Cyclophosphamide treatment-induced leukopenia rates in ANCA-associated vasculitis are influenced by variant CYP450 2C9 genotypes

Pharmacogenomics. 2016 Mar;17(4):367-74. doi: 10.2217/pgs.15.176. Epub 2016 Feb 19.

Abstract

Aim: 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.

Patients & 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.

Conclusion: Patients with variant CYP2C9 are at increased risk for cyclophosphamide-induced leukopenia but may have a better chance to respond to treatment.

Keywords: ANCA-associated vasculitis; CYP450; cyclophosphamide; drug metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / drug therapy*
  • Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / genetics
  • Cyclophosphamide / adverse effects*
  • Cytochrome P-450 CYP2C9 / genetics*
  • Female
  • Humans
  • Immunosuppressive Agents / adverse effects*
  • Leukopenia / chemically induced*
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Treatment Outcome
  • Young Adult

Substances

  • Immunosuppressive Agents
  • Cyclophosphamide
  • Cytochrome P-450 CYP2C9