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

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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.

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Data availability

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Funding

This project was supported by Award Numbers UL1TR001876 and KL2TR001877 from the NIH National Center for Advancing Translational Sciences, a Hyundai Hope on Wheels Impact Grant 2017, and funds from the Children’s National Heroes Curing Childhood Cancer Gala. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Center for advancing Translational Sciences or the National Institutes of Health.

Author information

Authors and Affiliations

  1. Division of Oncology, Children’s National Hospital, Washington, DC, USA

    Shana S. Jacobs, Jeffrey S. Dome, Elena Postell & Catriona Mowbray

  2. George Washington University School of Medicine and Health Sciences, Washington, DC, USA

    Shana S. Jacobs, Jeffrey S. Dome & Pamela S. Hinds

  3. Biostatistics and Study Methodology Department, Children’s National Hospital, Washington, DC, USA

    Jiaxiang Gai

  4. Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD, USA

    Andrea M. Gross

  5. Department of Nursing Science, Professional Practice & Quality, Children’s National Hospital, Washington, DC, USA

    Pamela S. Hinds

  6. Division of Pathology and Lab Medicine, Molecular Diagnostics, Children’s National Hospital, Washington, DC, USA

    Lionel Davenport

  7. Division of Clinical Pharmacology, Children’s National Hospital, Washington, DC, USA

    John N. van den Anker

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  1. Shana S. Jacobs
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Contributions

Conceptualization: SJ, JD, CM, AG, PH, and JvdA. Methodology: CM, EP. Analysis and investigation: SJ, CM, JG. Writing original draft and preparation: SJ, CM, JG. Writing — review and editing: all authors.

Corresponding author

Correspondence to Shana S. Jacobs.

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Ethics approval

This study was approved by the Institutional Review Board at Children’s National Hospital.

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Parents (for children less than 18) or participants provided informed consent according to institutional guidelines. Patients 7 to 17 also provided assent.

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N/A

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The authors declare no competing interests.

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Jacobs, S.S., Dome, J.S., Gai, J. et al. Pharmacogenetic and clinical predictors of ondansetron failure in a diverse pediatric oncology population. Support Care Cancer 30, 3513–3520 (2022). https://doi.org/10.1007/s00520-022-06818-9

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  • DOI: https://doi.org/10.1007/s00520-022-06818-9

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