Measurable Residual Disease (MRD) as a Surrogate Efficacy-Response Biomarker in AML

Abstract

In acute myeloid leukemia (AML) many patients experience relapse, despite the achievement of morphological complete remission; therefore, conventional morphologic criteria are currently considered inadequate for assessing the quality of the response after treatment. Quantification of measurable residual disease (MRD) has been established as a strong prognostic marker in AML and patients that test MRD negative have lower relapse rates and better survival than those who test positive. Different techniques, varying in their sensitivity and applicability to patients, are available for the measurement of MRD and their use as a guide for selecting the most optimal post-remission therapy is an area of active investigation. Although still controversial, MRD prognostic value promises to support drug development serving as a surrogate biomarker, potentially useful for accelerating the regulatory approval of new agents. In this review, we will critically examine the methods used to detect MRD and its potential role as a study endpoint.

Measurable Residual Disease Detection in Acute Myeloid Leukemia: Current Challenges and Future Directions

“…International collaborative efforts to compare and standardize MRD measurement methods are currently under way and their results will be crucial in fortifying the clinical utility of MRD. Of note, the FDA recently accepted the achievement of an MRD lower than 0.01% in the BM as evidence for the efficacy of new drugs administered in relapsed or refractory AML patients [ 128 ]. Eventually, the advancements of MRD detection in AML may enable physicians to tailor personalized therapy with the goal of achieving and sustaining an MRD-negative complete remission while minimizing treatment toxicity in the majority of patients.…”

Standardization of Molecular MRD Levels in AML Using an Integral Vector Bearing ABL and the Mutation of Interest

“…Response assessment by regular flow cytometry with a cut-off of 5% blasts is limited by its ability to detect a low level of disease, which would translate to a high rate of relapse. MRD evaluation either by flow cytometry [2] or by mutation-based analysis [3] has proved a powerful tool in the post remission induction period to evaluate deep anti-leukemia therapy efficacy, detection of early relapse, consolidation assignment (e.g., selection of transplant vs. no-transplant strategy as well as conditioning intensity), and as surrogate end-point in clinical trials [4][5][6][7][8]. Data clearly show that patients who achieve MRD negativity have a significantly longer progression free survival (PFS) and overall survival (OS) [9].…”

“…Techniques for molecular monitoring of MRD such as quantitative PCR for both gDNA and RNA targets, digital droplet PCR for known hotspots in gDNA and next generation sequencing (NGS) MRD monitoring are evolving; however, they have still not been widely accepted [7,14,15]. Quantitative PCR (qPCR) KITs for routine diagnostics and MRD followup of fusion oncogenes expression and DNA point mutation/deletion/insertions are widely available and contain a serial of plasmid standards for quantification.…”