title: Cyclophosphamide treatment-induced leukopenia rates in ANCA-associated vasculitis are influenced by variant CYP450 2C9 genotypes.
abstract: OBJECTIVE
  Correlation of outcomes of cyclophosphamide (CP) therapy in antineutrophil cytoplasmic antibody-associated vasculitis with genotype polymorphisms in prodrug activating cytochrome P450 enzyme genes CYP2C9 and CYP2C19.
  
  
  METHODS
  One hundred and ninety six patients with antineutrophil cytoplasmic antibody-associated vasculitis treated with CP, either as intravenous pulse or as daily oral medication, were included. Genotypes of CYP2C9 and CYP2C19 were correlated with clinical outcomes (leukopenia, infection, urotoxicity and treatment response).
  
  
  RESULTS
  Sixty five (33.2%) patients had variant CYP2C9 and 55 (28.1%) had variant CYP2C19 genotype. In patients bearing variant CYP2C9, leukopenia was documented significantly more frequent than in carriers of wild-type CYP2C9 (55.4 vs 37.4%; odds ratio: 2.08; 95% CI: 1.14-3.80; p = 0.017). The impact of the CYP2C9 genotype was stronger in patients treated with oral CP (69.6 vs 45.6%; odds ratio: 2.73; 95% CI: 1.27-5.89; p = 0.009), but was not present in patients treated with intravenous pulsed CP. We observed less refractory disease courses in patients with variant CYP2C9, not reaching statistical significance.
  
  
  CONCLUSIONS
  Patients with variant CYP2C9 are at increased risk for cyclophosphamide-induced leukopenia but may have a better chance to respond to treatment.
authors.affiliation: Department of Rheumatology & Clinical Immunology, Vasculitis Center, University Hospital Schleswig-Holstein & Klinkum Bad Bramstedt, Bad Bramstedt, Germany.|Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Jan Henrik
authors.initials: JH
authors.lastname: Schirmer
authors.affiliation: Department of Rheumatology & Clinical Immunology, Vasculitis Center, University Hospital Schleswig-Holstein & Klinkum Bad Bramstedt, Bad Bramstedt, Germany.
authors.forename: Jan Phillip
authors.initials: JP
authors.lastname: Bremer
authors.affiliation: Department of Rheumatology & Clinical Immunology, Vasculitis Center, University Hospital Schleswig-Holstein & Klinkum Bad Bramstedt, Bad Bramstedt, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Moosig
authors.affiliation: Department of Rheumatology & Clinical Immunology, Vasculitis Center, University Hospital Schleswig-Holstein & Klinkum Bad Bramstedt, Bad Bramstedt, Germany.
authors.forename: Julia Ulrike
authors.initials: JU
authors.lastname: Holle
authors.affiliation: Department of Rheumatology & Comprehensive Center for Inflammation Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lamprecht
authors.affiliation: Human Genetics, Ruhr University Bochum, Bochum, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wieczorek
authors.affiliation: Institute for Experimental & Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Sierk
authors.initials: S
authors.lastname: Haenisch
authors.affiliation: Institute for Experimental & Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Ingolf
authors.initials: I
authors.lastname: Cascorbi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000188:drug therapy* / Q000235:genetics; D003520:Cyclophosphamide / Q000009:adverse effects*; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007970:Leukopenia / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D065729:Cytochrome P-450 CYP2C9
keywords: ANCA-associated vasculitis; CYP450; cyclophosphamide; drug metabolism