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

Authors

Shana S. Jacobs, Division of Oncology, Children's National Hospital, Washington, DC, USA. ssjacobs@childrensnational.org.
Jeffrey S. Dome, Division of Oncology, Children's National Hospital, Washington, DC, USA.
Jiaxiang Gai, Biostatistics and Study Methodology Department, Children's National Hospital, Washington, DC, USA.
Andrea M. Gross, Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD, USA.
Elena Postell, Division of Oncology, Children's National Hospital, Washington, DC, USA.
Pamela S. Hinds, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Lionel Davenport, Division of Pathology and Lab Medicine, Molecular Diagnostics, Children's National Hospital, Washington, DC, USA.
John N. van den Anker, Division of Clinical Pharmacology, Children's National Hospital, Washington, DC, USA.
Catriona Mowbray, Division of Oncology, Children's National Hospital, Washington, DC, USA.

Document Type

Journal Article

Publication Date

4-1-2022

Journal

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

Volume

30

Issue

4

DOI

10.1007/s00520-022-06818-9

Keywords

Chemotherapy-induced nausea; Ondansetron; Pediatric cancer; Pharmacogenomics

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: 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). 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.

APA Citation

Jacobs, Shana S.; Dome, Jeffrey S.; Gai, Jiaxiang; Gross, Andrea M.; Postell, Elena; Hinds, Pamela S.; Davenport, Lionel; van den Anker, John N.; and Mowbray, Catriona, "Pharmacogenetic and clinical predictors of ondansetron failure in a diverse pediatric oncology population" (2022). GW Authored Works. Paper 180.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/180

Department

Pediatrics