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Application of CXCR4 Inhibitors in Leukemia

  • George Ansstas
  • Fazia Mir
  • Michael P. Rettig
  • Mark Schroeder
  • Linda Eissenberg
  • John F. DiPersio
Chapter

Abstract

Hematopoietic and cancer cells express the CXCR4 receptor, which in conjunction with its SDF-1/CXCL12 ligand mediates leukemia cell trafficking and homing to the marrow microenvironment. This interaction brings CXCR4-bearing cells within close proximity to marrow stromal cells, thus providing a niche for leukemic cell growth and contributing to drug resistance. Historically, CXCR4 antagonists were developed for the treatment of human immunodeficiency virus (HIV), but were also found to induce leukocytosis upon administration. This led to their use in hematopoietic stem cell mobilization. However, since CXCR4 plays a key role in homing and retention of normal and leukemic stem cells as well as other cancer cells to their microenvironments, the use of CXCR4 antagonists may provide for a novel therapeutic approach to interrupt these protective interactions and thus sensitize AML blasts to chemotherapy in vivo. Preclinical and/or clinical studies have shown that these novel drugs mobilize both normal hematopoietic progenitors and AML blasts into the peripheral circulation and that they are synergistic with G-CSF. In this chapter we will discuss CXCR4 inhibitors and their effects on mobilizing normal and leukemic cells when given alone or with G-CSF in preclinical models and in the clinic.

Keywords

Leukemia CXCR4 antagonists AMD 3100 Hematopoietic stem cell mobilization CXCR4 Plerixafor SDF-1 CXCL12 G-CSF CD34+ cells 

References

  1. 1.
    Wilson A, Trumpp A (2006) Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol 6(2):93–106PubMedCrossRefGoogle Scholar
  2. 2.
    Lapidot T, Dar A, Kollet O (2005) How do stem cells find their way home? Blood 106(6): 1901–1910PubMedCrossRefGoogle Scholar
  3. 3.
    Kollet O, Dar A, Lapidot T (2007) The multiple roles of osteoclasts in host defense: bone remodeling and hematopoietic stem cell mobilization. Annu Rev Immunol 25:51–69PubMedCrossRefGoogle Scholar
  4. 4.
    Kollet O, Shivtiel S, Chen YQ et al (2003) HGF, SDF-1, and MMP-9 are involved in stress-induced human CD34+ stem cell recruitment to the liver. J Clin Invest 112(2):160–169PubMedGoogle Scholar
  5. 5.
    Kiel MJ, Morrison SJ (2008) Uncertainty in the niches that maintain haematopoietic stem cells. Nat Rev Immunol 8(4):290–301PubMedCrossRefGoogle Scholar
  6. 6.
    Hartmann O, Le Corroller AG, Blaise D, et al (1997) Peripheral blood stem cell and bone marrow transplantation for solid tumors and lymphomas: hematologic recovery and costs. A randomized, controlled trial. Ann Intern Med 126(8):600–607Google Scholar
  7. 7.
    Beyer J, Schwella N, Zingsem J et al (1995) Hematopoietic rescue after high-dose chemotherapy using autologous peripheral-blood progenitor cells or bone marrow: a randomized comparison. J Clin Oncol 13(6):1328–1335PubMedGoogle Scholar
  8. 8.
    Bensinger WI, Martin PJ, Storer B et al (2001) Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med 344(3):175–181PubMedCrossRefGoogle Scholar
  9. 9.
    Schmitz N, Linch DC, Dreger P et al (1996) Randomised trial of filgrastim-mobilised peripheral blood progenitor cell transplantation versus autologous bone-marrow transplantation in lymphoma patients. Lancet 347(8998):353–357PubMedCrossRefGoogle Scholar
  10. 10.
    Bernhagen J, Krohn R, Lue H et al (2007) MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med 13:587–596PubMedCrossRefGoogle Scholar
  11. 11.
    Pruijt JF, Fibbe WE, Laterveer L et al (1999) Prevention of interleukin-8-induced mobilization of hematopoietic progenitor cells in rhesus monkeys by inhibitory antibodies against the metalloproteinase gelatinase B (MMP-9). Proc Natl Acad Sci USA 96(19):10863–10868PubMedCrossRefGoogle Scholar
  12. 12.
    Bensinger W, DiPersio JF, McCarty JM (2009) Improving stem cell mobilization strategies: future directions. Bone Marrow Transplant 43(3):181–195PubMedCrossRefGoogle Scholar
  13. 13.
    Levesque JP, Hendy J, Takamatsu Y, Simmons PJ, Bendall LJ (2003) Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide. J Clin Invest 111(2):187–196PubMedGoogle Scholar
  14. 14.
    Burger JA, Tsukada N, Burger M, Zvaifler NJ, Dell’Aquila M, Kipps TJ (2000) Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell-derived factor-1. Blood 96(8):2655–2663Google Scholar
  15. 15.
    Kessinger A, Armitage JO, Landmark JD, Weisenburger DD (1986) Reconstitution of human hematopoietic function with autologous cryopreserved circulating stem cells. Exp Hematol 14(3):192–196PubMedGoogle Scholar
  16. 16.
    Korbling M, Dorken B, Ho AD, Pezzutto A, Hunstein W, Fliedner TM (1986) Autologous transplantation of blood-derived hemopoietic stem cells after myeloablative therapy in a patient with Burkitt’s lymphoma. Blood 67(2):529–532PubMedGoogle Scholar
  17. 17.
    Bensinger W, Dipersio JF, McCarty JM (2009) Improving stem cell mobilization strategies: future directions. Bone Marrow Transplant 43(3):181–195Google Scholar
  18. 18.
    Bensinger W, Appelbaum F, Rowley S et al (1995) Factors that influence collection and engraftment of autologous peripheral-blood stem cells. J Clin Oncol 13(10):2547–2555PubMedGoogle Scholar
  19. 19.
    Reiffers J, Faberes C, Boiron JM et al (1994) Peripheral blood progenitor cell transplantation in 118 patients with hematological malignancies: analysis of factors affecting the rate of engraftment. J Hematother Fall 3(3):185–191CrossRefGoogle Scholar
  20. 20.
    Weaver CH, Hazelton B, Birch R et al (1995) An analysis of engraftment kinetics as a function of the CD34 content of peripheral blood progenitor cell collections in 692 patients after the administration of myeloablative chemotherapy. Blood 86(10):3961–3969PubMedGoogle Scholar
  21. 21.
    Haas R, Mohle R, Fruhauf S et al (1994) Patient characteristics associated with successful mobilizing and autografting of peripheral blood progenitor cells in malignant lymphoma. Blood 83(12):3787–3794PubMedGoogle Scholar
  22. 22.
    Sugrue MW, Williams K, Pollock BH et al (2000) Characterization and outcome of “hard to mobilize” lymphoma patients undergoing autologous stem cell transplantation. Leuk Lymphoma 39(5–6):509–519PubMedCrossRefGoogle Scholar
  23. 23.
    Ozkurt ZN, Yegin ZA, Suyani E et al (2010) Factors affecting stem cell mobilization for autologous hematopoietic stem cell transplantation. J Clin Apher 25(5):280–286PubMedCrossRefGoogle Scholar
  24. 24.
    de la Rubia J, Arbona C, de Arriba F et al (2002) Analysis of factors associated with low peripheral blood progenitor cell collection in normal donors. Transfusion 42(1):4–9PubMedCrossRefGoogle Scholar
  25. 25.
    De Clercq E (2003) The bicyclam AMD3100 story. Nat Rev Drug Discov 2(7):581–587PubMedCrossRefGoogle Scholar
  26. 26.
    Donzella GA, Schols D, Lin SW et al (1998) AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor. Nat Med 4(1):72–77PubMedCrossRefGoogle Scholar
  27. 27.
    Hendrix CW, Flexner C, MacFarland RT et al (2000) Pharmacokinetics and safety of AMD-3100, a novel antagonist of the CXCR-4 chemokine receptor, in human volunteers. Antimicrob Agents Chemother 44(6):1667–1673PubMedCrossRefGoogle Scholar
  28. 28.
    Lack NA, Green B, Dale DC et al (2005) A pharmacokinetic-pharmacodynamic model for the mobilization of CD34+ hematopoietic progenitor cells by AMD3100. Clin Pharmacol Ther 77(5):427–436PubMedCrossRefGoogle Scholar
  29. 29.
    Liles WC, Broxmeyer HE, Rodger E et al (2003) Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist. Blood 102(8):2728–2730PubMedCrossRefGoogle Scholar
  30. 30.
    Liles WC, Rodger E, Broxmeyer HE et al (2005) Augmented mobilization and collection of CD34+ hematopoietic cells from normal human volunteers stimulated with granulocyte-colony-stimulating factor by single-dose administration of AMD3100, a CXCR4 antagonist. Transfusion 45(3):295–300PubMedCrossRefGoogle Scholar
  31. 31.
    Choi HY, Yong CS, Yoo BK (2010) Plerixafor for stem cell mobilization in patients with non-Hodgkin’s lymphoma and multiple myeloma. Ann Pharmacother 44(1):117–126PubMedCrossRefGoogle Scholar
  32. 32.
    Devine SM, Flomenberg N, Vesole DH et al (2004) Rapid mobilization of CD34+ cells following administration of the CXCR4 antagonist AMD3100 to patients with multiple myeloma and non-Hodgkin’s lymphoma. J Clin Oncol 22(6):1095–1102PubMedCrossRefGoogle Scholar
  33. 33.
    Flomenberg N, Devine SM, Dipersio JF et al (2005) The use of AMD3100 plus G-CSF for autologous hematopoietic progenitor cell mobilization is superior to G-CSF alone. Blood 106(5):1867–1874PubMedCrossRefGoogle Scholar
  34. 34.
    Calandra G, McCarty J, McGuirk J et al (2008) AMD3100 plus G-CSF can successfully mobilize CD34+ cells from non-Hodgkin’s lymphoma, Hodgkin’s disease and multiple myeloma patients previously failing mobilization with chemotherapy and/or cytokine treatment: compassionate use data. Bone Marrow Transplant 41(4):331–338PubMedCrossRefGoogle Scholar
  35. 35.
    Cashen A, Lopez S, Gao F et al (2008) A phase II study of plerixafor (AMD3100) plus G-CSF for autologous hematopoietic progenitor cell mobilization in patients with Hodgkin lymphoma. Biol Blood Marrow Transplant 14(11):1253–1261PubMedCrossRefGoogle Scholar
  36. 36.
    Fowler CJ, Dunn A, Hayes-Lattin B et al (2009) Rescue from failed growth factor and/or chemotherapy HSC mobilization with G-CSF and plerixafor (AMD3100): an institutional experience. Bone Marrow Transplant 43(12):909–917PubMedCrossRefGoogle Scholar
  37. 37.
    Stiff P, Micallef I, McCarthy P et al (2009) Treatment with plerixafor in non-Hodgkin’s ­lymphoma and multiple myeloma patients to increase the number of peripheral blood stem cells when given a mobilizing regimen of G-CSF: implications for the heavily pretreated patient. Biol Blood Marrow Transplant 15(2):249–256PubMedCrossRefGoogle Scholar
  38. 38.
    Stewart DA, Smith C, MacFarland R, Calandra G (2009) Pharmacokinetics and pharmacodynamics of plerixafor in patients with non-Hodgkin lymphoma and multiple myeloma. Biol Blood Marrow Transplant 15(1):39–46PubMedCrossRefGoogle Scholar
  39. 39.
    Dugan MJ, Maziarz RT, Bensinger WI et al (2010) Safety and preliminary efficacy of plerixafor (Mozobil) in combination with chemotherapy and G-CSF: an open-label, multicenter, exploratory trial in patients with multiple myeloma and non-Hodgkin’s lymphoma undergoing stem cell mobilization. Bone Marrow Transplant 45(1):39–47PubMedCrossRefGoogle Scholar
  40. 40.
    Shaughnessy P, Islas-Ohlmayer M, Murphy J, et al (2009) Plerixafor plus G-CSF compared to chemotherapy plus G-CSF for mobilization of autologous CD34+ cells resulted in similar cost but more predictable days of apheresis and less hospitalization. Blood (ASH Annual Meeting Abstracts) 114(22): http://abstracts.hematologylibrary.org/cgi/content/abstract/114/22/2277?maxtoshow=&hits=10&RESULTFORMAT=&fulltext=2277&searchid=1&FIRSTINDEX=0&volume=114&issue=22&resourcetype=HWCIT abstract [2277]
  41. 41.
    DiPersio JF, Micallef IN, Stiff PJ et al (2009) Phase III prospective randomized double-blind placebo-controlled trial of plerixafor plus granulocyte colony-stimulating factor compared with placebo plus granulocyte colony-stimulating factor for autologous stem-cell mobilization and transplantation for patients with non-Hodgkin’s lymphoma. J Clin Oncol 27(28):4767–4773PubMedCrossRefGoogle Scholar
  42. 42.
    DiPersio JF, Stadtmauer EA, Nademanee A et al (2009) Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. Blood 113(23):5720–5726PubMedGoogle Scholar
  43. 43.
    Micallef IN, Stiff PJ, DiPersio JF et al (2009) Successful stem cell remobilization using plerixafor (mozobil) plus granulocyte colony-stimulating factor in patients with non-hodgkin lymphoma: results from the plerixafor NHL phase 3 study rescue protocol. Biol Blood Marrow Transplant 15(12):1578–1586PubMedCrossRefGoogle Scholar
  44. 44.
    Devine SM, Vij R, Rettig M et al (2008) Rapid mobilization of functional donor hematopoietic cells without G-CSF using AMD3100, an antagonist of the CXCR4/SDF-1 interaction. Blood 112(4):990–998PubMedCrossRefGoogle Scholar
  45. 45.
    Rettig MP, Lopez S, McFarland K, et al (2010) Rapid and prolonged mobilization of human CD34+ hematopoietic stem cells following intravenous (IV) administration of plerixafor. Blood (ASH Annual Meeting Abstracts) 116:abstract [2261]Google Scholar
  46. 46.
    Peled A, Petit I, Kollet O et al (1999) Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science 283:845–848PubMedCrossRefGoogle Scholar
  47. 47.
    Tavor S, Petit I, Proozov S et al (2004) CXCR4 regulates migration and development of human acute myelogenous leukemia stem cells in transplanted NOD/SCID mice. Cancer Res 64:12817–12824CrossRefGoogle Scholar
  48. 48.
    Burger JA, Spoo A, Dwenger A et al (2003) CXCR4 chemokine receptors (CD184) and alpha4beta1 integrins mediate spontaneous migration of human CD34+ progenitors and acute myeloid leukaemia cells beneath marrow stromal cells (pseudoemperipolesis). Br J Haematol 122:579–589PubMedCrossRefGoogle Scholar
  49. 49.
    Westervelt P, Lane AA, Pollock JL et al (2003) High-penetrance mouse model of acute promyelocytic leukemia with very low levels of PML-RARalpha expression. Blood 102:1857–1865PubMedCrossRefGoogle Scholar
  50. 50.
    Nervi B, Ramirez P, Rettig MP et al (2009) Chemosensitization of AML following mobilization by the CXCR4 antagonist AMD3100. Blood 113(24):6206–6214PubMedCrossRefGoogle Scholar
  51. 51.
    Fukudas S, Broxmeyer HE, Pelus LM (2005) Flt3 ligand and the Flt3 receptor regulate hematopoietic cell migration by modulating the SDF-1α(CXCL12)/CXCR4 axis. Blood 105:3117–3126CrossRefGoogle Scholar
  52. 52.
    Zeng Z, Shi YX, Samudio IJ et al (2009) Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML. Blood 113(24):6215–6224PubMedCrossRefGoogle Scholar
  53. 53.
    Bradostock KF, Makrynikola V, Bianchi A et al (2000) Effects of the chemokine stromal cell-derived factor-1 on the migration and localization of precursor-B acute lymphoblastic leukemia cells within bone marrow stromal layers. Leukemia 14(5):882–888CrossRefGoogle Scholar
  54. 54.
    Juarez J, Bradotock KF, Gottlieb DJ, Bendall LJ (2003) Effects of inhibitors of the chemokine receptor CXCR4 on acute lymphoblastic leukemia cells in vitro. Leukemia 17(7):1294–300PubMedCrossRefGoogle Scholar
  55. 55.
    Spiegel A, Kollet O, Peled A et al (2004) Unique SDF-1-induced activation of human precursor-B ALL cells as a result of altered CXCR4 expression and signaling. Blood 103(8): 2900–2907PubMedCrossRefGoogle Scholar
  56. 56.
    Juarez J, Dela Pena A, Baraz R, et al (2007) CXCR4 antagonists mobilize childhood acute lymphoblastic leukemia cells into the peripheral blood and inhibit engraftment. Leukemia 21(6):1249–1257Google Scholar
  57. 57.
    Nagasawa T, Hirota S, Tachibana K et al (1996) Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 382: 635–638PubMedCrossRefGoogle Scholar
  58. 58.
    Hernandez PA, Gorlin RJ, Lukens JN et al (2003) Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. Nat Genet 34:70–74PubMedCrossRefGoogle Scholar
  59. 59.
    Rombouts EJ, Pavic B, Lowenberg B et al (2004) Relation between CXCR-4 expression, Flt3 mutations, and unfavorable prognosis of adult acute myeloid leukemia. Blood 104(2): 550–557PubMedCrossRefGoogle Scholar
  60. 60.
    Spoo AC, Lubbert M, Wierda WG et al (2007) CXCR4 is a prognostic marker in acute myelogenous leukemia. Blood 109:786–791PubMedCrossRefGoogle Scholar
  61. 61.
    Konoplev S, Rassidakis GZ, Estey E et al (2007) Overexpression of CXCR4 predicts adverse overall and event-free survival in patients with unmutated FLT3 acute myeloid leukemia with normal karyotype. Cancer 109(6):1152–1156PubMedCrossRefGoogle Scholar
  62. 62.
    Andreeff M, Konoplev S, Wang R, et al (2006) Massive mobilization of AML cells into circulation by disruption of leukemia/stroma cell interactions using CXCR4 antagonist AMD3100: first evidence in patients and potential for abolishing bone marrow microenvironment-mediated resistance. Blood (ASH Annual Meeting Abstracts) 108–171A: abstract [568]Google Scholar
  63. 63.
    Uy GL, Rettig MP, Mc Farland K, et al (2009) A phase I/II study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory AML. Blood (ASH Annual Meeting Abstracts) 114(22): http://abstracts.hematologylibrary.org/cgi/content/abstract/114/22/787?maxtoshow=&hits=10&RESULTFORMAT=&fulltext=787&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT abstract [787]
  64. 64.
    Ghobrial I, Azab AA, Laubch JP, et al (2010) Phase I trial of plerixafor and bortezomib as a chemosensitization strategy in relapsed or relapsed/refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts) 116(21): http://abstracts.hematologylibrary.org/cgi/content/abstract/116/21/1943?maxtoshow=&hits=10&RESULTFORMAT=&fulltext=1943&searchid=1&FIRSTINDEX=0&volume=116&issue=21&resourcetype=HWCIT abstract [1943]
  65. 65.
    Andritsos L, Byrd JC, Jones JA, et al (2010) Preliminary results from a phase I dose escalation study to determine the maximum tolerated dose of plerixafor in combination with rituximab in patients with relapsed chronic lymphocytic leukemia. Blood (ASH Annual Meeting Abstracts) 116(21): http://abstracts.hematologylibrary.org/cgi/content/abstract/116/21/2450?maxtoshow=&hits=10&RESULTFORMAT=&fulltext=2450&searchid=1&FIRSTINDEX=0&sortspec=relevance&resourcetype=HWCIT abstract [2450]

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • George Ansstas
    • 1
  • Fazia Mir
    • 1
  • Michael P. Rettig
    • 1
  • Mark Schroeder
    • 1
  • Linda Eissenberg
    • 1
  • John F. DiPersio
    • 1
  1. 1.Division of Oncology, Siteman Cancer CenterWashington University School of MedicineSaint LouisUSA

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