title: Genomic polymorphisms provide prognostic information in intermediate-risk acute myeloblastic leukemia.
abstract: Current prognostic factors for acute myeloblastic leukemia (AML) are not sufficient to accurately predict the group of patients in the intermediate-risk category who will successfully respond to treatment. Distinct patterns of inherited functional genomic polymorphisms might explain part of these heterogeneous prognoses. We used the allelic discrimination method to identify polymorphisms in GSTT1, SULT1C2, CDA, SXR (drug metabolic pathways), XPD, XPA, XPG, ERCC1, TOP2A (DNA repair), VEGF (angiogenesis), and MDR1 (multidrug resistance) genes in 110 adult patients with intermediate-risk AML, enrolled in the CETLAM-99 prospective trial. A multivariate prognostic model adjusted for age, white blood cell (WBC) count, French-American-British group, cytogenetics, MLL rearrangement, internal tandem duplication of FLT3 (FLT3-ITD), induction courses to achieve complete remission, and germline polymorphisms, was used to detect independent risk factors associated with clinical outcome. This analysis showed an increased risk of refractoriness to chemotherapy in the group of patients with XPA variant alleles (RR = 14; P = .02). In the same model, increased relapse risk was associated with SULT1C2 heterozygosity (RR = 4.1; P = .004), FLT3-ITD (RR 3.3; P = .003), and MDR1 variant alleles (RR = 2.4; P = .02). Adverse prognostic variables for overall survival were XPA (RR = 3.4; P = .02) and MDR1 (RR = 2.1; P = .02) variant alleles, and WBC count (RR = 2.1; P = .02). These findings might be useful in selecting risk-adapted treatment strategies in intermediate-risk AML.
authors.affiliation: Hospital Clínic, Hospital Universitario de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Mariano
authors.initials: M
authors.lastname: Monzo
authors.forename: Salut
authors.initials: S
authors.lastname: Brunet
authors.forename: Alvaro
authors.initials: A
authors.lastname: Urbano-Ispizua
authors.forename: Alfons
authors.initials: A
authors.lastname: Navarro
authors.forename: Granada
authors.initials: G
authors.lastname: Perea
authors.forename: Jordi
authors.initials: J
authors.lastname: Esteve
authors.forename: Rosa
authors.initials: R
authors.lastname: Artells
authors.forename: Miquel
authors.initials: M
authors.lastname: Granell
authors.forename: Juan
authors.initials: J
authors.lastname: Berlanga
authors.forename: Josep M
authors.initials: JM
authors.lastname: Ribera
authors.forename: Javier
authors.initials: J
authors.lastname: Bueno
authors.forename: Andreu
authors.initials: A
authors.lastname: Llorente
authors.forename: Ramon
authors.initials: R
authors.lastname: Guardia
authors.forename: Mar
authors.initials: M
authors.lastname: Tormo
authors.forename: Pio
authors.initials: P
authors.lastname: Torres
authors.forename: Josep F
authors.initials: JF
authors.lastname: Nomdedéu
authors.forename: Emili
authors.initials: E
authors.lastname: Montserrat
authors.forename: Jordi
authors.initials: J
authors.lastname: Sierra
mesh_terms: D000328:Adult; D000483:Alleles; D018572:Disease-Free Survival; D005260:Female; D006579:Heterozygote; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D007958:Leukocyte Count; D008297:Male; D015999:Multivariate Analysis; D009363:Neoplasm Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D011379:Prognosis; D011446:Prospective Studies; D012008:Recurrence; D012074:Remission Induction; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D009363:Neoplasm Proteins