Computational assessment of measurable residual disease in acute myeloid leukemia using mixture models
Tim R Mocking1,2, Angèle Kelder1,2, Tom Reuvekamp1,2,3
1Department of Hematology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Background:
The proportion of residual leukemic blasts after chemotherapy assessed by multiparameter flow cytometry, is an important prognostic factor for the risk of relapse and overall survival in acute myeloid leukemia (AML). This measurable residual disease (MRD) is used in clinical trials to stratify patients for more or less intensive consolidation therapy. However, an objective and reproducible analysis method to assess MRD status from flow cytometry data is lacking, yet is highly anticipated for broader implementation of MRD testing.
Methods:
We propose a computational pipeline based on Gaussian mixture modeling that allows a fully automated assessment of MRD status while remaining completely interpretable for clinical diagnostic experts. Our pipeline requires limited training data, which makes it easily transferable to other medical centers and cytometry platforms.
Results:
We identify all healthy and leukemic immature myeloid cells in with high concordance (Spearman's Rho = 0.974) and classification performance (median F-score = 0.861) compared to manual analysis. Using control samples (n = 18), we calculate a computational MRD percentage with high concordance to expert gating (Spearman's rho = 0.823) and predict MRD status in a cohort of 35 AML follow-up measurements with high accuracy (97%).
Conclusions:
We demonstrate that our pipeline provides a powerful tool for fast (~3 s) and objective automated MRD assessment in AML.
