Pharmacogenetics of cyclophosphamide and CYP2C19 polymorphism in Thai systemic lupus erythematosus

Abstract

To assess whether the CYP2C19 polymorphism modified the effect of cyclophosphamide on ovarian toxicity in Thai patients with SLE. We performed a case-control study of female patients with SLE who were treated with cyclophosphamide at Ramathibodi Hospital, Bangkok, Thailand. Cases were patient who had ovarian toxicity (sustained amenorrhoea >12 months or lack of menstruation for >4 months). CYP2C19 polymorphism was genotyped using PCR-RFLP method. Logistic regression was applied to assess CYP2C19 polymorphism as an effect modifier of cyclophosphamide. Seventy-one patients with SLE were enrolled, of which 36 (59.7%) had ovarian toxicity. CYP2C19*2 allele frequencies were 27.8 and 21.4% in the ovarian and non-ovarian toxicity groups. Patients with CYP2C19*1/*1 genotype and higher cumulative dose of cyclophosphamide (>23.75 g) had the highest odds of ovarian toxicity, i.e. 11.0 (95% CI: 1.2-99.1) times higher than patients with the CYP2C19*1/*2 or *2/*2 genotypes who received less cyclophosphamide (<23.75 g). After adjusting for age at start of treatment, this risk increased to 13.6 (95% CI: 1.1-162.2). Our results suggest that a cumulative cyclophosphamide dose of 23.75 g or higher carries a twofold higher risk of ovarian toxicity and the CYP2C19*1/*1 genotype increases the risk of toxicity a further fivefold.

Impact of genetic polymorphisms on chemotherapy toxicity in childhood acute lymphoblastic leukemia

“…Other polymorphisms reportedly associated with increased cyclophosphamide-induced toxicity are CYP2C19*2 (Takada et al, 2004; Ngamjanyaporn et al, 2011), CYP3A4*1B (Su et al, 2010), GSTM1/T1 null (Cho et al, 2010), ALDH3A1*2 and ALDH1A1*2 (Ekhart et al, 2008), ABCC4 rs9561778 (Low et al, 2009), or ABCG2 Q141K (rs2231142; Kim et al, 2008). It should be stated that some of these studies were conducted in patients with hematological malignancies but there are as yet no available data on ALL.…”

Moderate-dose cyclophosphamide for severe aplastic anemia has significant toxicity and does not prevent relapse and clonal evolution

“…13 Unknown ethnic differences in Cy pharmacokinetics could contribute to the different toxicity outcomes. 16,17 The occurrence of late events of hematologic relapse and clonal evolution were also unsatisfactory ( Figure 2B). In this cohort, these events occurred early, which differs from the experience with ATG therapies in which late events usually occur after the first year from immunosuppression.…”

The importance of both CYP2C19 and CYP2B6 germline variations in cyclophosphamide pharmacokinetics and clinical outcomes

“…Whilst not the focus of this review, it is important to note that the role of pharmacogenetics in the risk of excessive toxicity (due to high levels of bioactivation of this cytotoxic drug) have also been assessed. Associations between CYP2C19 and/or CYP2B6 , as well as other pharmacogenes such as ALDH , GSTP1 and CYP3A4 , and the severity of neutropenia or premature ovarian failure have been reported …”

“…Associations between CYP2C19 and/or CYP2B6, as well as other pharmacogenes such as ALDH, GSTP1 and CYP3A4, and the severity of neutropenia or premature ovarian failure have been reported. 40,65,67,[70][71][72][73][74][75]…”