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

SIMPLE SUMMARY: Measurable residual disease (MRD) is emerging as an important prognostic and predictive biomarker in acute myeloid leukemia (AML). However, its use is currently hampered by the disparity and lack of harmonization between the available MRD methodologies. In addition, the current assessment of MRD in AML focuses only on the quantification of the residual leukemic burden, without addressing the parallel alterations of the antineoplastic immune response that can critically affect the course and outcome of AML, often despite MRD persistence. Incorporating parameters of immune competence provides more consistency with the biological concept of MRD and may lead to higher accuracy. Multiparameter flow cytometry (MFC) is a highly efficacious and sensitive technology for the thorough and synchronous investigation of the kinetics of both antitumor immunity and the leukemic clone. MFC-based MRD provides the platform for the development of a composite leukemia- and immune-based biomarker which can outcompete the current MRD assessment. ABSTRACT: Acute myeloid leukemia (AML) is a heterogeneous group of clonal myeloid disorders characterized by intrinsic molecular variability. Pretreatment cytogenetic and mutational profiles only partially inform prognosis in AML, whereas relapse is driven by residual leukemic clones and mere morphological evaluation is insensitive for relapse prediction. Measurable residual disease (MRD), an independent post-diagnostic prognosticator, has recently been introduced by the European Leukemia Net as a new outcome definition. However, MRD techniques are not yet standardized, thus precluding its use as a surrogate endpoint for survival in clinical trials and MRD-guided strategies in real-life clinical practice. AML resistance and relapse involve a complex interplay between clonal and immune cells, which facilitates the evasion of the leukemic clone and which is not taken into account when merely quantifying the residual leukemia. Multiparameter flow cytometry (MFC) offers the possibility of capturing an overall picture of the above interactions at the single cell level and can simultaneously assess the competence of anticancer immune response and the levels of residual clonal cells. In this review, we focus on the current status of MFC-based MRD in diverse AML treatment settings and introduce a novel perspective of combined immune and leukemia cell profiling for MRD assessment in AML.