TY - JOUR
T1 - Cytochrome P450 2B6*5 increases relapse after cyclophosphamide-containing conditioning and autologous transplantation for lymphoma
AU - Bachanova, Veronika
AU - Shanley, Ryan
AU - Malik, Farhana
AU - Chauhan, Lata
AU - Lamba, Vishal
AU - Weisdorf, Daniel J.
AU - Burns, Linda J.
AU - Lamba, Jatinder Kaur
N1 - Publisher Copyright:
© 2015 American Society for Blood and Marrow Transplantation.
PY - 2015/5/1
Y1 - 2015/5/1
N2 - 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 (120mg/kg) combined with carmustine/etoposide (n=61) or Cy (6000mg/m2) 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.
AB - 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 (120mg/kg) combined with carmustine/etoposide (n=61) or Cy (6000mg/m2) 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.
KW - Autologous hematopoietic cell transplantation
KW - Cyclophosphamide
KW - Cytochrome P450 polymorphism
KW - Hodgkin lymphoma
KW - Non-Hodgkin lymphoma
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U2 - 10.1016/j.bbmt.2015.02.001
DO - 10.1016/j.bbmt.2015.02.001
M3 - Article
C2 - 25677220
AN - SCOPUS:84928153682
SN - 1083-8791
VL - 21
SP - 944
EP - 948
JO - Biology of Blood and Marrow Transplantation
JF - Biology of Blood and Marrow Transplantation
IS - 5
ER -