In a study reported in the Journal of Clinical Oncology, Elsayed et al developed a risk score based on single nucleotide polymorphisms (SNPs) associated with cytarabine pharmacodynamics or clinical outcomes that identified pediatric patients with acute myeloid leukemia (AML) who could benefit from augmented chemotherapy.
Study Details
In the study, SNPs in cytarabine pathway genes were analyzed for association with clinical outcomes in 116 patients in the St. Jude AML02 trial, in which 91 patients received standard low-dose cytarabine and 75 received augmented high-dose cytarabine. The top SNPs predictive of measurable residual disease and event-free survival in this cohort were combined with four SNPs previously associated with cytarabine triphosphate levels in another trial (AML97) to form the 10-SNP Ara-C_SNP score (ACS10). For each SNP, each genotype was assigned a point value of –2, –1, 0, +1, or +2, with total scores for each patient being dichotomized as low (≤ 0) or high (> 0).
ACS10 was then evaluated in the low-dose and high-dose groups of the AML02 cohort and in the standard cytarabine, daunorubicin, and etoposide (ADE) group (n = 465) and augmented ADE plus gemtuzumab ozogamicin groups (ADE + GO, n = 466) of the Children’s Oncology Group AAML0531 trial.
Key Findings
In the standard low-dose cytarabine group of the AML02 cohort, the low ACS10 score group had significantly poorer event-free survival (hazard ratio [HR] = 2.81, 95% confidence interval [CI] = 1.45–5.43, P = .002) and overall survival (HR = 2.98, 95% CI = 1.32–6.75, P = .009) compared with the high ACS10 score group.
In the standard ADE group of the AAML0531 cohort, patients with a low ASC10 score had poorer event-free survival (HR = 1.35, 95% CI = 1.04–1.75, P = .026) and overall survival (HR = 1.64, 95% CI = 1.2–2.22, P = .002) compared to those with a high ASC10 score.
In the augmented chemotherapy groups, no significant differences in event-free or overall survival were observed between low vs high ACS10 scores in the AML02 high-dose cytarabine group (HRs = 1.28, 95% CI = 0.63–2.61, P = .49; and 1.56, 95% CI = 0.68–3.6, P = .298) or the AAML0531 ADE + GO group (HRs = 1.06, 95% CI = 0.81–1.39, P = .67; and 1.05, 95% CI = 0.76–1.45, P = .758).
In both the AML02 and AAML0531 cohorts, patients with a low ACS10 score consistently exhibited a 10% improvement in 5-year event-free survival with augmented chemotherapy vs standard therapy.
The investigators concluded, “Patients with a low ACS10 score experienced significantly poor outcome when treated on standard regimen. Augmentation with either high-dose [cytarabine] or GO addition improved outcomes in the low ACS10 group. A polygenic ACS10 score can identify patients with unfavorable pharmacogenetic characteristics and offers a potential for an elective augmented therapy option.”
Jatinder K. Lamba, PhD, of the Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by the National Institutes of Health, American Cancer Society, St. Baldrick’s Foundation, and others. For full disclosures of the study authors, visit ascopubs.org.
