Abdelrahman H Elsayed1, Xueyuan Cao2,3, Kristine R Crews4, Varsha Gandhi5, William Plunkett5, Jeffrey E Rubnitz6, Raul C Ribeiro6, Stanley B Pounds2, Jatinder K Lamba1. 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.
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 AMLpatients (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.
Authors: Amit K Mitra; Kristine R Crews; Stanley Pounds; Xueyuan Cao; Tanya Feldberg; Yogita Ghodke; Varsha Gandhi; William Plunkett; M Eileen Dolan; Christine Hartford; Susana Raimondi; Dario Campana; James Downing; Jeffrey E Rubnitz; Raul C Ribeiro; Jatinder K Lamba Journal: J Pharmacol Exp Ther Date: 2011-06-28 Impact factor: 4.030
Authors: A C Verschuur; J Brinkman; A H Van Gennip; R Leen; R J Vet; L M Evers; P A Voûte; A B Van Kuilenburg Journal: Leuk Res Date: 2001-10 Impact factor: 3.156
Authors: Ingrid Jakobsen Falk; Anna Fyrberg; Esbjörn Paul; Hareth Nahi; Monica Hermanson; Richard Rosenquist; Martin Höglund; Lars Palmqvist; Dick Stockelberg; Yuan Wei; Henrik Gréen; Kourosh Lotfi Journal: Am J Hematol Date: 2013-09-09 Impact factor: 10.047
Authors: Abdelrahman H Elsayed; Xueyuan Cao; Amit K Mitra; Huiyun Wu; Susana Raimondi; Christopher Cogle; Zeina Al-Mansour; Raul C Ribeiro; Alan Gamis; Edward Anders Kolb; Richard Aplenc; Todd A Alonzo; Soheil Meshinchi; Jeffrey Rubnitz; Stanley Pounds; Jatinder K Lamba Journal: J Clin Oncol Date: 2022-01-06 Impact factor: 50.717