title: CYP2B6*6 is an independent determinant of inferior response to fludarabine plus cyclophosphamide in chronic lymphocytic leukemia.
abstract: Fludarabine plus cyclophosphamide (FC) is the chemotherapy backbone of modern chronic lymphocytic leukemia (CLL) treatment. CYP2B6 is a polymorphic cytochrome P450 isoform that converts cyclophosphamide to its active form. This study investigated the possible impact of genetic variation in CYP2B6 on response to FC chemotherapy in CLL. Available DNA samples from the LRF CLL4 trial, which compared chlorambucil, fludarabine, and FC, were screened by TaqMan real-time polymerase chain reaction assays for CYP2B6 SNPs c.516G>T and c.785A>G, which define the most common variant allele (*6). Among the 455 samples successfully genotyped, 265 (58.2%), 134 (29.5%), and 29 (6.4%) were classified as *1/*1, *1/*6, and *6/*6, respectively. Patients expressing at least one *6 allele were significantly less likely to achieve a complete response (CR) after FC (odds ratio 0.27; P = .004) but not chlorambucil or fludarabine. Analysis of individual response indicators confirmed that this inferior response resulted from impaired cytoreduction rather than delayed hemopoietic recovery. Multivariate analysis controlling for age, gender, stage, IGHV mutational status, 11q deletion, and TP53 deletion/mutation identified CYP2B6*6 and TP53 mutation/deletion as the only independent determinants of CR attainment after FC. Our study provides the first demonstration that host pharmacogenetics can influence therapeutic response in CLL. This trial is registered as an International Standard Randomised Control Trial, number NCT 58585610 at www.clinicaltrials.gov.
authors.affiliation: Directorate of Blood Sciences, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK;
authors.forename: Gillian G
authors.initials: GG
authors.lastname: Johnson
authors.forename: Ke
authors.initials: K
authors.lastname: Lin
authors.forename: Trevor F
authors.initials: TF
authors.lastname: Cox
authors.forename: Melanie
authors.initials: M
authors.lastname: Oates
authors.forename: David R
authors.initials: DR
authors.lastname: Sibson
authors.forename: Richard
authors.initials: R
authors.lastname: Eccles
authors.forename: Bryony
authors.initials: B
authors.lastname: Lloyd
authors.forename: Laura-Jayne
authors.initials: LJ
authors.lastname: Gardiner
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Carr
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Strefford
authors.forename: David G
authors.initials: DG
authors.lastname: Oscier
authors.forename: David
authors.initials: D
authors.lastname: Gonzalez de Castro
authors.forename: Monica
authors.initials: M
authors.lastname: Else
authors.forename: Daniel
authors.initials: D
authors.lastname: Catovsky
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Pettitt
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000009:adverse effects; D065702:Cytochrome P-450 CYP2B6; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D011379:Prognosis; D012074:Remission Induction; D014740:Vidarabine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*
chemical_list: D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D014740:Vidarabine; C024352:fludarabine