Utilizing the prognostic impact of minimal residual disease in treatment decisions for pediatric acute lymphoblastic leukemia

ABSTRACT

Introduction

Acute lymphoblastic leukemia (ALL) is the first pediatric cancer where the assessment of early response to therapy by minimal residual disease (MRD) monitoring has demonstrated its importance to improve risk-based treatment approaches. The most standardized tools to study MRD in ALL are multiparametric flow cytometry and realtime-quantitative polymerase chain reaction amplification-based methods. In recent years, MRD measurement has reached greater levels of sensitivity and standardization through international laboratory networks collaboration.

Areas covered

We herewith describe how to assess and apply the prognostic impact of MRD in treatment decisions, with specific focus on pediatric ALL. We also highlight the role of MRD monitoring in the context of genetically homogeneous subgroups of pediatric ALL. However, some queries remain to be addressed and emerging technologies hold the promise of improving MRD detection in ALL patients.

Expert opinion

Emerging technologies, like next generation flow cytometry, droplet digital PCR, and next generation sequencing appear to be important methods for assessing MRD in pediatric ALL. These more specific and/or sensitive MRD monitoring methods may help to predict relapse with greater accuracy, and are currently being used in clinical trials to improve pediatric ALL outcome by optimizing patient stratification and earlier MRD-based interventional therapy.

KEYWORDS:

• Acute lymphoblastic leukemia (all)
• pediatric
• prognostic factors
• minimal residual disease (mrd)

Article highlights

• MRD monitoring allows to refine the remission definition in childhood ALL.

• Several studies have found a clear link between MRD levels and outcome in children, supporting the hypothesis that measuring MRD after Induction chemotherapy provides a reliable indicator of leukemic blast drug sensitivity in vivo.

• MRD assessment has greatly improved risk-directed therapy, and it is now used to guide therapy decisions in major pediatric ALL clinical protocols.

• MRD has an impact in specific genetic subtypes

• Detection of MRD prior and after HSCT has been linked to an increased risk of relapse and poor survival in various clinical trials MFC and RQ-PCR are the most widely used consolidated approaches for MRD tracking in terms of technology, but they have inherent constraints that needs to be addressed.

• Novel techniques for evaluating MRD in ALL, such as next-generation flow cytometry, digital-droplet-PCR, and next-generation sequencing, are potentially useful tools because they have the ability to resolve the limitations of traditional methods. There is a need for a large-scale standardization in the future.

• More refined risk stratification is possible by combining MRD values at various time points based on leukemia genetic subtypes.

Acknowledgments

Data contained in this review were partially produced with support of the Italian Association for Cancer Research (GC: grants IG2015 number 17593), Comitato Maria Letizia Verga (GC and VC), Swiss Institute for Experimental Cancer Research-ISREC (FC).

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.