title: 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: Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota. Electronic address: veronikabachanova@msn.com.
authors: Veronika
authors: V
authors: Bachanova
authors: Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota.
authors: Ryan
authors: R
authors: Shanley
authors: Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota.
authors: Farhana
authors: F
authors: Malik
authors: Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, Florida.
authors: Lata
authors: L
authors: Chauhan
authors: Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, Florida.
authors: Vishal
authors: V
authors: Lamba
authors: Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota.
authors: Daniel J
authors: DJ
authors: Weisdorf
authors: Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota.
authors: Linda J
authors: LJ
authors: Burns
authors: Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, Florida.
authors: Jatinder Kaur
authors: JK
authors: Lamba
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D064592:Autografts; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000008:administration & dosage*; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D018380:Hematopoietic Stem Cell Transplantation; D006689:Hodgkin Disease / Q000201:enzymology / Q000235:genetics / Q000628:therapy; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000201:enzymology / Q000235:genetics / Q000628:therapy; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012008:Recurrence; D019172:Transplantation Conditioning
chemical_list: D003520:Cyclophosphamide; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6
keywords: Autologous hematopoietic cell transplantation; Cyclophosphamide; Cytochrome P450 polymorphism; Hodgkin lymphoma; Non-Hodgkin lymphoma