Measurable Residual Disease in Pediatric Acute Leukemia: Application and Interpretation of Current and Emerging Methodologies

Measurable/minimal residual disease (MRD) monitoring is an essential component of modern treatment protocols for ALL and AML. Early response to therapy, as measured by MRD levels at defined time points during treatment, serves as an important prognostic indicator and enables risk-adapted stratification with intensification of treatment for patients with poor response while potentially reducing therapy-related toxicity in those demonstrating excellent clearance of leukemic cells. MRD assays must be highly sensitive and specific; multidimensional/parameter flow cytometry (MFC), quantitative polymerase chain reaction (qPCR), and next generation sequencing (NGS) are most used, while morphology is no longer the gold standard of response. MRD by MFC is used globally for risk and response in ALL and AML and is applicable to nearly 100% of patients with a sensitivity of 10 −4 . For ALL, immunoglobulin/T-cell receptor rearrangements detected by qPCR or NGS offer a nearly universal target applicable to more than 90% of patients with B-ALL and up to 70% of patients with T-ALL with a sensitivity of 10 −5 . For AML, molecular testing is more frequently implemented in Europe and Asia than in the United States; however, the utilization of qPCR and/or digital droplet PCR (dPCR) methodologies for high-risk fusions is evolving. NGS for somatic mutations are not yet routinely implemented for risk or response in pediatric AML, but continued advances in NGS technologies will continue to transform the MRD landscape of pediatric leukemias.