Polygenic Score May Offer Personalized Treatment Options for Pediatric AML

Pediatric patients with acute myeloid leukemia (AML) may benefit from a more personalized treatment approach using the 10-SNP Ara-C_SNP score (ACS10), according to study findings published in the Journal of Clinical Oncology.

Data from the AML02 (NCT00136084) AAML0531 (NCT00372593) trials were used to develop and verify the patient-specific polygenic score, allowing investigators to predict which patients with AML would experience response to treatment with standard cytarabine (ara-C)–containing regimens and who would benefit from treatment augmentation with either high-dose ara-C or the addition of gemtuzumab ozogamicin (GO).

Using genotypes for the 10 most informative single-nucleotide polymorphisms, investigators were able to assign each patient a 10-SNP Ara-C_SNP score to help predict who may have poor outcomes and also examine alternative treatment strategies.

“This score predicts outcome in response to cytarabine-containing chemotherapy and further use of the score in patients can help us make decisions on therapy augmentation by either intensifying chemotherapy or adding additional antileukemic agents in patients who are classified as having a detrimental low polygenic score,” study investigator Jatinder K. Lamba, PhD, professor in the Department of Pharmacotherapy and Translational Research, University of Florida, said in an interview with CancerNetwork®.

The AML02 cohort was used in the discovery process and AAML0531 served as the validation cohort. Primary end points included positive minimal residual disease at the end of induction therapy, complete remission, event-free survival (EFS), and overall survival (OS).

The derived polygenic score, known as ACS10, was evaluated for association with outcomes in each of the clinical trial arms: the standard low-dose ara-C (LDAC) and augmented high-dose ara-C (HDAC) arms of AML02 and the standard ara-C, daunorubicin, and etoposide (ADE) and the augmented ADE plus gemtuzumab ozogamicin (GO) arms of the AAML0531 trial.

Investigators found that the low ACS10 score group in the standard LDAC arm of AML02 had significantly worse EFS (HR, 2.81; 95% CI, 1.45-5.43; P = .002) and OS (HR, 2.98; 95% CI, 1.32-6.75; P = .009) compared with the high ACS10 score group. The standard ADE arm of AAML0531 validated these results showing poor outcome in the low ACS10 group compared with the high ACS10 group for both 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). EFS and OS within the augmented arms of HDAC in AML02 and ADE plus GO in AAML0531 did not differ between low and high ACS10 score groups.

In both arms, patients with low ACS10 consistently showed a 10-percentage point improvement in the 5-year EFS rate with augmented vs standard therapy, investigators said.

On the AAML0531 clinical trial, the 5-year EFS rate for patients with low ACS10 was 40.9% (95% CI, 33.6%-49.7%) with standard ADE and 50.1% (95% CI, 43.2%-58.0%) with augmented ADE plus GO. On the AML02 clinical trial, the 5-year EFS rate for low ACS10 was 42.1% (95% CI, 29.0%-61.6%) with standard LDAC therapy and 54.8% (95% CI, 39.8%-75.5%) with augmented HDAC therapy.

In addition, a low ACS10 score resulted in a 5-year OS rate of 53% (95% CI, 45.4%-61.8%) with standard ADE therapy and 62.8% (95% CI, 55.9%-70.6%) with augmented ADE plus GO on AAML0531. On the AML02 trial, there was a 5-year OS rate of 57.9% (95% CI, 44.1%-75.9%) with standard LDAC therapy and 63.4% (95% CI, 48.3%-83.2%) with augmented HDAC therapy in patients with low ACS10.

“We have known for decades that genetics impacts how we respond to therapy and can have significant impact clinically,” Lamba said. “The field of pharmacogenomics have made so much progress that now the FDA has added genomic marker information in drug labels…It was only a matter of time for us to find which genetic variations hold potential relevance in acute myeloid leukemia chemotherapy and to figure out a way to develop a score based on the most informative genetic variants to allow for accelerated clinical translation.”

However, investigators noted that the study size limited their ability to analyze results by ethnicity or risk groups. They found a greater number of low ACS10 scores in Black compared with White patients in both the AML02 and AAML0531 arms.

“Historically, it has been observed that Black patients have poor outcome as compared with White patients with AML, and we observed the detrimental score to be more abundant in Black patients. This warrants further evaluation to see if the polygenic score is a major contributor to the observed differences,” Lamba said. “If so, a next step will be to see if polygenic score–informed therapy modifications can improve outcome.”

Overall, the polygenic score may help identify patients with unfavorable pharmacogenetic characteristics as well as warrant further testing to determine whether those within the low ACS10 score groups may benefit from augmentation with other existing or newly approved agents, such as clofarabine, glasdegib (Daurismo), and venetoclax (Venclexta), investigators concluded.

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. 2022;40(7):772-783. doi:10.1200/JCO.21.01422