Letter | Published:

Dynamics of chronic myeloid leukaemia

Abstract

The clinical success of the ABL tyrosine kinase inhibitor imatinib in chronic myeloid leukaemia (CML) serves as a model for molecularly targeted therapy of cancer1,2,3,4, but at least two critical questions remain. Can imatinib eradicate leukaemic stem cells? What are the dynamics of relapse due to imatinib resistance, which is caused by mutations in the ABL kinase domain? The precise understanding of how imatinib exerts its therapeutic effect in CML and the ability to measure disease burden by quantitative polymerase chain reaction provide an opportunity to develop a mathematical approach. We find that a four-compartment model, based on the known biology of haematopoietic differentiation5, can explain the kinetics of the molecular response to imatinib in a 169-patient data set. Successful therapy leads to a biphasic exponential decline of leukaemic cells. The first slope of 0.05 per day represents the turnover rate of differentiated leukaemic cells, while the second slope of 0.008 per day represents the turnover rate of leukaemic progenitors. The model suggests that imatinib is a potent inhibitor of the production of differentiated leukaemic cells, but does not deplete leukaemic stem cells. We calculate the probability of developing imatinib resistance mutations and estimate the time until detection of resistance. Our model provides the first quantitative insights into the in vivo kinetics of a human cancer.

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Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

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Acknowledgements

We thank R. Lawrence and C. Field for technical assistance with the BCR-ABL quantitative and mutation analysis. N.P.S. and C.L.S. acknowledge support from the Leukemia and Lymphoma Society. The Program for Evolutionary Dynamics at Harvard University is supported by J. Epstein. N.P.S. is the recipient of a Mentored Clinical Pharmacology Research Scholars Program Award. Author Contributions F.M. is a Junior Fellow of the Harvard Society of Fellows. C.L.S. is an Investigator of the Howard Hughes Medical Institute, and a Doris Duke Distinguished Clinical Scientist.

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Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Correspondence to Franziska Michor.

Supplementary information

Supplementary Notes

The basic model, the probability of resistance mutations, quantitative real-time polymerase-chain-reaction measurements, additional references and Supplementary Figure Legend. (PDF 53 kb)

Supplementary Figures and Supplementary Tables

Supplementary Figure S1 shows the molecular response to imatinib. Also contains Supplementary Table S1, Supplementary Table S2 and Supplementary Table S3. (PDF 155 kb)

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Further reading

Figure 1: Imatinib leads to a biphasic decline of leukaemic cells.
Figure 2: Discontinuation of imatinib therapy in three patients after 1–3 years led to a rapid increase of leukaemic cells to levels at or beyond pre-treatment baseline.
Figure 3: About 40 different point mutations in BCR-ABL have been identified that confer various degrees of resistance to imatinib therapy.
Figure 4: Model dynamics of different treatment responses to imatinib.

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