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Simple Summary: Acute myeloid leukemia (AML) is the second most frequent leukemia entity in children and adolescents, and definitely the most aggressive variant. Multiparameter flow-cytometry is one of the methodologies most useful to monitor the number of remaining leukemic cells in bone marrow (minimal residual disease, MRD) in AML patients, because it is widely available and applicable to most patients. However, AML flow cytometry data show very complex patterns and identifying leukemic cells in the data is subjective, time-consuming and requires experienced operators who are not available world-wide. In this paper, we approach automatic assessment of AML flow cytometry samples with a novel semi-supervised machine learning model, leveraging implicit expert knowledge stored in a collection of manually assessed samples. Because AML data exhibit a high degree of variability in the patterns of blast cell populations that is difficult to model, the model detects anomalies starting from the appearance of normal cell populations. Leukemia is the most frequent malignancy in children and adolescents, with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) as the most common subtypes. Minimal residual disease (MRD) measured by flow cytometry (FCM) has proven to be a strong prognostic factor in ALL as well as in AML. Machine learning techniques have been emerging in the field of automated MRD quantification with the objective of superseding subjective and time-consuming manual analysis of FCM-MRD data. In contrast to ALL, where supervised multi-class classification methods have been successfully deployed for MRD detection, AML poses new challenges: AML is rarer (with fewer available training data) than ALL and much more heterogeneous in its immunophenotypic appearance, where one-class classification (anomaly detection) methods seem more suitable. In this work, a new semi-supervised approach based on the UMAP algorithm for MRD detection utilizing only labels of blast free FCM samples is presented. The method is tested on a newly gathered set of AML FCM samples and results are compared to state-of-the-art methods. We reach a median F 1 -score of 0.794, while providing a transparent classification pipeline with explainable results that facilitates inter-disciplinary work between medical and technical experts. This work shows that despite several issues yet to overcome, the merits of automated MRD quantification can be fully exploited also in AML. [ABSTRACT FROM AUTHOR]