NGS-defined measurable residual disease (MRD) after initial chemotherapy as a prognostic biomarker for acute myeloid leukemia

Abstract

Treated AML patients often have measurable residual disease (MRD) due to persisting low-level clones. This study assessed whether residual post-treatment somatic mutations, detected by NGS, were significantly prognostic for subsequent clinical outcomes. AML patients (n = 128) underwent both pre-and post-treatment testing with the same 42-gene MRD-validated NGS assay. After induction, 59 (46%) patients were mutation-negative (0.0024 VAF detection limit) and 69 (54%) had ≥1 persisting NGS-detectable mutation. Compared with NGS-negative patients, NGS-positive patients had shorter overall survival (17 months versus median not reached; P = 0.004; hazard ratio = 2.2 [95% CI: 1.3–3.7]) and a shorter time to relapse (14 months versus median not reached; P = 0.014; HR = 1.9 [95% CI: 1.1–3.1]). Among 95 patients with a complete morphologic remission (CR), 43 (45%) were MRD-positive by NGS and 52 (55%) were MRD-negative. These MRD-positive CR patients had a shorter overall survival (16.8 months versus median not reached; P = 0.013; HR = 2.1 [95% CI: 1.2–3.9]) than did the MRD-negative CR patients. Post-treatment persisting MRD positivity, defined by the same NGS-based test used at diagnosis, is thus a more sensitive biomarker for low-level leukemic clones compared to traditional non-molecular methods and is prognostic of subsequent relapse and death.

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

“…Currently, validated, and standardized molecular MRD evaluation is limited to qPCR transcript determination in CBF translocations and type A, B and D NPM1 mutations [22]. NGS-based MRD assessment methods are evolving but are still not widely available and lack good standardization [28]. Standard amplicon-based or capture-based NGS techniques allow for detection of mutations at 3-5% VAF, making them not suitable for MRD monitoring.…”

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

“…Continued MRD positivity after treatment, as determined by the same NGS panel as employed during diagnosis, serves as a more sensitive biomarker for detecting persisting leukemic clones when compared with conventional non-molecular techniques. Furthermore, it has been proven to show prognostic value in predicting future relapse and mortality [ 49 , 50 ]. After the first consolidation therapy, MRD assessment by NGS was shown to predict relapse risk most accurately [ 51 ].…”

“…MRD monitoring using MFC after EOT is currently not recommended. NGS of mutations initially detected at diagnosis, during CR, or follow-up after EOT can be done to gain additional information on patients’ molecular remission status, while performing NGS alone cannot be advised for detection of MRD [ 5 , 49 , 50 ].…”

Minimal Residual Disease in Acute Myeloid Leukemia: Old and New Concepts

“…A good correlation between NGS-based MRD and flow-cytometry-based MRD has also been demonstrated by Patkar et al [93], with almost 80% concordance between the two techniques. Several studies have also shown that molecular MRD assessment using NGS is an independent predictor of relapse and survival [26,94,95]. For example, another study by Thol et al [96] showed that NGS-based MRD was applicable to all 96 patients in complete remission and that it was an independent predictor of relapse risk after undergoing stem cell transplantation (HR of 5.58 for NGSpositive MRD vs. NGS-negative MRD).…”