Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Dynamics of chronic myeloid leukaemia

Nature volume 435, pages 1267–1270 (2005)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Druker, B. J. et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nature Med. 2, 561–566 (1996)

    Article  CAS  PubMed  Google Scholar 

  2. Sawyers, C. L. et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 99, 3530–3539 (2002)

    Article  CAS  PubMed  Google Scholar 

  3. Holtz, M. S. et al. Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation. Blood 99, 3792–3800 (2002)

    Article  CAS  PubMed  Google Scholar 

  4. Hughes, T. P. et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N. Engl. J. Med. 349, 1423–1432 (2003)

    Article  CAS  PubMed  Google Scholar 

  5. Spangrude, G. J., Heimfeld, S. & Weissman, I. L. Purification and characterization of mouse hematopoietic stem cells. Science 241, 58–62 (1988)

    Article  ADS  CAS  PubMed  Google Scholar 

  6. Bhatia, R. et al. Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood 101, 4701–4707 (2003)

    Article  CAS  PubMed  Google Scholar 

  7. Chu, S. et al. Detection of BCR-ABL kinase mutations in CD34 + cells from chronic myelogenous leukemia patients in complete cytogenetic remission on imatinib mesylate treatment. Blood 105, 2093–2098 (2005)

    Article  CAS  PubMed  Google Scholar 

  8. Gorre, M. E. et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293, 876–880 (2001)

    Article  CAS  PubMed  Google Scholar 

  9. Branford, S. et al. High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance. Blood 99, 3472–3475 (2002)

    Article  CAS  PubMed  Google Scholar 

  10. Branford, S. et al. Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood 102, 276–283 (2003)

    Article  CAS  PubMed  Google Scholar 

  11. Branford, S. et al. Real-time quantitative PCR analysis can be used as a primary screen to identify imatinib-treated patients with CML who have BCR-ABL kinase domain mutations. Blood 104, 2926–2932 (2004)

    Article  CAS  PubMed  Google Scholar 

  12. Hochhaus, A. et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 16, 2190–2196 (2002)

    Article  CAS  PubMed  Google Scholar 

  13. Shah, N. P. et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2, 117–125 (2002)

    Article  CAS  PubMed  Google Scholar 

  14. Roche-Lestienne, C. et al. Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment. Blood 100, 1014–1018 (2002)

    Article  CAS  PubMed  Google Scholar 

  15. Roche-Lestienne, C., Lai, J. L., Darre, S., Facon, T. & Preudhomme, C. A mutation conferring resistance to imatinib at the time of diagnosis of chronic myelogenous leukemia. N. Engl. J. Med. 348, 2265–2266 (2003)

    Article  PubMed  Google Scholar 

  16. Branford, S., Hughes, T. P. & Rudzki, Z. Monitoring chronic myeloid leukaemia therapy by real-time quantitative PCR in blood is a reliable alternative to bone marrow cytogenetics. Br. J. Haematol. 107, 587–599 (1999)

    Article  CAS  PubMed  Google Scholar 

  17. Cortes, J., O'Brien, S. & Kantarjian, H. Discontinuation of imatinib therapy after achieving a molecular response. Blood 104, 2204–2205 (2004)

    Article  CAS  PubMed  Google Scholar 

  18. Higashi, T. et al. Imatinib mesylate-sensitive blast crisis immediately after discontinuation of imatinib mesylate therapy in chronic myelogenous leukemia: report of two cases. Am. J. Hematol. 76, 275–278 (2004)

    Article  CAS  PubMed  Google Scholar 

  19. Graham, S. M. et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 99, 319–325 (2002)

    Article  CAS  PubMed  Google Scholar 

  20. Chaudhary, P. M. & Roninson, I. B. Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells. Cell 66, 85–94 (1991)

    Article  CAS  PubMed  Google Scholar 

  21. Mahon, F. X. et al. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood 101, 2368–2373 (2003)

    Article  CAS  PubMed  Google Scholar 

  22. Branford, S. et al. The incidence of BCR-ABL kinase mutations in chronic myeloid leukemia patients is as high in the second year of imatinib therapy as the first but survival after mutation detection is significantly longer for patients with mutations detected in the second year of therapy. Blood 102, 414 (2003)

    Article  Google Scholar 

  23. Kunkel, T. A. & Bebenek, K. DNA replication fidelity. Annu. Rev. Biochem. 69, 497–529 (2000)

    Article  CAS  PubMed  Google Scholar 

  24. Holyoake, T. L., Jiang, X., Drummond, M. W., Eaves, A. C. & Eaves, C. J. Elucidating critical mechanisms of deregulated stem cell turnover in the chronic phase of chronic myeloid leukemia. Leukemia 16, 549–558 (2002)

    Article  CAS  PubMed  Google Scholar 

  25. Holyoake, T., Jiang, X., Eaves, C. & Eaves, A. Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. Blood 94, 2056–2064 (1999)

    CAS  PubMed  Google Scholar 

  26. Mahon, F. X. et al. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood 101, 2368–2373 (2003)

    Article  CAS  PubMed  Google Scholar 

  27. Chaudhary, P. M. & Roninson, I. B. Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells. Cell 66, 85 (1991)

    Article  CAS  PubMed  Google Scholar 

  28. Bedi, A. et al. BCR-ABL gene rearrangement and expression of primitive hematopoietic progenitors in chronic myeloid leukemia. Blood 81, 2898–28902 (1993)

    CAS  PubMed  Google Scholar 

  29. Shah, N. P. et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305, 399–401 (2004)

    Article  ADS  CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Program for Evolutionary Dynamics, Department of Organismic and Evolutionary Biology, Department of Mathematics, Harvard University, Cambridge, Massachusetts, 02138, USA

    Franziska Michor & Martin A. Nowak

  2. Institute of Medical and Veterinary Science, Adelaide, Australia

    Timothy P. Hughes & Susan Branford

  3. Department of Biology, Kyushu University, 812-8581, Fukuoka, Japan

    Yoh Iwasa

  4. Department of Medicine,

    Neil P. Shah & Charles L. Sawyers

  5. Howard Hughes Medical Institute, Molecular Biology Institute, Department of Urology, Department of Medical and Molecular Pharmacology, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, California, 90095, USA

    Charles L. Sawyers

Authors
  1. Franziska Michor
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Timothy P. Hughes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yoh Iwasa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Susan Branford
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Neil P. Shah
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Charles L. Sawyers
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Martin A. Nowak
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Franziska Michor.

Ethics declarations

Competing interests

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

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)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Michor, F., Hughes, T., Iwasa, Y. et al. Dynamics of chronic myeloid leukaemia. Nature 435, 1267–1270 (2005). https://doi.org/10.1038/nature03669

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature03669

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing