Pathogenesis, treatment effects, and resistance dynamics in chronic myeloid leukemia - insights from mathematical model analyses
- 126 Downloads
Mathematical models and simulation studies are powerful tools to investigate dynamic properties of complex systems. Specifically, they can be used to test alternative hypotheses on underlying biological mechanisms for their consistency with real data and therefore to effectively guide the design of new experimental strategies or clinical trials. In this study, we present an overview of recently published mathematical approaches applied to the description of chronic myeloid leukemia (CML). We discuss three different fields relevant to clinical issues: the pathogenesis of the malignancy, the treatment effects of the tyrosine kinase inhibitor imatinib, and the process of acquired treatment resistance highlighting both the differences and the consistencies in the proposed hypotheses and the resulting conclusions. The mathematical models presented agree that CML can adequately be described as a clonal competition between normal and leukemic stem cells for a common resource. Furthermore, a certain therapeutic effect of imatinib on leukemic stem cells turned out to be necessary to consistently explain clinical data on the long-term response of CML patients under imatinib treatment. However, the approaches described cannot resolve the question whether or not this effect is sufficient to ultimately eradicate malignant stem cells. A number of different hypotheses have been proposed concerning the initiation and the dynamics of treatment-resistant malignant stem cell clones. The theoretical results clearly indicate that further experimental effort with the particular focus on the quantitative monitoring of resistant clones will be required to definitely distinguish between these hypotheses.
KeywordsChronic myeloid leukemia (CML) Imatinib treatment Resistant clone dynamics Mathematical model Simulation analysis
The authors thank Michael Cross and Matthias Horn for their assistance in preparing the manuscript. This work has partially been supported by the German Research Foundation DFG grant RO3500–1/1.
- 7.Holyoake TL, Jiang X, Jorgensen HG, Graham S, Alcorn MJ, Laird C et al (2001) Primitive quiescent leukemic cells from patients with chronic myeloid leukemia spontaneously initiate factor-independent growth in vitro in association with up-regulation of expression of interleukin-3. Blood 97:720–728PubMedCrossRefGoogle Scholar
- 30.Roy L, Guilhot J, Krahnke T, Guerci-Bresler A, Druker BJ, Larson RA et al (2006) Survival advantage from imatinib compared with the combination interferon-alpha plus cytarabine in chronic-phase chronic myelogenous leukemia: historical comparison between two phase 3 trials. Blood 108:1478–1484PubMedCrossRefGoogle Scholar
- 37.Bornhauser M, Illmer T, Le Coutre P, Pursche J, Bonin Mv, Freiberg-richter J et al (2004) Imatinib mesylate selectively influences the cellular metabolism of cytarabine in BCR/ABL negative leukemia cell lines and normal CD34+ progenitor cells. Ann Hematol 83(Suppl 1):61–64Google Scholar
- 49.Jorgensen HG, Copland M, Allan EK, Jiang X, Eaves A, Eaves C et al (2006) Intermittent exposure of primitive quiescent chronic myeloid leukemia cells to granulocyte-colony stimulating factor in vitro promotes their elimination by imatinib mesylate. Clin Cancer Res 12:626–633PubMedCrossRefGoogle Scholar
- 50.Hochhaus A, Reiter A, Reichert SS, Emig M, Kaeda J, Schultheis B et al (2000) Molecular heterogeneity in complete cytogenetic responders after interferon-alpha therapy for chronic myelogenous leukemia: low levels of minimal residual disease are associated with continuing remission. Blood 95:62–66PubMedGoogle Scholar
- 53.Shah NP, Nicoll JM, Nagar B, Gorre ME, Paquette RL, Kuriyan J et al (2002) 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 2:117–125PubMedCrossRefGoogle Scholar
- 54.Roche-Lestienne C, Soenen-Cornu V, Grardel-Duflos N, Lai JL, Philippe N, Facon T et al (2002) 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 100:1014–1018PubMedCrossRefGoogle Scholar