Modeling early treatment response in AML from cell-free tumor DNA

Dantong Wang; Christian Rausch; Simon A Buerger; Sebastian Tschuri; Maja Rothenberg-Thurley; Melanie Schulz; Jan Hasenauer; Frank Ziemann; Klaus H Metzeler; Carsten Marr

doi:10.1016/j.isci.2023.108271

Modeling early treatment response in AML from cell-free tumor DNA

iScience. 2023 Oct 19;26(12):108271. doi: 10.1016/j.isci.2023.108271. eCollection 2023 Dec 15.

Authors

Dantong Wang^{1

2}, Christian Rausch^{3

4}, Simon A Buerger³, Sebastian Tschuri³, Maja Rothenberg-Thurley³, Melanie Schulz^{1

2}, Jan Hasenauer^{2

5

6}, Frank Ziemann^{3

4}, Klaus H Metzeler⁷, Carsten Marr^{1

2}

Affiliations

¹ Institute of AI for Health, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg 85764, Germany.
² Center for Mathematics, Technische Universität München, Garching 85748, Germany.
³ Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital (LMU), Munich, Germany.
⁴ German Cancer Consortium (DKTK), partner sites Munich/Dresden, Germany.
⁵ Computational Health Center, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg 85764, Germany.
⁶ Faculty of Mathematics and Natural Sciences, Rheinische Friedrich-Wilhelms-Universität Bonn, 53115 Bonn, Germany.
⁷ Department of Hematology and Cell Therapy, University Hospital Leipzig (UHL) 04103, Germany.

Abstract

Monitoring disease response after intensive chemotherapy for acute myeloid leukemia (AML) currently requires invasive bone marrow biopsies, imposing a significant burden on patients. In contrast, cell-free tumor DNA (ctDNA) in peripheral blood, carrying tumor-specific mutations, offers a less-invasive assessment of residual disease. However, the relationship between ctDNA levels and bone marrow blast kinetics remains unclear. We explored this in 10 AML patients with NPM1 and IDH2 mutations undergoing initial chemotherapy. Comparison of mathematical mixed-effect models showed that (1) inclusion of blast cell death in the bone marrow, (2) transition of ctDNA to peripheral blood, and (3) ctDNA decay in peripheral blood describes kinetics of blast cells and ctDNA best. The fitted model allows prediction of residual bone marrow blast content from ctDNA, and its scaling factor, representing clonal heterogeneity, correlates with relapse risk. Our study provides precise insights into blast and ctDNA kinetics, offering novel avenues for AML disease monitoring.

Keywords: Biological sciences; Disease.