Minimal residual disease in acute myelogenous leukemia

Abstract

Treatment of acute myelogenous leukemia (AML) over the past four decades remains mostly unchanged and the prognosis for the majority of patients remains poor. Most of the significant advances that have been observed are in defining cytogenetic abnormalities, as well as the genetic and epigenetic profiles of AML patients. While new cytogenetic and genetic aberrations such as the FLT3-ITD and NPM1 mutations are able to guide prognosis for the majority of patients with AML, outcomes are still dismal and relapse rates remain high. It is thought that relapse in AML is in part driven by minimal residual disease (MRD) that remains in the patient following treatment. Thus, there is a need for sensitive and objective methodology for MRD detection. Methodologies such as multiparameter flow cytometry (MFC), quantitative real-time polymerase chain reaction (RQ-PCR), digital PCR (dPCR), or next-generation sequencing (NGS) are being employed to evaluate their utility in MRD assessment. In this review, we will provide an overview of AML and the clinical utility of MRD measurement. We will discuss optimal timing to MRD measurement, the different approaches that are available, and efforts in the standardization across laboratories.

Clinical impact of the loss of chromosome 7q on outcomes of patients with myelodysplastic syndromes treated with allogeneic hematopoietic stem cell transplantation

“…Thus, the monitoring of minimal residual disease may be helpful for -7/del(7q) using novel molecular-based approaches (e.g. a digital polymerase chain reaction [PCR] method and next-generation sequencing), multiparameter flow cytometry, and WT1 expression levels with PCR [36][37][38]. These approaches may help to employ and optimize post-transplant therapy, such as the introduction of DNA hypomethylating agents, other compounds, and donor lymphocyte infusion as pre-emptive strategies to prevent the future relapse of MDS [39][40][41][42][43][44][45].…”

Challenges in the introduction of next-generation sequencing (NGS) for diagnostics of myeloid malignancies into clinical routine use

“…Most AML patients show more than one molecular marker 4 . However, MRD detection is limited by the background noise of NGS 94 , 95 . Already known mutations are re-identifiable at best at a variant allele fraction as low as 1%.…”

Measurable residual disease testing for personalized treatment of acute myeloid leukemia

“…Combinations of cell surface biomarkers form the basis or detection of residual AML with MFC, whereas quantification of RNA transcripts can be performed in APL with PML-RARA fusions, CBF leukemias with RUNX1-RUNX1T1 or CBFB-MYH11 fusions and NPM1-mutated AML for higher sensitivity (6). DNA can also serve as a highly sensitive residual molecular biomarker in NPM1-mutated AML and AMLs with other specific mutations (53)(54)(55)(56)(57)(65)(66)(67)(68).…”

“…With the knowledge of the mutational content of an AML determined by NGS (e.g., panel sequencing, whole exome or whole‐genome sequencing), mutations can also be chosen for follow‐up by ddPCR. This method is currently not used in a routine setting, but provides a promising way for sensitive, specific, and personalized molecular characterization with the possibility to monitor several mutations simultaneously, suitable for MRD assessment .…”