Dynamics of chronic myeloid leukaemia

The clinical success of the ABL tyrosine kinase inhibitor imatinib in chronic myeloid leukaemia (CML) serves as a model for molecularly targeted therapy of cancer, 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 differentiation, 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.

[1]  J. Melo,et al.  MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. , 2003, Blood.

[2]  H. Kantarjian,et al.  Discontinuation of imatinib therapy after achieving a molecular response. , 2004, Blood.

[3]  John H. Jopson,et al.  A REPORT OF TWO CASES , 1902 .

[4]  Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. , 1999, Blood.

[5]  Branford,et al.  Monitoring chronic myeloid leukaemia therapy by real‐time quantitative PCR in blood is a reliable alternative to bone marrow cytogenetics , 1999, British journal of haematology.

[6]  T. Kunkel,et al.  DNA replication fidelity. , 1992, The Journal of biological chemistry.

[7]  R. Larson,et al.  Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. , 2002, Blood.

[8]  Helen Moore,et al.  A mathematical model for chronic myelogenous leukemia (CML) and T cell interaction. , 2004, Journal of theoretical biology.

[9]  M. Slovak,et al.  Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. , 2003, Blood.

[10]  J. Goldman,et al.  Quantification of residual disease in chronic myelogenous leukemia patients on interferon-alpha therapy by competitive polymerase chain reaction. , 1996, Blood.

[11]  I. Weinstein.  Addiction to Oncogenes--the Achilles Heal of Cancer , 2002, Science.

[12]  A. Elmaagacli,et al.  Estimating the relapse stage in chronic myeloid leukaemia patients after allogeneic stem cell transplantation by the amount of BCR‐ABL fusion transcripts detected using a new real‐time polymerase chain reaction method , 2001, British journal of haematology.

[13]  J. Kuriyan,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. , 2002, Cancer cell.

[14]  I. Roninson,et al.  Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells , 1991, Cell.

[15]  C. Preudhomme,et al.  A mutation conferring resistance to imatinib at the time of diagnosis of chronic myelogenous leukemia. , 2003, The New England journal of medicine.

[16]  Jürg Zimmermann,et al.  Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells , 1996, Nature Medicine.

[17]  P. Browett,et al.  Imatinib produces significantly superior molecular responses compared to interferon alfa plus cytarabine in patients with newly diagnosed chronic myeloid leukemia in chronic phase , 2003, Leukemia.

[18]  M. Slovak,et al.  Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation. , 2002, Blood.

[19]  Susan Branford,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. , 2003, Blood.

[20]  M C Mackey,et al.  Periodic chronic myelogenous leukaemia: spectral analysis of blood cell counts and aetiological implications , 1999, British journal of haematology.

[21]  C. Sawyers,et al.  Detection of BCR-ABL kinase mutations in CD34+ cells from chronic myelogenous leukemia patients in complete cytogenetic remission on imatinib mesylate treatment. , 2005, Blood.

[22]  P. Sperryn,et al.  Blood. , 1989, British journal of sports medicine.

[23]  Susan Branford,et al.  Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. , 2003, The New England journal of medicine.

[24]  I. Weissman,et al.  The biology of hematopoietic stem cells. , 1995, Annual review of cell and developmental biology.

[25]  Claude Preudhomme,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. , 2002, Blood.

[26]  R. Herrmann,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. , 2002, Blood.

[27]  Yoshiya Tanaka,et al.  Imatinib mesylate‐sensitive blast crisis immediately after discontinuation of imatinib mesylate therapy in chronic myelogenous leukemia: Report of two cases , 2004, American journal of hematology.

[28]  I. Weissman,et al.  Purification and characterization of mouse hematopoietic stem cells. , 1988, Science.

[29]  AC Eaves,et al.  Elucidating critical mechanisms of deregulated stem cell turnover in the chronic phase of chronic myeloid leukemia , 2002, Leukemia.

[30]  R. Herrmann,et al.  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 mutations. , 2004, Blood.

[31]  T. Holyoake,et al.  Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. , 2002, Blood.

[32]  B. Druker,et al.  Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy , 2002, Leukemia.

[33]  A. Reiter,et al.  Accurate and rapid analysis of residual disease in patients with CML using specific fluorescent hybridization probes for real time quantitative RT-PCR , 1999, Leukemia.

[34]  Ping Chen,et al.  Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor , 2004, Science.

[35]  B. Zehnbauer,et al.  BCR-ABL gene rearrangement and expression of primitive hematopoietic progenitors in chronic myeloid leukemia. , 1993, Blood.

[36]  H. Kantarjian,et al.  Quantitative polymerase chain reaction monitoring of BCR-ABL during therapy with imatinib mesylate (STI571; gleevec) in chronic-phase chronic myelogenous leukemia. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[37]  A. Fokas,et al.  Mathematical model of granulocytopoiesis and chronic myelogenous leukemia. , 1991, Cancer research.

[38]  P. N. Rao,et al.  Clinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or Amplification , 2001, Science.