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

Abstract

Minimal residual disease (MRD) is of major importance in onco-hematology, particularly in acute myeloid leukemia (AML). MRD measures the amount of leukemia cells remaining in a patient after treatment, and is an essential tool for disease monitoring, relapse prognosis, and guiding treatment decisions. Patients with a negative MRD tend to have superior disease-free and overall survival rates. Considerable effort has been made to standardize MRD practices. A variety of techniques, including flow cytometry and molecular methods, are used to assess MRD, each with distinct strengths and weaknesses. MRD is recognized not only as a predictive biomarker, but also as a prognostic tool and marker of treatment efficacy. Expected advances in MRD assessment encompass molecular techniques such as NGS and digital PCR, as well as optimization strategies such as unsupervised flow cytometry analysis and leukemic stem cell monitoring. At present, there is no perfect method for measuring MRD, and significant advances are expected in the future to fully integrate MRD assessment into the management of AML patients.

Keywords: AML; FlowSOM; LAIP; MRD; NGS; PCR; flow cytometry.

Figure 1

MRD principle. (1) AML at diagnosis. (2) Residual leukemic cells in cytologic remission after chemotherapy. (3) Relapse of AML in cytologic remission. (4) Cytological relapse of AML. Created with BioRender.com (accessed on 15 November 2023).

Figure 2

Summary of current methods for MRD monitoring. MFC: multicolor flow cytometry, qPCR: quantitative PCR, NGS: next-generation sequencing, dPCR: digital PCR, CHIP: clonal hematopoiesis of indeterminate potential. Created with BioRender.com. (accessed on 15 November 2023).

Figure 3

Schematic representation of MFC strategies for investigating AML MRD. Markers enable differentiation by MFC of the stem/progenitor/mature compartments of normal hematopoiesis, as well as “purple,” “blue,” and “green” phenotypic profiles (A). Additionally, they help determine normal differentiation pathways (red arrow, (B)). Leukemic blasts are distinguished by the expression of aberrant markers, which can be heterogeneous within an AML, schematized by a majority “green” LAIP and a minority “red” LAIP (C). The DfN strategy encompasses the portion of leukemic cells that phenotypically deviate from normal differentiation pathways (D). It can be observed that neither of these two strategies is perfect for the detection of MRD: (i) the “green” LAIP phenotype already exists in a subpopulation of hematopoietic progenitors, reduced under normal conditions (A) but increased under conditions of post-chemotherapy hematopoietic recovery (E), limiting the sensitivity threshold of this LAIP; (ii) the interpretation of DfN is linked to knowledge of the modifications of hematopoiesis under conditions of recovery (green arrow, (F)). The LAIP of relapsed blasts is modified in 90% of cases (here, relapse on a “red” LAIP profile, near-total disappearance of the “green” LAIP, and emergence of an “orange” LAIP, (G)). Relapse remains detectable using the DfN strategy (H).