nature medicine
Dynamic modeling of imatinib-treated chronic myeloid leukemia: functional insights and clinical implications
Ingo Roeder1,
Matthias Horn1,
Ingmar Glauche1,
Andreas Hochhaus2,
Martin C Mueller2 &
Markus Loeffler1
Nature Medicine volume 12, pages 1181–1184 (2006)Cite this article
Treatment of chronic myeloid leukemia (CML) with the tyrosine kinase inhibitor imatinib represents a successful application of molecularly targeted cancer therapy. A rapid hematologic and cytogenetic response can be induced in the majority of people, even in advanced disease. However, complete eradication of malignant cells, which are characterized by the expression of the BCR-ABL1 fusion protein, is rare. Reasons for the persistence of the malignant clone are currently not known and provide a substantial challenge for clinicians and biologists. Based on a mathematical modeling approach that quantitatively explains a broad range of phenomena, we show for two independent datasets that clinically observed BCR-ABL1 transcript dynamics during imatinib treatment of CML can consistently be explained by a selective functional effect of imatinib on proliferative leukemia stem cells. Our results suggest the general potential of imatinib to induce a complete elimination of the malignant clone. Moreover, we predict that the therapeutic benefit of imatinib can, under certain circumstances, be accelerated by combination with proliferation-stimulating treatment strategies.
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Figure 1: BCR-ABL1 transcript dynamics.
Figure 2: Model predictions for combination treatments and long-term dynamics.
Figure 3: Model scheme.
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We thank the members of the German CML study group, coinvestigators, nursing and research staff for their collaboration and S. Fruehauf for critical reading of an earlier version of this manuscript. The modeling work (I.R., M.H., I.G. and M.L.) was partially supported by the Deutsche Forschungsgemeinschaft, grants LO-942/1-1, 2 and RO3500/1-1. Molecular and clinical studies (A.H. and M.C.M.) were supported by Novartis Pharma, the Competence Network 'Akute und chronische Leukämien' sponsored by the German Bundesministerium für Bildung und Forschung (Projektträger Gesundheitsforschung, DLR e.V. – 01 GI9980/6), and the European LeukemiaNet within the Sixth European Framework Program for Research and Technology Development.
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Haertelstrasse 16–18, Leipzig, D-04107, Germany
Ingo Roeder, Matthias Horn, Ingmar Glauche & Markus Loeffler
III. Medizinische Klinik, Fakultät für klinische Medizin Mannheim, University of Heidelberg, Wiesbadener Strasse 7–11, Mannheim, D-68305, Germany
Andreas Hochhaus & Martin C Mueller
Ingo Roeder
Matthias Horn
Ingmar Glauche
Andreas Hochhaus
Martin C Mueller
Markus Loeffler
Correspondence to Ingo Roeder.
The authors declare no competing financial interests.
Supplementary Fig. 1
Simulation of CML genesis. (PDF 134 kb)
Transition characteristics. (PDF 228 kb)
Individual subject data. (PDF 587 kb)
Model prediction for combination of imatinib with cytotoxic treatment. (PDF 190 kb)
Computer simulation of prolonged imatinib administration. (PDF 192 kb)
Model parameters for normal and leukemic cells. (PDF 56 kb)
Model parameters for treatment simulation. (PDF 50 kb)
Supplementary Note (PDF 207 kb)
Roeder, I., Horn, M., Glauche, I. et al. Dynamic modeling of imatinib-treated chronic myeloid leukemia: functional insights and clinical implications. Nat Med 12, 1181–1184 (2006). https://doi.org/10.1038/nm1487
Issue Date: 01 October 2006
DOI: https://doi.org/10.1038/nm1487
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