: M
authors.lastname: Baccarani
authors.forename: R
authors.initials: R
authors.lastname: Fanin
authors.forename: G
authors.initials: G
authors.lastname: Martinelli
mesh_terms: D000617:Aminoglycosides / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D003561:Cytarabine / Q000008:administration & dosage; D004798:Enzymes / Q000235:genetics* / Q000378:metabolism; D005260:Female; D000079982:Gemtuzumab; D018740:Genetic Heterogeneity; D005838:Genotype; D006801:Humans; D015255:Idarubicin / Q000008:administration & dosage; D008658:Inactivation, Metabolic / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000235:genetics; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D000617:Aminoglycosides; D061067:Antibodies, Monoclonal, Humanized; C571163:CD33 protein, human; D004798:Enzymes; D063268:Sialic Acid Binding Ig-like Lectin 3; D003561:Cytarabine; D000079982:Gemtuzumab; D014740:Vidarabine; C024352:fludarabine; D015255:Idarubicin