MRD in AML: The Role of New Techniques

Abstract

In the context of precision medicine, assessment of minimal residual disease (MRD) has been used in acute myeloid leukemia (AML) to direct individual treatment programs, including allogeneic stem cell transplantation in patients at high-risk of relapse. One of the limits of this approach has been in the past the paucity of AML markers suitable for MRD assessment. Recently, the number of biomarkers has increased, due to the identification of highly specific leukemia-associated immunophenotypes by multicolor flow-cytometry, and of rare mutated gene sequences by digital droplet PCR, or next-generation sequencing (NGS). In addition, NGS allowed unraveling of clonal heterogeneity, present in AML at initial diagnosis or developing during treatment, which influences reliability of specific biomarkers, that may be unstable during the disease course. The technological advances have increased the application of MRD-based strategies to a significantly higher number of AML patients, and the information deriving from MRD assessment has been used to design individual post-remission protocols and pre-emptive treatments in patients with sub-clinical relapse. This led to the definition of MRD-negative complete remission as outcome definition in the recently published European Leukemianet MRD guidelines. In this review, we summarized the principles of modern technologies and their clinical applications for MRD detection in AML patients, according to the specific leukemic markers.

Secondary Acute Myeloid Leukemia and the Role of Allogeneic Stem Cell Transplantation in a Population-Based Setting

“…Additional methods with even higher sensitivity, e.g. digital droplet PCR and NGS, are likely to be used in the future [142]. MRD usage depends on the clinical situation, but is especially useful to guide HCT in low-risk patients with detectable MRD in CR1, to refrain HCT in intermediate-risk patients with low risk of relapse, to identify patients with elevated relapse risk post-HCT and to monitor patients after treatment [17].…”

Pharmacologic Therapies to Prevent Relapse of Acute Myeloid Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation

“…Currently, the most widely applied strategy for molecular MRD monitoring is real-time quantitative PCR (RQ-PCR) which can detect mutated genes, fusion gene transcripts or overexpressed genes and can detect leukemic cells at 10 −6 sensitivity (42,43). PCR based methods are characterized by high specificity and sensitivity for leukemic cells detection and low risk of contamination; however, their use depends on identifying pretreatment AML-associated mutation at diagnosis and these molecular targets must be stable while on therapy (52,53). For instance, some mutations like NPM1 mutation, RUNX1-RUNX1T1 and CBF-MYH11 in core binding factor (CBF) AML are relatively stable during disease course hereby are suitable for PCR MRD monitoring (12).…”

Is There Still a Role for Autologous Stem Cell Transplantation for the Treatment of Acute Myeloid Leukemia?

“…Finally, it is mandatory to use standardized techniques, apply rigorous bioinformatic analyses and define specific time-points, developed in the context of laboratory networks. In this regard, the ELN MRD Working Group is currently aiming to improve and harmonize methodologies for NGS-based detection of MRD in AML [46,47].…”