ACS10- Cytarabine Pharmacogenomics Score Impacts Survival in Pediatric AML Patients Treated on AAML1031 Trial and Associates with Outcome Differences in Black AML Patients

Cytarabine (ara-C) has been used to treat acute myeloid leukemia (AML) for decades. While ara-C based regimens successfully induce remission in the majority of patients, significant number of patients experience relapse. Although advances in hematopoietic stem cell transplantation (HSCT) and supportive care regimens have improved over the years, it is imperative that personalized methods to optimize pharmacological intervention and improve outcomes are needed. To identify genetic predictors of ara-C response, we recently reported an ara-C pharmacogenomics score (ACS10) consisting of 10 SNPs in nine ara-C pathway genes (PMID: 34990262). In pediatric patients treated on AML02 and AAML0531 trials, low ACS10 score (0). Given these promising results, we sought to investigate the ACS10 score in a large cohort of children treated on Children's Oncology Group clinical trial AAML1031 (NCT01371981). AAML1031 trial enrolled 1,097 newly diagnosed patients from 0 to 29.5 years of age that received either conventional AML treatment (ara-C, daunorubicin and etoposide (ADE): arm A) or conventional treatment with the addition of bortezomib (ADE+bortezomib: arm B). Overall, no benefit for adding bortezomib was observed (PMID: 32029509). The current study included 717 patients with both DNA specimens and clinical outcome data available. ACS10 SNPs were genotyped using Taqman assays and ACS10 score was calculated for each patient as per previous report (PMID: 34990262). Overall, for the 717 patients included in this study, 249 patients had low ACS10score (< 0) and 468 patients had a high ACS10 score (>0). When combining patients treated on arm A and arm B, ACS10 score was not associated with overall survival (OS). However, patients with low ACS10 scores had poorer event-free survival (EFS) than those with high ACS10 scores, although this difference was not statistically significant (HR: 0.827, 95% CI (0.669-1.022), P=0.078). Patients with high ACS10 scores in arm A had improved EFS (HR: 0.689, 95% CI (0.50-0.94), P=0.023, Fig1), while OS did not show significant differences (P=0.378). Excluding the patients who received HSCT, showed increased EFS for patients with high ACS10 scores as compared to low ACS10 scores when treated with standard chemotherapy (HR: 0.628, 95% CI (0.445-0.887), P=0.008 Fig 1). In contrast, a significant difference was not observed within the standard ADE+bortezomib arm (ar