Comprehensive Ara-C SNP score predicts leukemic cell intracellular ara-CTP levels in pediatric acute myeloid leukemia patients

Abdelrahman H. Elsayed, Xueyuan Cao, Kristine R. Crews, Varsha Gandhi, William Plunkett, Jeffrey E. Rubnitz, Raul C. Ribeiro, Stanley B. Pounds, Jatinder K. Lamba

Research output: Contribution to journalArticle

Abstract

Aim: Cytarabine (Ara-C), a mainstay of acute myeloid leukemia (AML) treatment, is a prodrug requiring activation to ara-CTP for its antileukemic activity. Aim of this study was to evaluate impact of genetic variants in the key genes involved in ara-C metabolism on the leukemic cell intracellular levels of ara-CTP. Method: We investigated SNPs in 14 ara-C metabolic-pathway genes, for association with intracellular ara-CTP levels, in leukemic cells obtained post-initiation of cytarabine infusion in pediatric AML patients (n = 68). Results: Nine SNPs were significantly associated with leukemic cell intracellular concentration of ara-CTP. A comprehensive ara-CTP-SNP-score (ACSS) was further developed from top four SNPs identified in regression model. Patients were classified into three groups based on ACSS: High-ACSS (score >0), intermediate-ACSS (score = 0) and low-ACSS (score <0). ACSS designation was significant predictor of intracellular ara-CTP levels (p = 0.00012), suggesting a cumulative or synergistic effect of the significant SNPs. Conclusion: ACSS score designation holds promise in definfing ara-C dose. Validation of the clinical utility of ACSS score in other independent cohorts will help identification of patients with potentially lower or higher levels of the ara-CTP in leukemic cells, thereby opening up opportunities for dose management to reduce toxicity and enhance efficacy.

Original languageEnglish (US)
Pages (from-to)1101-1110
Number of pages10
JournalPharmacogenomics
Volume19
Issue number14
DOIs
StatePublished - Jan 1 2018

Fingerprint

Arabinofuranosylcytosine Triphosphate
Cytarabine
Acute Myeloid Leukemia
Single Nucleotide Polymorphism
Pediatrics

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Genetics
  • Pharmacology

Cite this

Comprehensive Ara-C SNP score predicts leukemic cell intracellular ara-CTP levels in pediatric acute myeloid leukemia patients. / Elsayed, Abdelrahman H.; Cao, Xueyuan; Crews, Kristine R.; Gandhi, Varsha; Plunkett, William; Rubnitz, Jeffrey E.; Ribeiro, Raul C.; Pounds, Stanley B.; Lamba, Jatinder K.

In: Pharmacogenomics, Vol. 19, No. 14, 01.01.2018, p. 1101-1110.

Research output: Contribution to journalArticle

Elsayed, AH, Cao, X, Crews, KR, Gandhi, V, Plunkett, W, Rubnitz, JE, Ribeiro, RC, Pounds, SB & Lamba, JK 2018, 'Comprehensive Ara-C SNP score predicts leukemic cell intracellular ara-CTP levels in pediatric acute myeloid leukemia patients', Pharmacogenomics, vol. 19, no. 14, pp. 1101-1110. https://doi.org/10.2217/pgs-2018-0086
Elsayed, Abdelrahman H. ; Cao, Xueyuan ; Crews, Kristine R. ; Gandhi, Varsha ; Plunkett, William ; Rubnitz, Jeffrey E. ; Ribeiro, Raul C. ; Pounds, Stanley B. ; Lamba, Jatinder K. / Comprehensive Ara-C SNP score predicts leukemic cell intracellular ara-CTP levels in pediatric acute myeloid leukemia patients. In: Pharmacogenomics. 2018 ; Vol. 19, No. 14. pp. 1101-1110.
@article{56eebd18bedf48f78b88d819f4d33102,
title = "Comprehensive Ara-C SNP score predicts leukemic cell intracellular ara-CTP levels in pediatric acute myeloid leukemia patients",
abstract = "Aim: Cytarabine (Ara-C), a mainstay of acute myeloid leukemia (AML) treatment, is a prodrug requiring activation to ara-CTP for its antileukemic activity. Aim of this study was to evaluate impact of genetic variants in the key genes involved in ara-C metabolism on the leukemic cell intracellular levels of ara-CTP. Method: We investigated SNPs in 14 ara-C metabolic-pathway genes, for association with intracellular ara-CTP levels, in leukemic cells obtained post-initiation of cytarabine infusion in pediatric AML patients (n = 68). Results: Nine SNPs were significantly associated with leukemic cell intracellular concentration of ara-CTP. A comprehensive ara-CTP-SNP-score (ACSS) was further developed from top four SNPs identified in regression model. Patients were classified into three groups based on ACSS: High-ACSS (score >0), intermediate-ACSS (score = 0) and low-ACSS (score <0). ACSS designation was significant predictor of intracellular ara-CTP levels (p = 0.00012), suggesting a cumulative or synergistic effect of the significant SNPs. Conclusion: ACSS score designation holds promise in definfing ara-C dose. Validation of the clinical utility of ACSS score in other independent cohorts will help identification of patients with potentially lower or higher levels of the ara-CTP in leukemic cells, thereby opening up opportunities for dose management to reduce toxicity and enhance efficacy.",
author = "Elsayed, {Abdelrahman H.} and Xueyuan Cao and Crews, {Kristine R.} and Varsha Gandhi and William Plunkett and Rubnitz, {Jeffrey E.} and Ribeiro, {Raul C.} and Pounds, {Stanley B.} and Lamba, {Jatinder K.}",
year = "2018",
month = "1",
day = "1",
doi = "10.2217/pgs-2018-0086",
language = "English (US)",
volume = "19",
pages = "1101--1110",
journal = "Pharmacogenomics",
issn = "1462-2416",
publisher = "Future Medicine Ltd.",
number = "14",

}

TY - JOUR

T1 - Comprehensive Ara-C SNP score predicts leukemic cell intracellular ara-CTP levels in pediatric acute myeloid leukemia patients

AU - Elsayed, Abdelrahman H.

AU - Cao, Xueyuan

AU - Crews, Kristine R.

AU - Gandhi, Varsha

AU - Plunkett, William

AU - Rubnitz, Jeffrey E.

AU - Ribeiro, Raul C.

AU - Pounds, Stanley B.

AU - Lamba, Jatinder K.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Aim: Cytarabine (Ara-C), a mainstay of acute myeloid leukemia (AML) treatment, is a prodrug requiring activation to ara-CTP for its antileukemic activity. Aim of this study was to evaluate impact of genetic variants in the key genes involved in ara-C metabolism on the leukemic cell intracellular levels of ara-CTP. Method: We investigated SNPs in 14 ara-C metabolic-pathway genes, for association with intracellular ara-CTP levels, in leukemic cells obtained post-initiation of cytarabine infusion in pediatric AML patients (n = 68). Results: Nine SNPs were significantly associated with leukemic cell intracellular concentration of ara-CTP. A comprehensive ara-CTP-SNP-score (ACSS) was further developed from top four SNPs identified in regression model. Patients were classified into three groups based on ACSS: High-ACSS (score >0), intermediate-ACSS (score = 0) and low-ACSS (score <0). ACSS designation was significant predictor of intracellular ara-CTP levels (p = 0.00012), suggesting a cumulative or synergistic effect of the significant SNPs. Conclusion: ACSS score designation holds promise in definfing ara-C dose. Validation of the clinical utility of ACSS score in other independent cohorts will help identification of patients with potentially lower or higher levels of the ara-CTP in leukemic cells, thereby opening up opportunities for dose management to reduce toxicity and enhance efficacy.

AB - Aim: Cytarabine (Ara-C), a mainstay of acute myeloid leukemia (AML) treatment, is a prodrug requiring activation to ara-CTP for its antileukemic activity. Aim of this study was to evaluate impact of genetic variants in the key genes involved in ara-C metabolism on the leukemic cell intracellular levels of ara-CTP. Method: We investigated SNPs in 14 ara-C metabolic-pathway genes, for association with intracellular ara-CTP levels, in leukemic cells obtained post-initiation of cytarabine infusion in pediatric AML patients (n = 68). Results: Nine SNPs were significantly associated with leukemic cell intracellular concentration of ara-CTP. A comprehensive ara-CTP-SNP-score (ACSS) was further developed from top four SNPs identified in regression model. Patients were classified into three groups based on ACSS: High-ACSS (score >0), intermediate-ACSS (score = 0) and low-ACSS (score <0). ACSS designation was significant predictor of intracellular ara-CTP levels (p = 0.00012), suggesting a cumulative or synergistic effect of the significant SNPs. Conclusion: ACSS score designation holds promise in definfing ara-C dose. Validation of the clinical utility of ACSS score in other independent cohorts will help identification of patients with potentially lower or higher levels of the ara-CTP in leukemic cells, thereby opening up opportunities for dose management to reduce toxicity and enhance efficacy.

UR - http://www.scopus.com/inward/record.url?scp=85052968419&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85052968419&partnerID=8YFLogxK

U2 - 10.2217/pgs-2018-0086

DO - 10.2217/pgs-2018-0086

M3 - Article

VL - 19

SP - 1101

EP - 1110

JO - Pharmacogenomics

JF - Pharmacogenomics

SN - 1462-2416

IS - 14

ER -