Effect of race on vincristine-associated neurotoxicity in pediatric acute lymphoblastic leukemia patients

Jamie Renbarger, Kevin C. McCammack, Caroline E. Rouse, Stephen D. Hall

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

Background. This report examines the association between race and vincristine-associated neurotoxicity in pediatric patients with precursor B cell acute lymphoblastic leukemia (preB ALL). Given that in vitro vincristine is metabolized more efficiently by cytochrome P450 (CYP) 3A5 than by CYP3A4 and that 70% African-Americans (vs. 20% of Caucasians) express CYP3A5, one may hypothesize that African-Americans metabolize vincristine more efficiently resulting in lower vincristine exposure and associated-toxicity. Procedure. A retrospective analysis of vincristine-related side effects in pediatric patients treated for preB ALL was performed. Data were compared between Caucasians (n = 92) and African-Americans (n = 21) to examine the relationship between race and vincristine-associated neurotoxicity thus using race as a surrogate for CYP3A5 genotype. Race, age, gender, disease subtype, highest grade of vincristine-associated neurotoxicity (per NIH Common Terminology Criteria for Adverse Events version 3.0), number of omitted and reduced vincristine doses, cumulative vincristine dose, and disease outcome were captured. Results. 34.8% of Caucasians experienced symptoms consistent with vincristine-related neurotoxicity compared to 4.8% of African-Americans (P = 0.007). The average grade of neurotoxicity for Caucasians was 2.72 versus grade 1 neurotoxicity in the African-American (P < 0.0001). Four percent of total doses administered to Caucasian patients were reduced due to vincristine-related neurotoxicity compared to 0.1% given to African-Americans (P < 0.0001). 1.2% of all protocol-indicated doses for Caucasians were held due to severe vincristine-associated toxicity compared to 0.1% of doses for African-Americans (P < 0.01). Conclusions. The data support the hypothesis pharmacogenetic polymorphisms in CYP3A5 expression contribute to variability in vincristine metabolism and neurotoxicity.

Original languageEnglish
Pages (from-to)769-771
Number of pages3
JournalPediatric Blood and Cancer
Volume50
Issue number4
DOIs
StatePublished - Apr 2008

Fingerprint

Vincristine
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Pediatrics
African Americans
Cytochrome P-450 CYP3A
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
Pharmacogenetics
Terminology
Genotype

Keywords

  • Acute lymphoblastic leukemia
  • Neurotoxicity
  • Pharmacology
  • Vincristine

ASJC Scopus subject areas

  • Cancer Research
  • Pediatrics, Perinatology, and Child Health
  • Hematology

Cite this

Effect of race on vincristine-associated neurotoxicity in pediatric acute lymphoblastic leukemia patients. / Renbarger, Jamie; McCammack, Kevin C.; Rouse, Caroline E.; Hall, Stephen D.

In: Pediatric Blood and Cancer, Vol. 50, No. 4, 04.2008, p. 769-771.

Research output: Contribution to journalArticle

Renbarger, Jamie ; McCammack, Kevin C. ; Rouse, Caroline E. ; Hall, Stephen D. / Effect of race on vincristine-associated neurotoxicity in pediatric acute lymphoblastic leukemia patients. In: Pediatric Blood and Cancer. 2008 ; Vol. 50, No. 4. pp. 769-771.
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abstract = "Background. This report examines the association between race and vincristine-associated neurotoxicity in pediatric patients with precursor B cell acute lymphoblastic leukemia (preB ALL). Given that in vitro vincristine is metabolized more efficiently by cytochrome P450 (CYP) 3A5 than by CYP3A4 and that 70{\%} African-Americans (vs. 20{\%} of Caucasians) express CYP3A5, one may hypothesize that African-Americans metabolize vincristine more efficiently resulting in lower vincristine exposure and associated-toxicity. Procedure. A retrospective analysis of vincristine-related side effects in pediatric patients treated for preB ALL was performed. Data were compared between Caucasians (n = 92) and African-Americans (n = 21) to examine the relationship between race and vincristine-associated neurotoxicity thus using race as a surrogate for CYP3A5 genotype. Race, age, gender, disease subtype, highest grade of vincristine-associated neurotoxicity (per NIH Common Terminology Criteria for Adverse Events version 3.0), number of omitted and reduced vincristine doses, cumulative vincristine dose, and disease outcome were captured. Results. 34.8{\%} of Caucasians experienced symptoms consistent with vincristine-related neurotoxicity compared to 4.8{\%} of African-Americans (P = 0.007). The average grade of neurotoxicity for Caucasians was 2.72 versus grade 1 neurotoxicity in the African-American (P < 0.0001). Four percent of total doses administered to Caucasian patients were reduced due to vincristine-related neurotoxicity compared to 0.1{\%} given to African-Americans (P < 0.0001). 1.2{\%} of all protocol-indicated doses for Caucasians were held due to severe vincristine-associated toxicity compared to 0.1{\%} of doses for African-Americans (P < 0.01). Conclusions. The data support the hypothesis pharmacogenetic polymorphisms in CYP3A5 expression contribute to variability in vincristine metabolism and neurotoxicity.",
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N2 - Background. This report examines the association between race and vincristine-associated neurotoxicity in pediatric patients with precursor B cell acute lymphoblastic leukemia (preB ALL). Given that in vitro vincristine is metabolized more efficiently by cytochrome P450 (CYP) 3A5 than by CYP3A4 and that 70% African-Americans (vs. 20% of Caucasians) express CYP3A5, one may hypothesize that African-Americans metabolize vincristine more efficiently resulting in lower vincristine exposure and associated-toxicity. Procedure. A retrospective analysis of vincristine-related side effects in pediatric patients treated for preB ALL was performed. Data were compared between Caucasians (n = 92) and African-Americans (n = 21) to examine the relationship between race and vincristine-associated neurotoxicity thus using race as a surrogate for CYP3A5 genotype. Race, age, gender, disease subtype, highest grade of vincristine-associated neurotoxicity (per NIH Common Terminology Criteria for Adverse Events version 3.0), number of omitted and reduced vincristine doses, cumulative vincristine dose, and disease outcome were captured. Results. 34.8% of Caucasians experienced symptoms consistent with vincristine-related neurotoxicity compared to 4.8% of African-Americans (P = 0.007). The average grade of neurotoxicity for Caucasians was 2.72 versus grade 1 neurotoxicity in the African-American (P < 0.0001). Four percent of total doses administered to Caucasian patients were reduced due to vincristine-related neurotoxicity compared to 0.1% given to African-Americans (P < 0.0001). 1.2% of all protocol-indicated doses for Caucasians were held due to severe vincristine-associated toxicity compared to 0.1% of doses for African-Americans (P < 0.01). Conclusions. The data support the hypothesis pharmacogenetic polymorphisms in CYP3A5 expression contribute to variability in vincristine metabolism and neurotoxicity.

AB - Background. This report examines the association between race and vincristine-associated neurotoxicity in pediatric patients with precursor B cell acute lymphoblastic leukemia (preB ALL). Given that in vitro vincristine is metabolized more efficiently by cytochrome P450 (CYP) 3A5 than by CYP3A4 and that 70% African-Americans (vs. 20% of Caucasians) express CYP3A5, one may hypothesize that African-Americans metabolize vincristine more efficiently resulting in lower vincristine exposure and associated-toxicity. Procedure. A retrospective analysis of vincristine-related side effects in pediatric patients treated for preB ALL was performed. Data were compared between Caucasians (n = 92) and African-Americans (n = 21) to examine the relationship between race and vincristine-associated neurotoxicity thus using race as a surrogate for CYP3A5 genotype. Race, age, gender, disease subtype, highest grade of vincristine-associated neurotoxicity (per NIH Common Terminology Criteria for Adverse Events version 3.0), number of omitted and reduced vincristine doses, cumulative vincristine dose, and disease outcome were captured. Results. 34.8% of Caucasians experienced symptoms consistent with vincristine-related neurotoxicity compared to 4.8% of African-Americans (P = 0.007). The average grade of neurotoxicity for Caucasians was 2.72 versus grade 1 neurotoxicity in the African-American (P < 0.0001). Four percent of total doses administered to Caucasian patients were reduced due to vincristine-related neurotoxicity compared to 0.1% given to African-Americans (P < 0.0001). 1.2% of all protocol-indicated doses for Caucasians were held due to severe vincristine-associated toxicity compared to 0.1% of doses for African-Americans (P < 0.01). Conclusions. The data support the hypothesis pharmacogenetic polymorphisms in CYP3A5 expression contribute to variability in vincristine metabolism and neurotoxicity.

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