2021 Update on MRD in acute myeloid leukemia: a consensus document from the European LeukemiaNet MRD Working Party

Abstract

Measurable residual disease (MRD) is an important biomarker in acute myeloid leukemia (AML) that is used for prognostic, predictive, monitoring, and efficacy-response assessments. The European LeukemiaNet (ELN) MRD Working Party evaluated standardization and harmonization of MRD in an ongoing manner and has updated the 2018 ELN MRD recommendations based on significant developments in the field. New and revised recommendations were established during in-person and online meetings, and a 2-stage Delphi poll was conducted to optimize consensus. All recommendations are graded by levels of evidence and agreement. Major changes include technical specifications for next-generation sequencing-based MRD testing and integrative assessments of MRD irrespective of technology. Other topics include use of MRD as a prognostic and surrogate end point for drug testing; selection of the technique, material, and appropriate time points for MRD assessment; and clinical implications of MRD assessment. In addition to technical recommendations for flow- and molecular-MRD analysis, we provide MRD thresholds and define MRD response, and detail how MRD results should be reported and combined if several techniques are used. MRD assessment in AML is complex and clinically relevant, and standardized approaches to application, interpretation, technical conduct, and reporting are of critical importance.

Figure 1.

MRD assessment algorithm for different subtypes of AML. *For NPM1 and CBF AML, PB may be used for MRD assessment at diagnosis if there are ≥20% blasts in the PB. If log reduction is used as a measure of MRD response both PB and BM should be analyzed at diagnosis to have both tissues as baseline comparators.

Figure 2.

Time points at which MRD is considered a clinically relevant biomarker. The time points and MRD cutoffs are indicated at which an MRD result may influence the therapeutic decision for a given patient. For example, in a patient with AML carrying an NPM1 mutation, who is monitored by qPCR, MRD persistence at ≥2% NPM1 mutant copies/ABL1 copies at the end of chemotherapy may trigger the decision to consider allo-HCT for this patient. *After 2 cycles of chemotherapy (either 2 induction cycles or 1 induction and 1 consolidation cycle), which includes the time point before allo-HCT. **Percentage NPM1 mutant copies per ABL1 copies measured in BM. ^***Log reduction of the ratio of target copies/ABL1 copies between the sample at diagnosis and the sample at end of treatment, measured in the same tissue (preferably BM).