By allowing chemotherapy regimens to be personalized, a genetic score holds promise for improving treatment results in patients with acute myeloid leukemia (AML) who have traditionally had poor outcomes, UF Health researchers have found.
The score could be used to identify patients more likely to have worse outcomes and optimize their treatment, according to the study of a large group of pediatric, adolescent and young adult patients with AML. The study was published on June 23 in JAMA Network Open.
“We showed the application of the score in one of the largest pediatric trials led by the Children’s Oncology Group and in adolescent and young adult patients treated across several trials led by Alliance,” said senior author Jatinder Lamba, Ph.D., a professor and dean in the UF College of Pharmacy and co-leader of the UF Health Cancer Center’s Cancer Targeting and Therapeutics research program. “Our results show the score is predictive of the outcome independent of the age groups, broadening its application.”
AML is the second most common form of childhood leukemia and is among childhood cancers with the worst outlook. Because the chemotherapy drugs used to treat AML are activated inside the body, a person’s genes can affect drug activation and treatment response. The multi-gene score, known as ACS10, combines 10 genetic factors into a single metric.
In the new study, researchers expanded on past findings about the score’s clinical potential. They analyzed data from a multicenter clinical trial led by the Children’s Oncology Group involving 717 pediatric, adolescent and young adult patients and a trial led by the Alliance for Clinical Trials in Oncology with 406 adolescent and young adult patients.
Participants in the Children’s Oncology Group trial were randomized into two arms: standard chemotherapy alone or standard chemotherapy with the addition of the anti-cancer drug bortezomib. Participants in the Alliance for Clinical Trials in Oncology trial were similarly treated with intensive firstline chemotherapy.
Researchers evaluated ACS10 scores for their association with outcome according to race, treatment arm and whether patients received a stem cell transplant.
Black patients with AML have historically had worse outcomes than white patients, although the reasons for this remain poorly understood. In the new study, a low ACS10 score, which was more abundant in Black patients than white patients, was associated with worse survival in pediatric, adolescent and young adult patients treated with standard chemotherapy. Moreover, this difference could be lessened by enhancing therapy, such as adding bortezomib.
Overall, these results, along with previous work from Lamba’s group, show the clinical utility of ACS10 not only in predicting poor outcomes in AML patients with low scores, but also in providing an opportunity to personalize induction regimens with augmentation options. The significant abundance of the low score in Black patients provides options to mitigate differences in outcome by augmenting induction regimens in the low-score group.
Next, researchers plan to test the score’s clinical validity through a clinical trial. That would support using it to guide treatment decisions based on an individual’s genetic profile.
Richard Marrero, Pharm.D., Ph.D., a recent graduate from Lamba’s lab, and Vivek Shastri, Ph.D., a research assistant professor in Lamba’s lab, were co-first authors on the study, which included investigators from children’s hospitals across the country.
Lamba and co-author Stanley Pounds, Ph.D., of St. Jude Children’s Research Hospital, have a patent pending on the ACS10 score. Lamba also has two other patents pending related to pharmacogenomics discoveries in AML. The group is building an app with St. Jude investigators to allow for rapid clinical translation of the score for its prognostic and predictive applications.
The study received funding from the National Cancer Institute, American Cancer Society, The Leukemia & Lymphoma Society, St. Baldrick’s Foundation, UF Opportunity seed funding and UF Health Cancer Center, which receives crucial support for its research from the Casey DeSantis Cancer Research Act (Fla. Stat. § 381.915).
