Minimal Residual Disease Detection in Pediatric Acute Lymphoblastic Leukemia

Abstract

Minimal residual disease (MRD) status is the strongest independent prognostic factor for patients with pediatric acute lymphoblastic leukemia (ALL). Monitoring of the MRD status allows risk-adapted therapy as its absence or presence guides patient therapy and can result in significant treatment reduction or intensification, respectively. MRD assays should be sensitive (exceeding a threshold of 10−4 per current guidelines), specific, widely applicable, rapid, and technically feasible. Classical MRD assays that are widely used in pediatric ALL include multiparameter flow cytometry (MFC), which identifies aberrant immunophenotypes, and real-time quantitative polymerase chain reaction (RQ-PCR), which detects fusion transcripts or clonal immunoglobulin/ T-cell receptor (IG/TCR) gene rearrangements. These assays have sensitivities of 10−3 to 10−5 and have been standardized internationally. However, each assay has its own pitfalls such as false negatives caused by immunophenotypic shifts in MFC, relatively limited applicability of the fusion transcript PCR, and the technical complexity associated with designing PCR for quantifying clonal IG/TCR gene rearrangements using allele-specific oligonucleotides. Next-generation flow cytometry, next-generation sequencing, and droplet digital PCR are expected to replace classical MRD assays, given their higher sensitivities (10−5 to 10−6) and accuracies as well as greater technical feasibilities. Before their incorporation into the standard practice for care for children with ALL, these assays require further exploration to ascertain whether their higher sensitivities are clinically relevant. Furthermore, standardization and quality assurance programs should be devised to enhance the clinical adoption of these new assays. Lastly, new targets should be identified to improve the monitoring of MRD; moreover, both the methodology and clinical significance of MRD evaluation should be revisited in the era of immunotherapy.

Keywords

• leukemia
• acute lymphoblastic
• pediatric
• minimal residual disease