Impact of Cytarabine Pharmacogenomics on Survival of Adolescent and Young Adults with AML and Its Clinical Relevance in Black Patients

Cytarabine (also known as ara-C) has been the mainstay of AML chemotherapy for both pediatric and adult patients (pts) since 1970s, and when given in combination with anthracycline it induces remission in ~60% of adult and 80% of pediatric pts. However, almost ~40% of pts relapse. Cytarabine is a prodrug requiring activation to ara-CTP for its antileukemic effect. Our group has been investigating the relevance of cytarabine pharmacogenomics and recently reported a pharmacogenomics-based polygenic score (ACS10) that includes 10 SNPs spanning 9 genes within metabolic pathway of cytarabine. ACS10 is predictive of intracellular levels of ara-CTP as well as outcome in pediatric AML pts enrolled in multiple clinical trials led by St Jude Children's Research Hospital and Children's Oncology Group (Elsayed et al, JCO 2022;40:772-3). Overall, pediatric AML pts with ACS10 low (≤0), had inferior outcomes compared with ACS10 high pts. Thus far, the ACS10 score has not been tested for its performance in adult AML, especially adolescent and young adult (AYA) AML pts. We hypothesized that ACS10 might be predictive of chemotherapy resistance in this defined pt population that is commonly treated with intensive induction therapy. Moreover, as several SNPs included in ACS10 show ancestry-enrichments, we speculated whether this might help explain the high resistance to treatment recently observed in Black AYA AML pts. A total of 406 newly diagnosed AYA AML pts (age 17-39y, median: 30y), similarly treated in 8 Alliance for Clinical Trials in Oncology frontline protocols were included in the study. All pts had centrally reviewed cytogenetics, targeted gene mutation profiling and SNP data (Illumina 2.5 omni array, see Walker et al, Leukemia 2019;33:771-5). ACS10 score was calculated for each pt using the equation defined by Elsayed et al (>0, ACS10 high; ≤0, ACS10 low) and Kaplan-Meier method and the log-rank test was used for survival analysis and Fisher's exact test was used for frequency comparison. Two hundred eighty-three pts were ACS10 high and 123 pts were ACS10 low. Though not statistically significant, ACS10 low pts tended to have a shorter overall survival (OS) compared with ACS10 high pts (p=.11). Restricting the analysis to those who received chemotherapy only (excluding allogeneic transplant recipients), showed that ACS10 low group had significantly shorter OS compared with ACS10 high group (p=.03). Further, event-free survival (EFS) was shorter (3y rates, 32% vs.