Mathematical multi-compartment modeling of chronic lymphocytic leukemia cell kinetics under ibrutinib
Melanie Schulz,
Sanne Bleser,
Manouk Groels,
Dragan Bošnački,
Jan A. Burger,
Nicholas Chiorazzi,
Carsten Marr
Affiliations
Melanie Schulz
Institute of AI for Health, Helmholtz Munich – German Research Centre for Environmental Health, Neuherberg, Germany; TUM School of Mathematics, Technical University of Munich, Munich, Germany
Sanne Bleser
Institute of AI for Health, Helmholtz Munich – German Research Centre for Environmental Health, Neuherberg, Germany; Faculty of Biomedical Engineering, Technichal University Eindhoven, Eindhoven, the Netherlands
Manouk Groels
Institute of AI for Health, Helmholtz Munich – German Research Centre for Environmental Health, Neuherberg, Germany; Faculty of Biomedical Engineering, Technichal University Eindhoven, Eindhoven, the Netherlands
Dragan Bošnački
Faculty of Biomedical Engineering, Technichal University Eindhoven, Eindhoven, the Netherlands
Jan A. Burger
Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Nicholas Chiorazzi
Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA; Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
Carsten Marr
Institute of AI for Health, Helmholtz Munich – German Research Centre for Environmental Health, Neuherberg, Germany; Corresponding author
Summary: The Bruton tyrosine kinase inhibitor ibrutinib is an effective treatment for patients with chronic lymphocytic leukemia (CLL). While it rapidly reduces lymph node and spleen size, it initially increases the number of lymphocytes in the blood due to cell redistribution. A previously published mathematical model described and quantified those cell kinetics. Here, we propose an alternative mechanistic model that outperforms the previous model in 26 of 29 patients. Our model introduces constant subcompartments for healthy lymphocytes and benign tissue and treats spleen and lymph nodes as separate compartments. This three-compartment model (comprising blood, spleen, and lymph nodes) performed significantly better in patients without a mutation in the IGHV gene, indicating a diverse response to ibrutinib for cells residing in lymph nodes and spleen. Additionally, high ZAP-70 expression was linked to less cell death in the spleen. Overall, our study enhances understanding of CLL genetics and patient response to ibrutinib and provides a framework applicable to the study of similar drugs.
