Pharmacogenetic and clinical predictors of ondansetron failure in a diverse pediatric oncology population.

Shana S Jacobs, Jeffrey S Dome, Jiaxiang Gai, Andrea M Gross, Elena Postell, Pamela S Hinds, Lionel Davenport, John N van den Anker, Catriona Mowbray

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 2022 Apr

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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. 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). One hundred twenty-nine patients were approached; 103 consented. Participants were less than 1 to 33 years (mean 6.85). A total of 39.8% was female, 58.3% was White (22.3% Black, 19.4% other), and 24.3% was 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). Select phenotypes of 5-HT3RB and ABCB1, age, and potentially BMI can help predict increased risk for CINV in a diverse pediatric oncology population. © 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Citation

Shana S Jacobs, Jeffrey S Dome, Jiaxiang Gai, Andrea M Gross, Elena Postell, Pamela S Hinds, Lionel Davenport, John N van den Anker, Catriona Mowbray. Pharmacogenetic and clinical predictors of ondansetron failure in a diverse pediatric oncology population. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2022 Apr;30(4):3513-3520