Abstract 4358: Single nucleotide polymorphisms located in PK/PD pathway genes of standard AML chemotherapy regimen predicts outcome in pediatric AML

Abstract Acute Myeloid Leukemia (AML) is an aggressive hematologic cancer with poor treatment outcomes in pediatric patients, particularly due to high relapse rates and drug resistance. Standard treatment involves cytarabine (Ara-C), daunorubicin, and etoposide (ADE) but resistance to these drugs remains a significant challenge. To better understand the genetic factors influencing drug resistance and treatment outcomes, we conducted a pharmacogenomic analysis of genetic variants in AML-related and drug-metabolizing genes within the context of (ADE) chemotherapy regimen. We extracted SNPs in genes involved in pharmacological pathways of ADE as well as genes representative of myeloid panel from an existing set of genome-wide Illumina 2.5 Omni microarray data obtained from genomic DNA of 400 patients treated on multi-site AML02 [NCT00136084, n=167] and AML08 [NCT00703820, n=233] clinical trials. SNPs within +/-10 kb region of the gene locus were evaluated for associations with multiple clinical endpoints such as minimal residual disease after induction 1 (MRD1), event-free survival (EFS), and overall survival (OS), adjusting for genetic ancestry. Our analysis results showed that at a p value of <0.01, 215 SNPs in 52 genes were predictive of at least one of the outcomes. SNPs in solute carrier (SLC) transporters, including SLC22A1, SLC28A1, and SLC28A3, were linked to increased MRD1 positivity, indicating poor prognosis. SLC28A1 and A3 have been implicated in uptake of nucleoside analogs such as Ara-C. In contrast, SNPs in SLCO1B1 were predictive of better EFS and OS, suggesting that variations in drug uptake influences treatment outcomes. Five SNPs within the cytidine deaminase (CDA), involved in inactivation of Ara-C were associated with poorer EFS and OS. These SNPs were linked to higher CDA mRNA expression in blood, as per the GTEx database, and showed regulatory potential in chromatin states. SNP rs1048977 has been associated with reduced CDA enzyme activity, further corroborating its role in poor treatment outcomes. Among the myeloid panel genes SNPs in the AML-related gene RUNX1, CSF3R and CDKN2A were associated with poor clinical outcomes. SNPs in CSF3R and CDKN2A genes were predictive of poor EFS and OS. RUNX1 is a critical factor for myeloid differentiation, CSF3R is involved in neutrophil biology and activates the JAK/STAT pathway, while CDKN2A functions as a tumor suppressor and regulates the cell cycle. Dual mutations in CSF3R and CEBPA have been linked to high relapse rates in pediatric AML. In conclusion, our comprehensive pharmacogenomic analysis of genes involved in drug metabolism and AML pathogenesis has identified key genetic variants that influence treatment outcomes. These findings, once validated in larger cohorts, could offer new opportunities for personalizing chemotherapy and improving prognosis prediction in pediatric AML patients. Citation Format: Aneesha Nath, Richard Marrero, Xueyuan Cao, Jeffrey E. Rubnitz, Stanley Pounds, Jatinder K. Lamba. Single nucleotide polymorphisms located in PK/PD pathway genes of standard AML chemotherapy regimen predicts outcome in pediatric AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4358.