Flow-Cytometric Monitoring of Minimal Residual Disease in Pediatric Patients With Acute Myeloid Leukemia: Recent Advances and Future Strategies

Barbara Buldini,Elena Varotto,Michael N Dworzak,Margarita Maurer-Granofszky

doi:10.3389/fped.2019.00412

Barbara Buldini, Elena Varotto + Show 2 more

Open Access

https://doi.org/10.3389/fped.2019.00412

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Abstract

Minimal residual disease (MRD) by multiparametric flow cytometry (MFC) has been recently shown as a strong and independent prognostic marker of relapse in pediatric AML (pedAML) when measured at specific time points during Induction and/or Consolidation therapy. Hence, MFC-MRD has the potential to refine the current strategies of pedAML risk stratification, traditionally based on the cytogenetic and molecular genetic aberrations at diagnosis. Consequently, it may guide the modulation of therapy intensity and clinical decision making. However, the use of non-standardized protocols, including different staining panels, analysis, and gating strategies, may hamper a broad implementation of MFC-MRD monitoring in clinical routine. Besides, the thresholds of MRD positivity still need to be validated in large, prospective and multi-center clinical studies, as well as optimal time points of MRD assessment during therapy, to better discriminate patients with different prognosis. In the present review, we summarize the most relevant findings on MFC-MRD testing in pedAML. We examine the clinical significance of MFC-MRD and the recent advances in its standardization, including innovative approaches with an automated analysis of MFC-MRD data. We also touch upon other technologies for MRD assessment in AML, such as quantitative genomic breakpoint PCR, current challenges and future strategies to enable full incorporation of MFC-MRD into clinical practice.

Highlights

Pediatric acute myeloid leukemia is a heterogeneous group of hematological malignancies classified according to morphology, immunophenotyping, and genomics [1]
This review focuses on the most relevant findings on MFCMRD in Pediatric acute myeloid leukemia (pedAML) and examines recent advances and new approaches for its standardization, including novel concepts for automated analysis of multiparametric flow cytometry (MFC)-Minimal residual disease (MRD) data
Regardless, the AML-BFM study published in 2006 did not find any significant role of MFC-MRD based on a standardized panel for four-color immunophenotyping in outcome prediction when compared to other known risk factors

Summary

INTRODUCTION

Pediatric acute myeloid leukemia (pedAML) is a heterogeneous group of hematological malignancies classified according to morphology, immunophenotyping, and genomics [1]. Regardless, the AML-BFM study published in 2006 did not find any significant role of MFC-MRD based on a standardized panel for four-color immunophenotyping in outcome prediction when compared to other known risk factors. Several national and international networks have been established to optimize and standardize MFC-MRD detection and quantification [46,47,48,49,50,51] In this context, the European Leukemia Network recently published an extensive consensus document [52] on MFC-MRD measurement in adult AML with recommendations for common approaches including definition of time-points, thresholds, technical requirements, marker panels, and results reporting [32]. Several approaches for automated MFC data analysis have been proposed [57,58,59,60,61,62,63,64] to overcome this bottleneck by (i) providing a superior resolution compared to conventional manual gating with the whole multi-parameter MFC data space at once (instead of 2-D plot-based visualization), (ii)

1–16 De novo

Findings

CONCLUSIONS