Cytochrome P450 2B6*5 Increases Relapse after Cyclophosphamide-Containing Conditioning and Autologous Transplantation for Lymphoma.

Abstract

Cyclophosphamide (Cy) is a prodrug that depends on bioactivation by hepatic cytochrome P450 (CYP) enzymes for its cytotoxicity. We evaluated the influence of single nucleotide polymorphisms (SNPs) of CYP enzymes on the efficacy of autologous hematopoietic cell transplantation (HCT) for lymphoma. SNPs of 22 genes were analyzed in 93 patients with Hodgkin (n = 52) and non-Hodgkin lymphoma (n = 41) treated with high-dose Cy followed by autologous HCT between 2004 and 2012. Preparative regimens contained Cy (120 mg/kg) combined with carmustine/etoposide (n = 61) or Cy (6000 mg/m(2)) with total body irradiation (n = 32). Lack of complete remission as measured by pretransplant positron emission tomography was the sole clinical factor associated with increased risk of relapse (HR, 2.1). In genomic analysis, we identified a single SNP (rs3211371) in exon 9 (C > T) of the CYP2B6 gene (allele designation 2B6*5) that significantly impacted patient outcomes. After adjusting for disease status and conditioning regimen, patients with the CYP2B6*1/*5 genotype had a higher 2-year relapse rate (HR, 3.3; 95% CI, 1.6 to 6.5; P = .041) and decreased overall survival (HR, 13.5; 95% CI, 3.5 to 51.9; P = .008) than patients with the wild-type allele. Two-year progression-free survival for patients with 2 hypofunctional CYP2B6 variant genotypes (*5 and *6) was only 11% (95% CI, 1% to 39%) compared with 67% (95% CI, 55% to 77%) for patients with the wild-type CYP2B6*1 allele in exon 9. Our results suggest that CYP2B6 SNPs influence the efficacy of high-dose Cy and significantly reduce the success of autologous HCT for lymphoma patients with the CYP2B6*5 variant.

• Authors: Veronika Bachanova, Ryan Shanley, Farhana Malik, Lata Chauhan, Vishal Lamba, Daniel J Weisdorf, Linda J Burns, Jatinder Kaur Lamba
• Journal: Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation (Biol Blood Marrow Transplant) Vol. 21 Issue 5 Pg. 944-8 (May 2015) ISSN: 1523-6536 [Electronic] United States
• PMID: 25677220 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Chemical References

• Cyclophosphamide
• CYP2B6 protein, human
• Cytochrome P-450 CYP2B6

Topics

• Adolescent
• Adult
• Aged
• Alleles
• Autografts
• Child
• Child, Preschool
• Cyclophosphamide (administration & dosage)
• Cytochrome P-450 CYP2B6 (genetics)
• Female
• Gene Frequency
• Hematopoietic Stem Cell Transplantation
• Hodgkin Disease (enzymology, genetics, therapy)
• Humans
• Lymphoma, Non-Hodgkin (enzymology, genetics, therapy)
• Male
• Middle Aged
• Polymorphism, Genetic
• Recurrence
• Transplantation Conditioning