Predicting EF Trajectory Phenotypes May Inform AML Treatment in Pediatric Patients

The accurate prediction of EF trajectory phenotypes may determine personalization of prognosis and treatment in a pediatric population with acute myeloid leukemia.

Predicting EF Trajectory Phenotypes May Inform AML Treatment in Pediatric Patients

Kelly D. Getz, PhD, MPH

New research suggests the accurate prediction of ejection fraction (EF) trajectory phenotypes may inform the personalization of prognosis and treatment for children with acute myeloid leukemia (AML).

The study’s group-based trajectory methods identified distinct EF trajectory phenotypes with differential event-free survival and overall survival for each group.

“Prediction models focused on trajectory-defined phenotypes may elucidate genomic and environmental determinants of anthracycline-associated cardiotoxicity more effectively than investigations of incident occurrence alone,” wrote study author Kelly D. Getz, PhD, MPH, Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania.

The findings were presented at the 2022 American Society of Hematology (ASH) Meeting in New Orleans.

Pediatric patients treated for AML receive high doses of anthracyclines that may cause substantial short- and long-term morbidity and mortality. As Getz and colleagues note, the knowledge of its natural history and impact on treatment outcomes is critical for care.

The prior evaluation of cardiotoxicity in pediatric AML focused on occurrence of incident declines below a left ventricular (LV) EF threshold. By broadening to longitudinal EF trajectories, it may provide a mechanism to better understand high-risk phenotypes, inform prognosis, and identify critical windows for intervention.

Thus between June 2011 and September 2018, the AAML1031 trial enrolled patients aged 30 years and younger with de novo AML. The treatment required echocardiographic evaluation before each treatment course, at the end of protocol therapy, and annually during off-protocol follow-up, where the resulting EF measures were collected.

A group-based trajectory model was utilized to identify latent subgroups with distinct patterns of longitudinal change in EF from baseline. The analyses were restricted to patients with a baseline measure of EF and at least two additional EF measures over the study period. Multivariable adjusted Cox regression compared event-free survival and overall survival for the identified EF trajectory groups.

A total of 1063 patients contributed a total of 7284 EF measurements (median, 6; IQR, 5 - 11 per person). In the final model, three distinct latent groups were identified including one linear and two cubic trajectories.

Data show 47% of patients were categorized into Group 1 (preserved EF), 47% into Group 2 (moderate persistent reduction in EF), and 6% into Group 3 (dramatic EF decline with incomplete recovery). The average posterior probabilities were reported as 0.87, 0.86, and 0.90 for Groups 1 - 3, respectively.

Further, the proportion of infants decreased from Group 1 to Group 3 (G1: 23%, G2: 16%, G3: 11%; P <.01). The third group had a higher proportion of Non-Hispanic Black patients (G1: 12%, G2: 11%, G3: 24%; P = .02) and a slightly higher proportion of females (G1: 49%, G2: 46%, G3: 58%; P = .17), compared to groups 1 and 2.

Dexrazocane use was less likely in groups 2 and 3 compared to group 1 (G1: 17%, G2: 7%, G3: 7%; P <.001). Investigators saw no significant differences in distributions of insurance, weight status, risk classification or treatment arm.

The event-free survival (G1: 48%, G2: 47%; P = .72) and overall survival (G1: 68%, G2: 64%; P = .22) were comparable between groups 1 and 2. Meanwhile, event-free survival (G1: 48%, G3: 30%; P = .003) and overall survival (G1: 68%, G3: 38%; P <.001) were significantly reduced.

Within analyses restricted to patients completing AAML1031 therapy, the investigator team identified comparable trajectories, but with higher average posterior probabilities (G1: 0.89, G2: 0.90, and G3: 0.94). These patients were noted to have more complete capture of LVEF measurements in the study database.

“Work is ongoing to identify supportive care practices that may modify distinct EF trajectory phenotypes,” Getz wrote.

The study, “Distinct Latent Trajectory Phenotype of Left Ventricular Function Associated with Differential Survival Among Children Treated for Acute Myeloid Leukemia: A Report from the Children’s Oncology Group,” was presented at ASH 2022.

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