PT-021 - DNA METHYLATION PATTERNS OF ARA-C, DAUNORUBICIN, AND ETOPOSIDE PHARMACOKINETIC/PHARMACODYNAMIC GENES ARE ASSOCIATED WITH THE CLINICAL OUTCOMES IN AML.

N. Alshameri^1,2, F. Marchi³, J. K. Lamba⁴; ¹University of Florida, Gainesville, FL, USA, ²College of Pharmacy, University of Hail, Hail City,Hail Region, Saudi Arabia, ³Unversity of Florida, Gainesville, Fl, , ⁴University of Florida Health Cancer Center, Gainesville, FL, USA.

Background: Acute myeloid leukemia (AML) is major contributor to leukemia associated deaths in children and adults. Dysregulated epigenetic processes have been shown to have relevance in AML etiology and therapeutic outcomes. In adult and pediatric AML differential methylation patterns have been associated with risk groups and treatment outcome. However, impact of DNA methylation of genes involved in pharmacokinetic/pharmacodynamics (PK/PD) of standard chemotherapeutic agents as Ara-C, daunorubicin, and etoposide (ADE) have not been investigated for association with clinical outcomes in pediatric AML.

Methods: Patients treated on Children’s Oncology Group trials- AAML1031, AAML0531 and AAML03P1 (n= 924) with DNA methylation and outcome data available from GEO and GDC datasets were used as discovery cohort. DNA methylation data from Infinium Methylation EPIC and 450 BeadChips were processed using Sesame and batch corrected using COMBAT packages and evaluated for association with Event free survival (EFS) and overall survival (OS) using cox proportional hazard models. Kaplan–Meier method was used to prepare survival curves.

Results: Within 60 PK/PD genes we evaluated 1765 CpG sites. Of these, 23 were associated OS at p ≤0.04. For cg00174851 in aldoketo reductase gene, AKR1B1, hypermethylation was associated with improved OS (p=0.029, HR= 0.785). For drug efflux transporter, ABCA3, greater methylation of 7 CpGs showed consistent association with poor OS (HR= 1.57, p < 10−6 for the most significant CpG). Myeloperoxidase had 9 CpGs that showed consisted association with unfavorable OS (HR= 1.49, p< 10−10 for most significant CpG). For CTP synthase 1, CTPS1, a gene involved in cytarabine metabolic pathway cg08114812 was associated with OS (p= 0.04, HR= 1.18).

Conclusion: These results show association of the methylation of key PK/PD genes with outcome in pediatric AML, thereby suggesting that DNA methylation-based regulation of gene expression is one of the mechanisms contributing to variability in response. Ongoing work is focused on thorough assessment of methylation, its integration with respective gene-expression, and clinical outcome, in our discovery cohort. Additionally, validation of these results in an independent cohort of patients is ongoing and will be presented at the meeting.