Increased risk of vincristine neurotoxicity associated with low CYP3A5 expression genotype in children with acute lymphoblastic leukemia

Akinbode Egbelakin, Michael J. Ferguson, Emily A. MacGill, Amalia S. Lehmann, Ariel R. Topletz, Sara Quinney, Lang Li, Kevin C. McCammack, Stephen D. Hall, Jamie Renbarger

Research output: Contribution to journalArticle

100 Citations (Scopus)

Abstract

Background: This study evaluates the relationship between cytochrome P450 (CYP) 3A5 genotype and vincristine-induced peripheral neuropathy (VIPN) in children with precursor B cell acute lymphoblastic leukemia (preB ALL). We have shown in vitro that vincristine is metabolized significantly more efficiently by CYP3A5 than by CYP3A4. We also found that vincristine neurotoxicity is less common in African-Americans (70% express CYP3A5) than in Caucasians. We test the hypothesis that CYP3A5 expressers experience less vincristine neuropathy than do CYP3A5 non-expressers.Procedure: This study of pharmacogenetics of vincristine neuropathy in children with preB ALL was completed at Indiana University Simon Cancer Center. Whole blood for DNA extraction and genotyping was collected as well as plasma from a single time-point for analysis of vincristine and primary metabolite (M1) concentrations. Vincristine neuropathy was captured via chart review and graded per the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0.Results: Eighty-nine percent of CYP3A5 expressers experienced neurotoxicity versus 100% of non-expressers (P = 0.03). The proportion of treatment months with neurotoxicity was significantly different between the expressers and non-expressers (16% vs. 27%, P = 0.0007). Limited pharmacokinetic data suggest different rates of vincristine metabolism between CYP3A5 genotype groups with higher primary metabolite (M1) plasma concentrations (P = 0.0004) and lower metabolic ratios ([vincristine]/[M1]) (P = 0.036) in the CYP3A5 expressers compared to the CYP3A5 non-expressers. M1 concentration was also inversely related to severity of neuropathy (P = 0.0316).Conclusions: In children with preB ALL, CYP3A5 expressers experience less VIPN, produce more M1, and have lower metabolic ratios compared to CYP3A5 non-expressers.

Original languageEnglish
Pages (from-to)361-367
Number of pages7
JournalPediatric Blood and Cancer
Volume56
Issue number3
DOIs
StatePublished - Mar 2011

Fingerprint

Cytochrome P-450 CYP3A
Vincristine
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Genotype
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
Peripheral Nervous System Diseases
National Cancer Institute (U.S.)
Terminology
African Americans

Keywords

  • Acute lymphoblastic leukemia
  • Peripheral neuropathy
  • Pharmacogenetics
  • Vincristine

ASJC Scopus subject areas

  • Oncology
  • Pediatrics, Perinatology, and Child Health
  • Hematology

Cite this

Increased risk of vincristine neurotoxicity associated with low CYP3A5 expression genotype in children with acute lymphoblastic leukemia. / Egbelakin, Akinbode; Ferguson, Michael J.; MacGill, Emily A.; Lehmann, Amalia S.; Topletz, Ariel R.; Quinney, Sara; Li, Lang; McCammack, Kevin C.; Hall, Stephen D.; Renbarger, Jamie.

In: Pediatric Blood and Cancer, Vol. 56, No. 3, 03.2011, p. 361-367.

Research output: Contribution to journalArticle

Egbelakin, Akinbode ; Ferguson, Michael J. ; MacGill, Emily A. ; Lehmann, Amalia S. ; Topletz, Ariel R. ; Quinney, Sara ; Li, Lang ; McCammack, Kevin C. ; Hall, Stephen D. ; Renbarger, Jamie. / Increased risk of vincristine neurotoxicity associated with low CYP3A5 expression genotype in children with acute lymphoblastic leukemia. In: Pediatric Blood and Cancer. 2011 ; Vol. 56, No. 3. pp. 361-367.
@article{1f21ef4c019d4bb8b4b25b484f6bbdc8,
title = "Increased risk of vincristine neurotoxicity associated with low CYP3A5 expression genotype in children with acute lymphoblastic leukemia",
abstract = "Background: This study evaluates the relationship between cytochrome P450 (CYP) 3A5 genotype and vincristine-induced peripheral neuropathy (VIPN) in children with precursor B cell acute lymphoblastic leukemia (preB ALL). We have shown in vitro that vincristine is metabolized significantly more efficiently by CYP3A5 than by CYP3A4. We also found that vincristine neurotoxicity is less common in African-Americans (70{\%} express CYP3A5) than in Caucasians. We test the hypothesis that CYP3A5 expressers experience less vincristine neuropathy than do CYP3A5 non-expressers.Procedure: This study of pharmacogenetics of vincristine neuropathy in children with preB ALL was completed at Indiana University Simon Cancer Center. Whole blood for DNA extraction and genotyping was collected as well as plasma from a single time-point for analysis of vincristine and primary metabolite (M1) concentrations. Vincristine neuropathy was captured via chart review and graded per the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0.Results: Eighty-nine percent of CYP3A5 expressers experienced neurotoxicity versus 100{\%} of non-expressers (P = 0.03). The proportion of treatment months with neurotoxicity was significantly different between the expressers and non-expressers (16{\%} vs. 27{\%}, P = 0.0007). Limited pharmacokinetic data suggest different rates of vincristine metabolism between CYP3A5 genotype groups with higher primary metabolite (M1) plasma concentrations (P = 0.0004) and lower metabolic ratios ([vincristine]/[M1]) (P = 0.036) in the CYP3A5 expressers compared to the CYP3A5 non-expressers. M1 concentration was also inversely related to severity of neuropathy (P = 0.0316).Conclusions: In children with preB ALL, CYP3A5 expressers experience less VIPN, produce more M1, and have lower metabolic ratios compared to CYP3A5 non-expressers.",
keywords = "Acute lymphoblastic leukemia, Peripheral neuropathy, Pharmacogenetics, Vincristine",
author = "Akinbode Egbelakin and Ferguson, {Michael J.} and MacGill, {Emily A.} and Lehmann, {Amalia S.} and Topletz, {Ariel R.} and Sara Quinney and Lang Li and McCammack, {Kevin C.} and Hall, {Stephen D.} and Jamie Renbarger",
year = "2011",
month = "3",
doi = "10.1002/pbc.22845",
language = "English",
volume = "56",
pages = "361--367",
journal = "Pediatric Blood and Cancer",
issn = "1545-5009",
publisher = "Wiley-Liss Inc.",
number = "3",

}

TY - JOUR

T1 - Increased risk of vincristine neurotoxicity associated with low CYP3A5 expression genotype in children with acute lymphoblastic leukemia

AU - Egbelakin, Akinbode

AU - Ferguson, Michael J.

AU - MacGill, Emily A.

AU - Lehmann, Amalia S.

AU - Topletz, Ariel R.

AU - Quinney, Sara

AU - Li, Lang

AU - McCammack, Kevin C.

AU - Hall, Stephen D.

AU - Renbarger, Jamie

PY - 2011/3

Y1 - 2011/3

N2 - Background: This study evaluates the relationship between cytochrome P450 (CYP) 3A5 genotype and vincristine-induced peripheral neuropathy (VIPN) in children with precursor B cell acute lymphoblastic leukemia (preB ALL). We have shown in vitro that vincristine is metabolized significantly more efficiently by CYP3A5 than by CYP3A4. We also found that vincristine neurotoxicity is less common in African-Americans (70% express CYP3A5) than in Caucasians. We test the hypothesis that CYP3A5 expressers experience less vincristine neuropathy than do CYP3A5 non-expressers.Procedure: This study of pharmacogenetics of vincristine neuropathy in children with preB ALL was completed at Indiana University Simon Cancer Center. Whole blood for DNA extraction and genotyping was collected as well as plasma from a single time-point for analysis of vincristine and primary metabolite (M1) concentrations. Vincristine neuropathy was captured via chart review and graded per the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0.Results: Eighty-nine percent of CYP3A5 expressers experienced neurotoxicity versus 100% of non-expressers (P = 0.03). The proportion of treatment months with neurotoxicity was significantly different between the expressers and non-expressers (16% vs. 27%, P = 0.0007). Limited pharmacokinetic data suggest different rates of vincristine metabolism between CYP3A5 genotype groups with higher primary metabolite (M1) plasma concentrations (P = 0.0004) and lower metabolic ratios ([vincristine]/[M1]) (P = 0.036) in the CYP3A5 expressers compared to the CYP3A5 non-expressers. M1 concentration was also inversely related to severity of neuropathy (P = 0.0316).Conclusions: In children with preB ALL, CYP3A5 expressers experience less VIPN, produce more M1, and have lower metabolic ratios compared to CYP3A5 non-expressers.

AB - Background: This study evaluates the relationship between cytochrome P450 (CYP) 3A5 genotype and vincristine-induced peripheral neuropathy (VIPN) in children with precursor B cell acute lymphoblastic leukemia (preB ALL). We have shown in vitro that vincristine is metabolized significantly more efficiently by CYP3A5 than by CYP3A4. We also found that vincristine neurotoxicity is less common in African-Americans (70% express CYP3A5) than in Caucasians. We test the hypothesis that CYP3A5 expressers experience less vincristine neuropathy than do CYP3A5 non-expressers.Procedure: This study of pharmacogenetics of vincristine neuropathy in children with preB ALL was completed at Indiana University Simon Cancer Center. Whole blood for DNA extraction and genotyping was collected as well as plasma from a single time-point for analysis of vincristine and primary metabolite (M1) concentrations. Vincristine neuropathy was captured via chart review and graded per the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0.Results: Eighty-nine percent of CYP3A5 expressers experienced neurotoxicity versus 100% of non-expressers (P = 0.03). The proportion of treatment months with neurotoxicity was significantly different between the expressers and non-expressers (16% vs. 27%, P = 0.0007). Limited pharmacokinetic data suggest different rates of vincristine metabolism between CYP3A5 genotype groups with higher primary metabolite (M1) plasma concentrations (P = 0.0004) and lower metabolic ratios ([vincristine]/[M1]) (P = 0.036) in the CYP3A5 expressers compared to the CYP3A5 non-expressers. M1 concentration was also inversely related to severity of neuropathy (P = 0.0316).Conclusions: In children with preB ALL, CYP3A5 expressers experience less VIPN, produce more M1, and have lower metabolic ratios compared to CYP3A5 non-expressers.

KW - Acute lymphoblastic leukemia

KW - Peripheral neuropathy

KW - Pharmacogenetics

KW - Vincristine

UR - http://www.scopus.com/inward/record.url?scp=78651110078&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78651110078&partnerID=8YFLogxK

U2 - 10.1002/pbc.22845

DO - 10.1002/pbc.22845

M3 - Article

VL - 56

SP - 361

EP - 367

JO - Pediatric Blood and Cancer

JF - Pediatric Blood and Cancer

SN - 1545-5009

IS - 3

ER -