The GSTA1 polymorphism and cyclophosphamide therapy outcomes in lupus nephritis patients

Wang, Hongna; Zhu, Xiaoye; Ying, Zhu; Xie, Qionghong; Lai, Lin-Yun; Zhao, Miao; Chen, Yuancheng; Xue, Jun; Hao, Chuan‐Ming; Gu, Yong; Lin, Shan-Yan

doi:10.1016/j.clim.2015.07.010

Cited by 12 publications

(5 citation statements)

References 27 publications

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“…GSTA1 also participates in the metabolism of cyclophosphamide [ 41 ] possibly explaining modulation of associations of clinical outcomes in BU-cyclophosphamide conditioning regimen. Interestingly in lupus nephritis patients, GSTA1*B genotypes have higher exposure to activated cyclophosphamide metabolites [ 42 ]. Therefore, these vulnerable patients might benefit from administration of cyclophosphamide before BU or alternative conditioning regimens such as BU/Fludarabine.…”

Section: Discussionmentioning

confidence: 99%

GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study

et al. 2017

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Busulfan (BU) dose adjustment following therapeutic drug monitoring contributes to better outcome of hematopoietic stem cell transplantation (HSCT). Further improvement could be achieved through genotype-guided BU dose adjustments. To investigate this aspect, polymorphism within glutathione S transferase genes were assessed. Particularly, promoter haplotypes of the glutathione S transferase A1 (GSTA1) were evaluated in vitro, with reporter gene assays and clinically, in a pediatric multi-center study (N =138) through association with BU pharmacokinetics (PK) and clinical outcomes. Promoter activity significantly differed between the GSTA1

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Section: Discussionmentioning

confidence: 99%

GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study

et al. 2017

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“…GSTA1 has 3 linked polymorphisms in the promoter region, and 2 genotypes (GSTA1 * A and GSTA1 * B) have been defined based on the linked polymorphisms −631 T>G, −567 T>G, −69 C>T (rs3957357), and −52 G>A. The GSTA1 * B haplotype (31) has been associated with reduced protein levels (32) and therefore reduced detoxification and increased exposure to activated Cy metabolites (33). Moreover, GSTA1 is the main enzyme involved in busulfan metabolism.…”

Section: Graft-versus-host-disease (Gvhd)mentioning

confidence: 99%

Association between gene polymorphisms in the cyclophosphamide metabolism pathway with complications after haploidentical hematopoietic stem cell transplantation

et al. 2022

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for patients with hematologic malignances. Haploidentical HSCT (Haplo-HSCT) is an alternative option for patients who do not have an HLA-matched donor. The use of post-transplantation high dose cyclophosphamide (PT-Cy) is commonly employed for graft-versus-host disease (GVHD) prophylaxis in haplo-HSCT. Cyclophosphamide (Cy) is an alkylating agent with antineoplastic and immunosuppressive activity, whose bioactivation requires the activity of polymorphic enzymes in the liver to produce phosphoramide mustard, which is a DNA alkylating agent. To identify polymorphisms in the genes of Cy metabolism and correlate them with post-HSCT complications [GVHD, sinusoidal obstruction syndrome (SOS), hemorrhagic cystitis (HC) and transplant-related mortality (TRM)], we designed a custom next-generation sequencing panel with Cy metabolism enzymes. We analyzed 182 patients treated with haplo-HSCT with PT-Cy from 2007 to 2019, detecting 40 variants in 11 Cy metabolism genes. Polymorphisms in CYP2B6, a major enzyme involved in Cy activation, were associated with decreased activity of this enzyme and a higher risk of Graf-versus-host disease (GVHD). Variants in other activation enzymes (CYP2A6, CYP2C8, CYP2C9, CYP2C19) lead to decreased enzyme activity and were associated with GVHD. Polymorphisms in detoxification genes such as glutathione S-transferases decreased the ability to detoxify cyclophosphamide metabolites due to lower enzyme activity, which leads to increased amounts of toxic metabolites and the development of III-IV acute GVHD. GSMT1*0 a single nucleotide polymorphism previously recognized as a risk factor for SOS was associated with a higher risk of SOS. We conclude that polymorphisms of genes involved in the metabolism of cyclophosphamide in our series are associated with severe grades of GVHD and toxicities (SOS and TRM) after haplo-HSCT and could be used to improve the clinical management of transplanted patients.

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“…A 24h hour interval between the 2 drugs is therefore recommended to limit NRM [6]. An association between GSTA1 and Cy-PK was also described in patients with lupus nephritis, with poorer response rate in GSTA1*A*A [34]. Our study was limited by the initial sample size set by the RCT and derived by a previous retrospective study [35].…”

Section: Discussionmentioning

confidence: 98%

Effect of pharmacokinetics and pharmacogenomics in adults with allogeneic hematopoietic cell transplantation conditioned with Busulfan

Seydoux

Uppugunduri

Medinger

et al. 2023

Bone Marrow Transplant

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Busulfan (Bu) combined with cyclophosphamide (Cy) is commonly used as a myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT). There is inter-individual variability of Bu pharmacokinetics (PK) and hence in toxicity and efficacy. The introduction of therapeutic drug monitoring (TDM) of Bu has decreased toxicity of the regimen. Hepatic metabolism of Bu is mediated through Glutathione-S-Transferases (GSTs), mainly GSTA1. Patients with GSTA1*A variants are considered normal metabolizers and GSTA1*B corresponds to poor metabolism, defined by nucleotide changes at −52 or −69 locus in GSTA1 promoter region. The aim of the study was to explore the correlation between GSTA1 polymorphisms and Bu-PK in 60 adult patients receiving an allo-HCT in the BuCyBu clinical study (ClinicalTrials.gov I, ID NCT01779882) comparing the sequence BuCy to CyBu. DNA samples prior to conditioning were genotyped for candidate variants at −52 (rs3957356) and −69 (rs3957357) loci in the GSTA1 promoter. Thirty-three % of patients were GSTA1*A*A, 49% GSTA1*A*B and 18% GSTA1*B*B. In GSTA1*A*A patients, median Bu-AUC was 3.6 ± 0.7 mg*h/L, in GSTA1*A*B 4.5 ± 1.6 and in GSTA1*B*B 4.9 ± 1.4 (AUC 35% higher than GSTA1*A*A, p = 0.03), with a similar significant correlation with Bu-clearance (p = 0.04). The correlation between GSTA1 polymorphism and AUC remained significant in multivariate linear regression analysis. There was a trend for lower non-relapse mortality (NRM) in patients with low AUC. We could not demonstrate a correlation between GSTA1 polymorphisms and NRM, acute graft-versus-host disease (aGvHD) in this small cohort, but there is a trend of higher aGvHD incidence in GSTA1*B*B patients.

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The GSTA1 polymorphism and cyclophosphamide therapy outcomes in lupus nephritis patients

Cited by 12 publications

References 27 publications

GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study

GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study

Association between gene polymorphisms in the cyclophosphamide metabolism pathway with complications after haploidentical hematopoietic stem cell transplantation

Effect of pharmacokinetics and pharmacogenomics in adults with allogeneic hematopoietic cell transplantation conditioned with Busulfan

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