Association of ABCB1 polymorphisms with the efficacy of ondansetron in chemotherapy-induced nausea and vomiting

Abstract

Purpose: Resistance to the antiemetic ondansetron is still a major problem resulting in discomfort and poor compliance with chemotherapy in acute myeloid leukemia (AML) patients. Based on our hypothesis that this clinical resistance to ondansetron is associated with ABCB1 genetic polymorphisms, we investigated whether ABCB1 gene variations affect the efficacy of ondansetron in chemotherapy-induced nausea and vomiting.

Methods: AML patients (n = 215) treated for 3 days with high-dose cytarabine were enrolled in this study. Thirty minutes before the beginning of chemotherapy, 8 mg ondansetron was administered intravenously, followed by 24 mg by continuous infusion and 8 mg intravenously, once per day, until 2 days after chemotherapy. Chemotherapy-induced nausea and vomiting occurrence in the acute and delayed phases was calculated. ABCB1 and CYP2D6 polymorphisms were analyzed by allele-specific matrix-assisted laser desorption. Basic clinical characteristics of the AML patients were collected from medical records.

Findings: No differences in genotype distribution frequencies of ABCB1 polymorphisms and haplotypes were observed in patients with different CYP2D6-predicted phenotypes. During the acute phase, patients with the CG haplotype (C3435T and G2677T) were associated with a high risk of grade 3/4 nausea and vomiting (P = 0.003 and P = 0.026, respectively). After adjustment for age, sex, smoking status, alcohol drinking status, body surface area, body mass index, and Eastern Cooperative Oncology Group-Performance Status, multivariate survival analysis implicated the CG haplotype as a predictive marker of the risk of grade 3/4 chemotherapy-induced nausea and vomiting in AML patients (P = 0.003 and P = 0.039, respectively). In addition, a significant association between the 3435CC genotype and grade 3/4 vomiting in AML patients was observed (P = 0.016). However, no association between these ABCB1 gene polymorphisms and ondansetron efficacy was found in the delayed phase.

Implications: These findings suggest that ABCB1 gene polymorphisms are associated with antiemetic efficacy of ondansetron in the acute phase after high-dose cytarabine chemotherapy in AML patients.

Keywords: ABCB1; cytarabine; efficacy; genetic polymorphism; ondansetron.