AML/Normal Progenitor Balance Instead of Total Tumor Load (MRD) Accounts for Prognostic Impact of Flowcytometric Residual Disease in AML

SIMPLE SUMMARY: Measurable residual disease (MRD), taken as the percentage of white blood cells in acute myeloid leukemia, has important prognostic value, but false negatives and false positives can occur. Immature populations make up the most important part of MRD (now referred to as WBC-MRD). We explored the influence on prognostic impact of the two compartments of WBC-MRD: (1) the AML part of the total primitive/progenitor (CD34+, CD117+, CD133+) compartment (primitive marker MRD; PM-MRD) and (2) the total progenitor compartment (as % of WBC, PM%). Both are related as follows: WBC-MRD = PM-MRD × PM%. In the HOVON/SAKK study (H102; n = 300), using two objectively assessed cut-off points (2.34% and 10%), PM-MRD was found to be prognostically more discriminative than WBC-MRD. The PM% parameter had no prognostic impact and, moreover, resulted in WBC-MRD false positives/false negatives. Highly important for present clinical practice is the identification of a PM-MRD ≥ 10% but MRD(negative) (MRD < 0.1, ELN consensus) poor prognosis subgroup. This suggests that a residual disease analysis using PM-MRD should be conducted. ABSTRACT: Measurable residual disease (MRD) in AML, assessed by multicolor flow cytometry, is an important prognostic factor. Progenitors are key populations in defining MRD, and cases of MRD involving these progenitors are calculated as percentage of WBC and referred to as white blood cell MRD (WBC-MRD). Two main compartments of WBC-MRD can be defined: (1) the AML part of the total primitive/progenitor (CD34+, CD117+, CD133+) compartment (referred to as primitive marker MRD; PM-MRD) and (2) the total progenitor compartment (% of WBC, referred to as PM%), which is the main quantitative determinant of WBC-MRD. Both are related as follows: WBC-MRD = PM-MRD × PM%. We explored the relative contribution of each parameter to the prognostic impact. In the HOVON/SAKK study H102 (300 patients), based on two objectively assessed cut-off points (2.34% and 10%), PM-MRD was found to offer an independent prognostic parameter that was able to identify three patient groups with different prognoses with larger discriminative power than WBC-MRD. In line with this, the PM% parameter itself showed no prognostic impact, implying that the prognostic impact of WBC-MRD results from the PM-MRD parameter it contains. Moreover, the presence of the PM% parameter in WBC-MRD may cause WBC-MRD false positivity and WBC-MRD false negativity. For the latter, at present, it is clinically relevant that PM-MRD ≥ 10% identifies a patient sub-group with a poor prognosis that is currently classified as good prognosis MRD(negative) using the European LeukemiaNet 0.1% consensus MRD cut-off value. These observations suggest that residual disease analysis using PM-MRD should be conducted.