Eradication of Chronic Myeloid Leukemia Stem Cells: A Novel Mathematical Model Predicts No Therapeutic Benefit of Adding G-CSF to Imatinib

Imatinib mesylate induces complete cytogenetic responses in patients with chronic myeloid leukemia (CML), yet many patients have detectable BCR-ABL transcripts in peripheral blood even after prolonged therapy. Bone marrow studies have shown that this residual disease resides within the stem cell compartment. Quiescence of leukemic stem cells has been suggested as a mechanism conferring insensitivity to imatinib, and exposure to the Granulocyte-Colony Stimulating Factor (G-CSF), together with imatinib, has led to a significant reduction in leukemic stem cells in vitro. In this paper, we design a novel mathematical model of stem cell quiescence to investigate the treatment response to imatinib and G-CSF. We find that the addition of G-CSF to an imatinib treatment protocol leads to observable effects only if the majority of leukemic stem cells are quiescent; otherwise it does not modulate the leukemic cell burden. The latter scenario is in agreement with clinical findings in a pilot study administering imatinib continuously or intermittently, with or without G-CSF (GIMI trial). Furthermore, our model predicts that the addition of G-CSF leads to a higher risk of resistance since it increases the production of cycling leukemic stem cells. Although the pilot study did not include enough patients to draw any conclusion with statistical significance, there were more cases of progression in the experimental arms as compared to continuous imatinib. Our results suggest that the additional use of G-CSF may be detrimental to patients in the clinic.

[1]  Andreas Trumpp,et al.  Hematopoietic Stem Cells Reversibly Switch from Dormancy to Self-Renewal during Homeostasis and Repair , 2008, Cell.

[2]  Dominik Wodarz,et al.  Drug resistance in cancer: principles of emergence and prevention. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[3]  G. Tjønnfjord,et al.  Sustained cytogenetic response after discontinuation of imatinib mesylate in a patient with chronic myeloid leukaemia , 2004, European journal of haematology.

[4]  A. Tsukamoto,et al.  The unexpected G0/G1 cell cycle status of mobilized hematopoietic stem cells from peripheral blood. , 1997, Blood.

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

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

[7]  D. Scadden,et al.  Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation , 2008, Nature Reviews Genetics.

[8]  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.

[9]  W. Thilly,et al.  A statistical model to estimate variance in long term-low dose mutation assays: testing of the model in a human lymphoblastoid mutation assay. , 1989, Mutation research.

[10]  I. Weissman,et al.  Stem cells, cancer, and cancer stem cells , 2001, Nature.

[11]  Doron Levy,et al.  Dynamics and Potential Impact of the Immune Response to Chronic Myelogenous Leukemia , 2008, PLoS Comput. Biol..

[12]  S. Forman,et al.  Growth factor stimulation reduces residual quiescent chronic myelogenous leukemia progenitors remaining after imatinib treatment. , 2007, Cancer research.

[13]  R. Gale,et al.  Chronic myeloid leukemia. , 1992, The American journal of medicine.

[14]  J. Cayuela,et al.  Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. , 2005, Blood.

[15]  T. Suda,et al.  Maintenance of Quiescent Hematopoietic Stem Cells in the Osteoblastic Niche , 2007, Annals of the New York Academy of Sciences.

[16]  Martin A Nowak,et al.  The age incidence of chronic myeloid leukemia can be explained by a one-mutation model , 2006, Proceedings of the National Academy of Sciences.

[17]  Franziska Michor,et al.  Successful Therapy Must Eradicate Cancer Stem Cells , 2006, Stem cells.

[18]  E. Orlandi,et al.  Outcome of four patients with chronic myeloid leukemia after imatinib mesylate discontinuation. , 2005, Haematologica.

[19]  A. Strife,et al.  Biology of chronic myelogenous leukemia: is discordant maturation the primary defect? , 1988, Seminars in hematology.

[20]  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.

[21]  Martin A. Nowak,et al.  Dynamics of chronic myeloid leukaemia , 2005, Nature.

[22]  C. Eaves,et al.  Human hematopoietic stem cells stimulated to proliferate in vitro lose engraftment potential during their S/G(2)/M transit and do not reenter G(0). , 2000, Blood.

[23]  F. Michor.  Chronic Myeloid Leukemia Blast Crisis Arises from Progenitors , 2007, Stem cells.

[24]  Rudolf Jaenisch,et al.  Analysis of histone 2B-GFP retention reveals slowly cycling hematopoietic stem cells , 2009, Nature Biotechnology.

[25]  D. Wodarz,et al.  Effect of cellular quiescence on the success of targeted CML therapy , 2022 .

[26]  B. Druker,et al.  Divergent clinical outcome in two CML patients who discontinued imatinib therapy after achieving a molecular remission. , 2004, Leukemia research.

[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]  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.

[29]  C. Eaves,et al.  Intermittent Exposure of Primitive Quiescent Chronic Myeloid Leukemia Cells to Granulocyte-Colony Stimulating Factor In vitro Promotes their Elimination by Imatinib Mesylate , 2006, Clinical Cancer Research.

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

[31]  R. Pyatt,et al.  Functional heterogeneity of human CD34(+) cells isolated in subcompartments of the G0 /G1 phase of the cell cycle. , 1997, Blood.

[32]  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.

[33]  Laurie E Ailles,et al.  Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. , 2004, The New England journal of medicine.

[34]  W. R. Bruce,et al.  A Quantitative Assay for the Number of Murine Lymphoma Cells capable of Proliferation in vivo , 1963, Nature.

[35]  Ben D. Chen,et al.  The Unexpected G 0 / G 1 Cell Cycle Status of Mobilized Hematopoietic Stem Cells From Peripheral Blood , 1997 .

[36]  Ingo Roeder,et al.  Dynamic modeling of imatinib-treated chronic myeloid leukemia: functional insights and clinical implications , 2006, Nature Medicine.

[37]  J. Dick,et al.  Cancer stem cells: lessons from leukemia. , 2005, Trends in cell biology.

[38]  J. Dick,et al.  Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity , 2004, Nature Immunology.

[39]  J. Apperley.  Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. , 2007, The Lancet. Oncology.

[40]  M. Caligiuri,et al.  A cell initiating human acute myeloid leukaemia after transplantation into SCID mice , 1994, Nature.

[41]  R. Clark,et al.  A pilot study of continuous imatinib vs pulsed imatinib with or without G-CSF in CML patients who have achieved a complete cytogenetic response , 2009, Leukemia.

[42]  C. Eaves,et al.  Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. , 1999, Blood.

[43]  B. Williams,et al.  Quiescence, cycling, and turnover in the primitive hematopoietic stem cell compartment. , 1997, Experimental hematology.

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

[45]  C. Eaves,et al.  Quantitation of the quiescent fraction of long-term culture-initiating cells in normal human blood and marrow and the kinetics of their growth factor-stimulated entry into S-phase in vitro. , 1995, Blood.

[46]  Irving L. Weissman,et al.  Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates , 2005, The Journal of experimental medicine.

[47]  R. Pyatt,et al.  Functional Heterogeneity of Human CD34+ Cells Isolated in Subcompartments of the G0 /G1 Phase of the Cell Cycle , 1997 .

[48]  T. Flores,et al.  A primitive hematopoietic cell is the target for the leukemic transformation in human philadelphia-positive acute lymphoblastic leukemia. , 2000, Blood.

[49]  C. Eaves,et al.  Changes in the Proliferative Activity of Human Hematopoietic Stem Cells in NOD/SCID Mice and Enhancement of Their Transplantability after In Vivo Treatment with Cell Cycle Inhibitors , 2002, The Journal of experimental medicine.

[50]  Christine Barett,et al.  Adaptive secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) mediates imatinib and nilotinib resistance in BCR/ABL+ progenitors via JAK-2/STAT-5 pathway activation. , 2006, Blood.

[51]  J. Rowley.  A New Consistent Chromosomal Abnormality in Chronic Myelogenous Leukaemia identified by Quinacrine Fluorescence and Giemsa Staining , 1973, Nature.

[52]  C. Sawyers,et al.  Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. , 2001, The New England journal of medicine.