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Dynamic modeling of imatinib-treated chronic myeloid leukemia: functional insights and clinical implications

Abstract

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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Acknowledgements

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.

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Correspondence to Ingo Roeder.

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Supplementary information

Supplementary Fig. 1

Simulation of CML genesis. (PDF 134 kb)

Supplementary Fig. 2

Transition characteristics. (PDF 228 kb)

Supplementary Fig. 3

Individual subject data. (PDF 587 kb)

Supplementary Fig. 4

Model prediction for combination of imatinib with cytotoxic treatment. (PDF 190 kb)

Supplementary Fig. 5

Computer simulation of prolonged imatinib administration. (PDF 192 kb)

Supplementary Table 1

Model parameters for normal and leukemic cells. (PDF 56 kb)

Supplementary Table 2

Model parameters for treatment simulation. (PDF 50 kb)

Supplementary Note (PDF 207 kb)

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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

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  • DOI: https://doi.org/10.1038/nm1487

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