Correlation of CYP2B6, CYP2C19, ABCC4 and SOD2 genotype with outcomes in allogeneic blood and marrow transplant patients

doi:10.1016/j.leukres.2011.06.020

Leukemia Research

Volume 36, Issue 1, January 2012, Pages 59-66

https://doi.org/10.1016/j.leukres.2011.06.020 Get rights and content

Abstract

CYP2B6, CYP2C19, ABCC4, and SOD2 have been implicated in adverse drug reactions and survival after cyclophosphamide (CPA) treatment. 110 BMT patients who received high dose CPA treatment were genotyped for variants in these genes and the results were correlated with toxicity and relapse. CYP2B6 genotype significantly influenced overall toxicity suggesting active CYP2B6 alleles led to higher rates of overall toxicity. The p.R487C deficiency allele was significantly associated with a lower rate of overall toxicity and a higher rate of relapse. SOD2 rs4880 V16A polymorphism was associated with significantly less CPA-related overall toxicity and significantly lower relapse rates by Kaplan–Meier analysis although the SOD2 finding regarding relapse was not significant when evaluated by the cumulative incidence function.

Introduction

Cyclophosphamide (CPA) is commonly used as part of the conditioning regimen prior to blood and marrow transplantation (BMT) for treatment of hematologic malignancies. There is interest in finding the genetic determinants for the wide range of observed responses to cyclophosphamide treatment including differing severities of adverse drug responses (ADRs) and responsiveness of the underlying malignancies. Response might differ due to variation in drug metabolism by CYP2B6 and CYP2C19 which activate CPA to 4-hydroxy CPA or transport of the parent drug or its metabolites by ABCC4. Another mechanism might be mediated through genetic determinants in the way tumor cells and the host respond to oxidative stress of chemotherapeutic agent exposure through SOD2 which is a mitochondrial enzyme that converts endogenously produced toxic superoxides into hydrogen peroxide. The goal of this study was to determine the impact of genetic variations in CYP2B6, CYP2C19, ABCC4 and SOD2 on risk of relapse and toxicity in BMT patients receiving high dose CPA as a conditioning regimen for hematologic malignancies.

Section snippets

Human subjects

This study was done after review and approval by the Mayo Clinic Institutional Review Board. 115 adult and pediatric patients were initially evaluated for inclusion in this study of which 110 samples met criteria and could be studied. Patients underwent high dose CPA treatment using CPA 120 mg/kg and total body irradiation (TBI) regimen, 200cGy twice daily for 3 days (N = 24) or 220cGy twice daily for 3 days (N = 72), or busulfan 1 mg/kg four times daily and CPA 120 mg/kg regimen (N = 14) as part of

Characterization of subjects

Samples from 115 individuals who underwent blood and marrow transplantation were available for this study. However, 4 patients’ DNA was of insufficient quantity or quality to allow genotyping and one patient did not meet inclusion criteria due to CR status, leaving 110 patients for analysis. Clinical characteristics, donor characteristics, stem cell source, and conditioning regimen of the patients are found in Table 1, Table 2.

26 individuals experience toxicity <100 days after CPA treatment. An

Discussion

The purpose of this research was to examine the impact of variability in four genes on severe drug toxicity and disease relapse in 110 patients who received high dose CPA as part of their conditioning regimen prior to BMT. The main findings are (1) individuals with CYP2B6 EM plus UM phenotype, which efficiently activates CPA, experienced a greater degree of toxicity <100 days compared to those in the IM plus PM category (p = 0.019). CYP2B6 p.R487C, which decreases CPA activation, was associated

Conflict of interest

All authors declare no conflicts of interest.

Acknowledgements

None.

Funding source. There are no external sources of support in the form of grants and/or equipment or drugs to declare. This research was funded by the Mayo Clinic Department of Laboratory Medicine and Pathology.

Contributions. All authors provided the conception, acquisition of data, analysis of data, drafting, revising of article and final approval submitted.

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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/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.
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As mentioned above, allele-effects, particularly for *4 and *6, appear to differ for cyclophosphamide, most likely due to substrate-specific effects of amino acid substitutions (Ariyoshi et al., 2011; Raccor et al., 2012). Furthermore, the *5 (R487C) variant, not found to be related to efavirenz disposition, was significantly associated with lower rate of overall toxicity and higher rate of relapse in patients who received high dose CPA treatment (Black et al., 2012). However, data concerning cyclophosphamide from in vivo and in vitro studies are so far not consistent.
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Correlation of CYP2B6, CYP2C19, ABCC4 and SOD2 genotype with outcomes in allogeneic blood and marrow transplant patients

Abstract

Introduction

Section snippets

Human subjects

Characterization of subjects

Discussion

Conflict of interest

Acknowledgements

Biology of Blood and Marrow Transplantation

European Journal of Pharmaceutical Studies

Genetic polymorphisms of CYP2B6 affect the pharmacokinetics/pharmacodynamics of cyclophosphamide in Japanese cancer patients

Pharmacogenetics and Genomics

Role of polymorphic human CYP2B6 in cyclophosphamide bioactivation

The Pharmacogenomics Journal

A natural CYP2B6 TATA box polymorphism (-82T-C) leading to enhanced transcription and relocation of the transcriptional start site

Molecular Pharmacology

Genetic variability of CYP2B6 in populations of African and Asian origin: allele frequencies, novel functional variants, and possible implications for anti-HIV therapy with efavirenz

Pharmacogenetics and Genomics

CYP2D6 and CYP2C19 genotype-based dose recommendations for antidepressants: a first step towards subpopulation-specific dosages

Acta Psychiatry Scandinavia

The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype

Clinical Pharmacology & Therapeutics

Allele-specific change of concentration and functional gene dose for the prediction of steady-state serum concentrations of amitriptyline and nortriptyline in CYP2C19 and CY2D6 extensive and intermediate metabolizers

Clinical Chemistry

Association study of genetic polymorphism in ABCC4 with cyclophosphamide-induced adverse drug reactions in breast cancer patients

Journal of Human Genetics