Abstract
Purpose: Chemotherapy induced nausea and vomiting (CINV) is a frequently seen burdensome adverse event of cancer therapy. The 5-HT3 receptor antagonist ondansetron has improved the rates of CINV but, unfortunately, up to 30% of patients do not obtain satisfactory control. This study examined whether genetic variations in a relevant drug metabolizing enzyme (CYP2D6), transporter (ABCB1) or receptor (5-HT3) were associated with ondansetron failure. Methods: DNA was extracted from blood and used to genotype: ABCB1 (3435C>T (rs1045642) and G2677A/T (rs2032582)), 5-HT3RB (rs3758987 T>C and rs45460698 (delAAG/dupAAG)) and CYP2D6 variants. Ondansetron failure was determined by review of the medical records and by patient-reported outcomes (PROs). Results: 129 patients were approached; 103 consented. Participants were less than 1 to 33 years (mean 6.85). 39.8% were female, 58.3% were White (22.3% Black, 19.4% other); and 24.3% were Hispanic. A majority had leukemia or lymphoma, and 41 (39.8%) met the definition of ondansetron failure. Of variants tested, rs45460698 independently showed a significant difference in risk of ondansetron failure between a mutant (any deletion) and normal allele (p=0.0281, OR 2.67). Age and BMI were both predictive of ondansetron failure (Age > 12 (OR 1.12, p=0.0012) and higher BMI (OR 1.13, p=0.0119)). In multivariate analysis, age > 12 was highly predictive of ondansetron failure (OR 7.108, p=0.0008). rs45460698 was predictive when combined with an increased nausea phenotype variant of rs1045642 (OR 3.45, p=0.0426). Conclusion: Select phenotypes of 5-HT3RB and ABCB1, age, and potentially BMI can help predict increased risk for CINV in a diverse pediatric oncology population.
Pharmacogenetic and clinical predictors of ondansetron failure in a diverse pediatric oncology population
