Background: In acute myeloid leukemia (AML), the most sensitive measurable residual disease (MRD) methods are single-gene approaches, but these are applicable only in ~60% of AML cases. Methods: We applied multi-omics single-cell analysis on diagnostic and first remission samples to identify leukemia-specific molecular markers for subsequent MRD monitoring in six AML patients lacking AML-defining variants. Results: Five selection criteria were defined to identify suitable MRD markers. Markers of primordial leukemic clones were identified by combining data from single-cell sequencing and immunophenotyping. Specific markers suitable for use in MRD follow-up were identified in 6/6 patients, in some cases in myelodysplasia-related genes and clonal hematopoiesis-related genes usually not recommended for use in MRD determinations. Patient-specific ddPCR (limits of detection: 0.06–0.0011%) or EC-NGS assays correlated with therapeutic responses: 0/4 markers displayed molecular relapses in three non-relapsing patients, contrary to 4/4 markers of three relapsing patients. Of these, 3/4 and 1/4 markers detected molecular relapses earlier than or simultaneous with conventional methods, respectively (−115 to −338 days). Conclusions: Our results demonstrate that single-cell subclonal mapping at diagnosis and during first remission enables selection of reliable MRD targets for personalized disease surveillance in patients lacking conventional MRD markers.
Sørensen et al. (Sat,) studied this question.
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