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

Author:

Elsayed Abdelrahman H1,Cao Xueyuan23,Crews Kristine R4,Gandhi Varsha5,Plunkett William5,Rubnitz Jeffrey E6,Ribeiro Raul C6,Pounds Stanley B2,Lamba Jatinder K1

Affiliation:

1. Department of Pharmacotherapy & Translational Research, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA

2. Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN 38105, USA

3. Department of Acute & Tertiary Care, University of Tennessee Health Science Center, Memphis 38163, TN, USA

4. Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN 38105, USA

5. Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, TX 77054, USA

6. Department of Oncology, St Jude Children's Research Hospital, Memphis, TN 38105, USA

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.

Publisher

Future Medicine Ltd

Subject

Pharmacology,Genetics,Molecular Medicine

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