Genetic Variants Associated With Vincristine‐Induced Peripheral Neuropathy in Two Populations of Children With Acute Lymphoblastic Leukemia

Li, Lang; Sajdyk, Tammy J.; Smith, Ellen M. Lavoie; Chang, Chun‐Wei; Li, Claire; Ho, Richard; Hutchinson, Raymond J.; Wells, Elizabeth; Skiles, Jodi; Winick, Naomi J.; Martin, Paul L.; Renbarger, Jamie L.

doi:10.1002/cpt.1324

Cited by 27 publications

(42 citation statements)

References 47 publications

(52 reference statements)

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“…ALL patient data collection. Children with newly diagnosed precursor B-cell ALL were recruited from four academic medical centers: Indiana University School of Medicine/Riley Hospital for Children, the University of Michigan Comprehensive Cancer Center/Mott Children's Hospital, Vanderbilt University Medical Center/ Monroe Carell Jr. Children's Hospital, and George Washington University/Children's National Medical Center 49 . Participants were between the ages of 1 and 18 at the time of diagnosis and received vincristine according to a Children's Oncology Group (COG) treatment trial for acute lymphoblastic leukemia.…”

Section: Methodsmentioning

confidence: 99%

A Metabolomics Approach for Early Prediction of Vincristine-Induced Peripheral Neuropathy

Verma

Devaraj

Skiles

et al. 2020

Sci Rep

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Vincristine is a core chemotherapeutic drug administered to pediatric acute lymphoblastic leukemia patients. Despite its efficacy in treating leukemia, it can lead to severe peripheral neuropathy in a subgroup of the patients. Peripheral neuropathy is a debilitating and painful side-effect that can severely impact an individual's quality of life. currently, there are no established predictors of peripheral neuropathy incidence during the early stage of chemotherapeutic treatment. As a result, patients who are not susceptible to peripheral neuropathy may receive sub-therapeutic treatment due to an empirical upper cap on the dose, while others may experience severe neuropathy at the same dose. contrary to previous genomics based approaches, we employed a metabolomics approach to identify small sets of metabolites that can be used to predict a patient's susceptibility to peripheral neuropathy at different time points during the treatment. Using those identified metabolites, we developed a novel strategy to predict peripheral neuropathy and subsequently adjust the vincristine dose accordingly. in accordance with this novel strategy, we created a free user-friendly tool, VIPNp, for physicians to easily implement our prediction strategy. our results showed that focusing on metabolites, which encompasses both genotypic and phenotypic variations, can enable early prediction of peripheral neuropathy in pediatric leukemia patients. Acute lymphoblastic leukemia (ALL) is the most common cancer among children, accounting for approximately 26% of all pediatric cancers in the USA 1. Although the 5-year survival rate of pediatric leukemia patients is as high as 86%, the side-effects of the treatment can severely impact the quality of life of survivors 2. In particular, vincristine, a core chemotherapeutic drug administrated as part of the ALL therapy that has been in use for more than 50 years, has a dose-limiting toxicity: peripheral neuropathy. Vincristine-induced peripheral neuropathy (VIPN) is characterized primarily by numbness, tingling, and a painful sensation felt in the hands and feet, muscle weakness, and constipation due to its effect on the sensory, motor, and autonomic nerves 3-5. In some instances, VIPN can be prolonged and may last even after discontinuation of the treatment, impairing patients' motor skills 6-9 which results in limitation of their daily life activities for many years after completion of therapy 10. While VIPN is severe in a subpopulation of patients, another subpopulation experiences negligible neuropathy. Currently, there are neither established ways of predicting susceptibility to VIPN in patients, nor ways to treat it effectively, resulting in a suboptimal management for both the cohorts. Predicting VIPN susceptibility in patients will enable better dosage decision making tools for physicians and in turn may improve the quality of life of these patients. Several researchers have studied the association between genomics and VIPN incidence; however, the majority of the results have been controve...

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Section: Methodsmentioning

confidence: 99%

A Metabolomics Approach for Early Prediction of Vincristine-Induced Peripheral Neuropathy

Verma

Devaraj

Skiles

et al. 2020

Sci Rep

Self Cite

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“…No association was found by Zgheib et al (2018) between VIPN and CEP72 (rs924607), Ewing's tumor-associated antigen 1 (ETAA1) (rs17032980) and Melatonin Receptor 1B (MTNR1B) (rs12786200). Li et al (2019) investigated two independent cohorts and used a meta-analysis to assess the association between multiple SNPs and VIPN. One SNP, rs1045644 (encoding for protein cochlin, which is associated with progressive hearing loss and vestibular imbalance), showed a protective effect against neuropathy, while rs7963521 (gene involved in angiogenesis) was associated with a higher risk of VIPN.…”

Section: Pharmacodynamics Stability Of Microtubules and Neurotoxicitmentioning

confidence: 99%

“… Li et al. (2019) investigated two independent cohorts and used a meta-analysis to assess the association between multiple SNPs and VIPN.…”

Section: Role Of Pharmacogenetic Variations In Chemotherapeutic Relatmentioning

confidence: 99%

Pharmacogenomics as a Tool to Limit Acute and Long-Term Adverse Effects of Chemotherapeutics: An Update in Pediatric Oncology

et al. 2020

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“…A recent GWAS study found no association between the CEP72 gene and VIPN [ 20 ]. This study was not included in our meta-analysis because genotyping data was not published.…”

Section: The Cep72 Gene Polymorphisms As Vipn Biommentioning

confidence: 99%

Centrosomal protein72 rs924607 and vincristine-induced Neuropathy in Pediatric Acute Lymphocytic Leukemia: meta-analysis

Zečkanović

Jazbec

2020

Future Sci. OA

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Aim: We examined the utility of the rs924607 TT genotype of the centrosomal protein 72 ( CEP72) as a potential biomarker for predilection toward vincristine-induced peripheral neuropathy in children treated for acute lymphoblastic leukemia. Materials & methods: We conducted a random-effects meta-analysis of data from four studies comprising 817 patients. We tested for an association using a recessive model where a one-sided p-value < 0.05 was considered statistically significant. Results and conclusion: We were unable to confirm the association between the rs924607 TT genotype and neurotoxicity (odds ratio: 1.99; p = 0.16; 95% CI: 0.76–5.25) in our global meta-analysis. Analysis of the continuation phase (following induction) studies showed significantly higher odds for neuropathy in CEP72 rs924607 TT homozygotes (odds ratio: 2.28; p = 0.02; 95% CI: 1.16–6.87).

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Genetic Variants Associated With Vincristine‐Induced Peripheral Neuropathy in Two Populations of Children With Acute Lymphoblastic Leukemia

Cited by 27 publications

References 47 publications

A Metabolomics Approach for Early Prediction of Vincristine-Induced Peripheral Neuropathy

A Metabolomics Approach for Early Prediction of Vincristine-Induced Peripheral Neuropathy

Pharmacogenomics as a Tool to Limit Acute and Long-Term Adverse Effects of Chemotherapeutics: An Update in Pediatric Oncology

Centrosomal protein72 rs924607 and vincristine-induced Neuropathy in Pediatric Acute Lymphocytic Leukemia: meta-analysis

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