Genetics, minimal residual disease help determine relapse risk in pediatric acute lymphoblastic leukemia

The use of a single threshold for determining minimal residual disease risk groups did not account for the response of different genetic subtypes among patients with pediatric acute lymphoblastic leukemia, according to findings published in Journal of Clinical Oncology.

Researchers recommended integrating genetics with minimal residual disease in identifying relapse risk.

“The assessment of treatment response via the measurement of minimal residual disease is now recognized as the most powerful prognostic factor in acute lymphoblastic leukemia,” Anthony V. Moorman, MD, professor of genetic epidemiology at Wolfson Childhood Cancer Research Centre in the U.K., and colleagues wrote.

Minimal residual disease monitoring has helped guide decision-making in therapy, the researchers added, but is not enough to fully predict outcomes.

“The extent to which the presence of specific genetic abnormalities influences the kinetics of disease clearance is not fully understood, and there is no consensus surrounding the best method of integrating genetic data and [minimal residual disease] data to stratify patients,” Moorman and colleagues wrote.

The researchers conducted a population-based cohort study of 3,113 patients with pediatric acute lymphoblastic leukemia. All patients participated in the UKALL2003 study, and were followed for a median of 7 years. Moorman and colleagues used polymerase chain reaction analysis of Ig/TCR gene rearrangements to evaluate minimal residual disease and assigned patients to genetic subtypes based on cytogenetics, immunophenotyped and fluorescence in situ hybridization. They also examined the kinetics of responses at the end of induction by log-transforming the absolute minimal residual disease value and examining distribution across all subgroups.

At the end of induction, minimal residual disease log was distributed normally; however, distribution among patients with distinct genetic subtypes appeared different (P < .001).

Patients who had cytogenetics indicating good risk had the fastest clearance of disease, whereas those with T-cell acute lymphoblastic leukemia and high-risk genetics showed slower responses.

Relapse risk was correlated with the kinetics of minimal residual disease, with each log reduction in disease level reducing risk for relapse by 20% (HR = 0.8; 95% CI, 0.77-0.83).

In each genetic subgroup, the risk for relapse appeared proportional to the minimal residual disease level. However, the absolute relapse associated with a specific category or minimal residual disease value appeared different across various genetic subtypes. Integrating subtype-specific minimal residual disease values refined the process of risk group stratification.

“This is an important study that provides new insights into the complex interplay between clinical risk factors, tumor genomics and minimal residual disease that is linked to relapse risk and outcome,” Stephen P. Hunger, chief of the division of oncology at Children’s Hospital of Philadelphia and professor of pediatrics at University of Pennsylvania, wrote in an accompanying editorial. “These results challenge cooperative groups to use minimal residual disease in a more sophisticated way than the typically dichotomous relationship of good or poor responders on the basis of one single threshold for all patients. To develop true precision medicine strategies for pediatric patients with acute lymphoblastic leukemia, we must accept this challenge and use integrated models in clinical trial design.” – by Andy Polhamus

Disclosures: Moorman reports no relevant financial disclosures. Please see the full study for a complete list of all other authors’ relevant financial disclosures. Hunger reports stock or ownership with Amgen, Express Scripts and Merck; honoraria from ERYTECH Pharma, Jazz Pharmaceuticals and Spectrum Pharmaceuticals; and a consulting or advisory role with Novartis.