Clinical implications of sequential MRD monitoring by NGS at 2 time points after chemotherapy in patients with AML

Abstract

Next-generation sequencing (NGS) has been applied to measurable/minimal residual disease (MRD) monitoring after induction chemotherapy in patients with acute myeloid leukemia (AML), but the optimal time point for the test remains unclear. In this study, we aimed to investigate the clinical significance of NGS MRD at 2 different time points. We performed targeted NGS of 54 genes in bone marrow cells serially obtained at diagnosis, first complete remission (first time point), and after the first consolidation chemotherapy (second time point) from 335 de novo AML patients. Excluding DNMT3A, TET2, and ASXL1 mutations, which are commonly present in individuals with clonal hematopoiesis of indeterminate potential, MRD could be detected in 46.4% of patients at the first time point (MRD1st), and 28.9% at the second time point (MRD2nd). The patients with detectable NGS MRD at either time point had a significantly higher cumulative incidence of relapse and shorter relapse-free survival and overall survival. In multivariate analysis, MRD1st and MRD2nd were both independent poor prognostic factors. However, the patients with positive MRD1st but negative MRD2nd had a similar good prognosis as those with negative MRD at both time points. The incorporation of multiparameter flow cytometry and NGS MRD revealed that the presence of NGS MRD predicted poorer prognosis among the patients without detectable MRD by multiparameter flow cytometry at the second time point but not the first time point. In conclusion, the presence of NGS MRD, especially after the first consolidation therapy, can help predict the clinical outcome of AML patients.

How to Improve Prognostication in Acute Myeloid Leukemia with CBFB-MYH11 Fusion Transcript: Focus on the Role of Molecular Measurable Residual Disease (MRD) Monitoring

“…However, NGS data interpretation in MRD monitoring is actually complicated by incurring in some common mutations of any prognostic value but is associated with clonal hematopoiesis of indeterminate potential [69,70]. To note, recent studies have aimed to investigate the clinical relevance of NGS MRD detection, at different timepoints, finding the stronger prognostic impact of NGS MRD status after the first consolidation (2nd timepoint) than at first remission, which could help to identify patient candidates for more aggressive treatment, even when MRD is undetectable by MFC [71]. Indeed, MFC and NGS might be suggested to be used in combination in monitoring the disease, as also MFC and qRT-PCR, especially in the post-induction phase [72,73].…”

Targeted Therapies and Druggable Genetic Anomalies in Acute Myeloid Leukemia: From Diagnostic Tools to Therapeutic Interventions

“…Next-generation sequencing (NGS) as well as whole-genome sequencing (WGS) has been recently integrated into clinical practice, allowing for a better risk stratification of AML patients. In fact, the routine use of NGS methodology has made possible the identification of one or more somatic mutations in more than 90% of patients with AML [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. The most frequently mutated genes include NPM1 , FLT3 , DNMT3A , IDH1 , IDH2 , TET2 , RUNX1 , TP53 , WT1 , NRAS , and CEBPα .…”

“…These aberrations might help to identify AML pathways of clonal dominance and shifts that could assist hematologists in targeting precision medicine therapies [ 7 , 8 , 9 ].…”

“…Over the last few years, there has been an increasing understanding of molecular aberrations that trigger the development of AML, and an increase in the use of novel molecular biology technologies, thus facilitating the development of investigational drugs targeting driver genetic mutations [ 7 , 8 , 9 ]. Based on this consideration, it could be postulated that identifying “druggable” mutations paves the way for the use of novel targeted therapies [ 12 ].…”

“…The role of minimal residual disease detection for the sharper management of acute leukemia is also considered in this issue, provided that the authors include a clinical setting in which one or multiple druggable genetic lesions are presented [ 3 , 8 , 31 ].…”