Measurable Residual Disease Detected by Multiparameter Flow Cytometry and Sequencing Improves Prediction of Relapse and Survival in Acute Myeloid Leukemia

Abstract

The clinically ideal time point and optimal approach for the assessment of measurable residual disease (MRD) in patients with acute myeloid leukemia (AML) are still inconclusive. We investigated the clinical value of multiparameter flow cytometry-based MRD (MFC MRD) after induction (n = 492) and two cycles of consolidation (n = 421). The latter time point was proved as a superior indicator with independent prognostic significance for both relapse-free survival (RFS, HR = 3.635, 95% CI: 2.433–5.431, P <0.001) and overall survival (OS: HR = 3.511, 95% CI: 2.191–5.626, P <0.001). Furthermore, several representative molecular MRD markers were compared with the MFC MRD. Both approaches can establish prognostic value in patients with NPM1 mutations, and FLT3, C-KIT, or N-RAS mutations involved in kinase-related signaling pathways, while the combination of both techniques further refined the risk stratification. The detection of RUNX1–RUNX1T1 fusion transcripts achieved a considerable net reclassification improvement in predicting the prognosis. Conversely, for patients with biallelic CEBPA or DNMT3A mutations, only the MFC method was recommended due to the poor prognostic discriminability in tracking mutant transcripts. In conclusion, this study demonstrated that the MFC MRD after two consolidation cycles independently predicted clinical outcomes, and the integration of MFC and molecular MRD should depend on different types of AML-related genetic lesions.

Measurable Residual Disease (MRD) by Flow Cytometry in Adult B-Acute Lymphoblastic Leukaemia (B-ALL) and Acute Myeloid Leukaemia (AML): Correlation with Molecular MRD Testing and Clinical Outcome at One Year

“…Statistical metrics of MRD analysis suggest that serial monitoring of MRD would be more relevant to clinical outcomes in both FC-MRD and Mol-MRD analyses, but despite this, not many FC-MRD studies have addressed this. [3] A study by Liu et al showed that sequential MRD monitoring had a greater prognostic impact compared with MRD values at specific timepoints [24]. A novel aspect of this study is that we describe five distinct FC-MRD patterns.…”

“…Previous work has demonstrated that MRD measurement is prognostic in favourable and intermediate-risk participants, while studies vary on the significance of adverse risk AML [22,24,45]. ELN stratification trended towards an association with FC-MRD patterns in AML.…”

“…These guidelines also underscore the importance of clinically validating MRD results. The current ELN guidelines propose a cutoff of 0.1% of CD45 + cells for AML MRD, supported by published data while acknowledging that lower levels of MRD, ranging from 0.01% to 0.1% CD45+ cells, may still hold clinical significance [5,14,24].…”

Monitoring of Measurable Residual Disease Using Circulating DNA after Allogeneic Hematopoietic Cell Transplantation

“…Early detection of MRD positivity after allo-HSCT prompts clinical decision making and eventually therapeutic intervention to control impending disease relapse. Several studies have shown the clinical utility of MRD detection in PBMCs or BMMCs [ 24 , 25 , 26 ]. However, few studies have investigated the usefulness of cfDNA for MRD detection after allo-HSCT [ 20 , 21 , 27 ].…”

MRD Monitoring by Multiparametric Flow Cytometry in AML: Is It Time to Incorporate Immune Parameters?

“…Regarding adult patients, in the study by Liu et al [ 22 ], MFC-MRD status after two consolidation cycles had greater accuracy in predicting relapse compared to MRD status after induction. This result was consistent for all different sub-groups (young vs. elderly patients, ELN cytogenetic low- or intermediate-risk patients).…”