A polygenic cytarabine response score identified young patients with acute myeloid leukemia (AML) who might benefit from augmented therapy, according to research published in the Journal of Clinical Oncology.

The study showed that patients with a low score had significantly worse outcomes when treated with standard cytarabine, daunorubicin, and etoposide (ADE) induction. For patients with a low score, augmenting ADE with either high-dose cytarabine (HDAC) or gemtuzumab ozogamicin (GO) improved event-free survival (EFS) and overall survival (OS).

The score consists of 10 single nucleotide polymorphisms (SNPs) in cytarabine pathway genes that have been tied to patient outcomes and cytarabine triphosphate levels. The researchers tested the 10-SNP score, called “ACS10,” in discovery and validation cohorts.


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The discovery cohort consisted of patients from the AML02 trial (ClinicalTrials.gov Identifier: NCT00136084). All 166 pediatric and adolescent/young adult (AYA) patients analyzed received ADE as a first course of chemotherapy. There were 91 patients who received ADE with standard low-dose cytarabine (LDAC) and 75 who received ADE augmented with HDAC.

The validation cohort consisted of patients from the AAML0531 trial (ClinicalTrials.gov Identifier: NCT00372593). Of the 931 pediatric and AYA patients evaluated, 465 received standard ADE, and 466 received ADE augmented with GO.

Results

A low ACS10 score (≤0) was significantly associated with poor outcomes on the standard treatment arms of AML02 (LDAC arm) and AAML0531 (ADE-alone arm).

In the standard LDAC arm of AML02, patients with a low ACS10 score had significantly worse EFS (hazard ratio [HR], 2.81; 95% CI, 1.45-5.43; P =.002) and OS (HR, 2.98; 95% CI, 1.32-6.75; P =.009) than patients with a higher ACS10 score (>0).

Likewise, in the standard ADE arm of AAML0531, patients with a low ACS10 score had worse EFS (HR, 1.35; 95% CI, 1.04-1.75, P =.026) and OS (HR, 1.64; 95% CI, 1.2-2.22, P =.002) than patients with a higher ACS10 score.

In both trials, augmented therapy was associated with an improvement in 5-year EFS among patients with a low ACS10 score. However, the improvement was only significant in the AAML0531 trial.

In the AML02 trial, the 5-year EFS for patients with a low score was 42.1% in the LDAC arm and 54.8% in the HDAC arm (HR, 1.39; 95% CI, 0.71-2.72; P =.337). In the AAML0531 trial, the 5-year EFS for patients with a low score was 40.9% in the standard ADE arm and 50.1% in the ADE-GO arm (HR, 1.39; 95% CI, 1.04-1.87; P =.027).

Similarly, patients with a low ACS10 score had an improvement in 5-year OS with augmented therapy. Again, the improvement was only significant in the AAML0531 trial.

In the AML02 trial, the 5-year OS for patients with a low score was 57.9% in the LDAC arm and 63.4% in the HDAC arm (HR, 1.19; 95% CI, 0.55-2.57; P =.651). In the AAML0531 trial, the 5-year OS for patients with a low score was 53% with standard ADE and 62.8% with ADE-GO (HR, 1.52; 95% CI, 1.08-2.14; P =.016).

Overall, these results suggest the ACS10 score “can identify patients with unfavorable pharmacogenetic characteristics and offers a potential for an elective augmented therapy option,” the researchers concluded.

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

Reference

Elsayed AH, Cao  X, Mitra AK, et al. Polygenic ara-C response score identifies pediatric patients with acute myeloid leukemia in need of chemotherapy augmentation. J Clin Oncol. Published online January 6, 2022. doi:10.1200/JCO.21.01422