Dynamics of chronic myeloid leukaemia
Top Cited Papers
- 30 June 2005
- journal article
- research article
- Published by Springer Nature in Nature
- Vol. 435 (7046) , 1267-1270
- https://doi.org/10.1038/nature03669
Abstract
Chronic myeloid leukaemia is associated with the oncogene BCR-ABL. The tyrosine kinase inhibitor imatinib (Gleevec), in the news as the first molecularly targeted anticancer drug, acts by impairing the function of this oncogene. A study of 169 patients receiving imatinib followed the kinetics of BCR-ABL in order to develop a mathematical model of the in vivo kinetics of a cancer. Imatinib reduced the rate of leukaemic cell production, but did not appear to deplete a population of leukaemic stem cells. The model also indicates when multiple drug therapy might be more effective than imatinib alone. 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.Keywords
This publication has 26 references indexed in Scilit:
- Detection of BCR-ABL kinase mutations in CD34+ cells from chronic myelogenous leukemia patients in complete cytogenetic remission on imatinib mesylate treatmentBlood, 2005
- Real-time quantitative PCR analysis can be used as a primary screen to identify patients with CML treated with imatinib who have BCR-ABL kinase domain mutationsBlood, 2004
- Discontinuation of imatinib therapy after achieving a molecular responseBlood, 2004
- Overriding Imatinib Resistance with a Novel ABL Kinase InhibitorScience, 2004
- Imatinib mesylate‐sensitive blast crisis immediately after discontinuation of imatinib mesylate therapy in chronic myelogenous leukemia: Report of two casesAmerican Journal of Hematology, 2004
- 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 prognosisBlood, 2003
- 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 treatmentBlood, 2002
- Elucidating critical mechanisms of deregulated stem cell turnover in the chronic phase of chronic myeloid leukemiaLeukemia, 2002
- Clinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or AmplificationScience, 2001
- Monitoring chronic myeloid leukaemia therapy by real‐time quantitative PCR in blood is a reliable alternative to bone marrow cytogeneticsBritish Journal of Haematology, 1999