Therapeutic Strategies and Concepts of Cure in CML

  • Tariq I Mughal
  • John M Goldman
Part of the Hematologic Malignancies book series (HEMATOLOGIC)


The molecular basis of chronic myeloid leukemia (CML) has been reasonably well defined in the last 20 years. The acquisition in a hematopoietic stem cell of a BCR-ABL fusion gene is generally considered to be the initiating event for the chronic phase of CML. It leads to expansion of a hematopoietic clone that expresses the Bcr-Abl oncoprotein with enhanced tyrosine kinase activity. Oral administration of the tyrosine kinase inhibitor imatinib mesylate (IM) reduces the leukemia cell mass by at least 2 logs and induces complete cytogenetic remissions in most patients with early phase CML. It probably prolongs survival in comparison with previous treatments, but fails to eradicate leukemia stem cells, some of which may be in a “quiescent” or “dormant” phase. IM is now considered to be the best initial therapy for the majority of patients with newly diagnosed CML, though the issues of optimal dose and duration of treatment are not yet resolved. Some patients who respond initially to IM later become resistant as a result of diverse mechanisms, which include the acquisition of mutations in the BCR-ABL kinase domain. Efforts to improve on the use of IM as a single agent include combining it with other agents and the introduction of second-generation tyrosine kinase inhibitors, such as dasatinib and nilotinib. The therapy of patients in the advanced phases of CML remains a significant challenge.


Chronic Myeloid Leukemia Chronic Myelogenous Leukemia Imatinib Mesylate Chronic Myeloid Leukemia Patient Cytogenetic Response 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Adams J, Palombella VJ, Sausville EA et al (1999) Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 59:2615–2622PubMedGoogle Scholar
  2. Aguayo A, Kantarjian H, Manshouri T et al (2000) Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes. Blood 96:2240–2245PubMedGoogle Scholar
  3. Aloisi A, Gregorio SD, Stagno F et al (2006) BCR-ABL nuclear entrapment kills human CML cells: ex-vivo study on 35 patients with combination of imatinib mesylate and leptomycin B. Blood 107:1591–1598PubMedGoogle Scholar
  4. Apperley JF, Boque C, Carella A et al (2004) Autografting in chronic myeloid leukaemia: a meta-analysis of six randomised trials. Bone Marrow Transplant 33(Suppl 1):S28Google Scholar
  5. Avery S, Nadal E, Marin D et al (2004) Lymphoid transformation in a CML patient in complete cytogenetic remission following treatment with imatinib. Leukemia Res 28(Suppl 1):75–77Google Scholar
  6. Baccarani M, Martinelli G, Rosti G et al (2004) Imatinib and pegylated human recombinant interferon-alpha2b in early chronic-phase chronic myeloid leukemia. Blood 104:4245–4251PubMedGoogle Scholar
  7. Baccarani M, Saglio G, Goldman J et al (2006) Evolving concepts in the management of chronic myeloid leukemia. Recommendations from an expert panel on behalf of the European Leukemia-net. Blood 108:1835–1840Google Scholar
  8. Barrett J (2003) Allogeneic stem cell transplantation for chronic myeloid leukemia. Semin Hematol 40:59–71PubMedGoogle Scholar
  9. Bhatia M, Wang JCY, Kapp U et al (1997) Purification of primitive human hematopoietic cells capable of repopulating immune-deficient mice. Proc Nat Acad Sci USA 94:5320–5325PubMedGoogle Scholar
  10. Bocchia M, Gentili S, Abruzzese E et al (2005) Effect of a p210 multipeptide vaccine associated with imatinib or interferon in patients with chronic myeloid leukaemia and persistent residual disease: a multicentre observational trial. Lancet 365:657–659PubMedGoogle Scholar
  11. Bornhäuser M, Kröger N, Schwerdtfeger R et al (2006) Allogeneic haematopoietic cell transplantation for chronic myelogenous leukaemia in the era of imatinib: a retrospective multicentre study. Eur J Haematol 76:9–17PubMedGoogle Scholar
  12. Burton C, Azzi A, Kerridge I (2002) Adverse effects after imatinib mesylate therapy. N Engl J Med 346:713Google Scholar
  13. Bumm T, Muller C, Al Ali HK et al (2003) Emergence of clonal cytogenetic abnormalities in Ph-cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority. Blood 101:1941–1949PubMedGoogle Scholar
  14. Burley S (2005) Application of FAST Fragment-based lead discovery and structure-guided design to discover small molecule inhibitors of Bcr-Abl tyrosine kinase active against the T315I imatinib-resistant mutant. Blood 106:abstract 698Google Scholar
  15. Carella AM, Lerma E, Corsetti MT et al (1999) Autografting with Philadelphia chromosome negative mobilized hematopoietic progenitor cells in chronic myelogenous leukemia. Blood 83:1534–1539Google Scholar
  16. Cathcart K, Pinilla-Ibarz J, Korontsvit T et al (2004) A multivalent bcr-abl fusion peptide vaccination trial in patients with chronic myeloid leukemia. Blood 103:1037–1042PubMedGoogle Scholar
  17. Clark RE, Dodi IA, Hill SC et al (2001) Direct evidence that leukemic cells present HLA-associated immunogenic peptides from the BCR-ABL b3a2 fusion protein. Blood 98:2887–2893PubMedGoogle Scholar
  18. Copland M, Fraser AR, Harrison SJ, Holyoake TL (2005) Targeting the silent minority: emerging immunotherapeutic strategies for eradication of malignant stem cells in chronic myeloid leukaemia. Cancer Immunol Immunother 54:297–306PubMedGoogle Scholar
  19. Cortes J, Kantarjian H (2005) New targeted approaches in chronic myeloid leukemia. J Clin Oncol 23:6316–6324PubMedGoogle Scholar
  20. Cortes J, Giles F, O’Brien S et al (2003a) Result of high-dose imatinib mesylate in patients with Philadelphia chromosome-positive chronic myeloid leukemia after failure of interferon-a. Blood 102:83–86PubMedGoogle Scholar
  21. Cortes J, Albitar M, Thomas D et al (2003b) Efficacy of the farnesyl transferase inhibitor R115777 in chronic myeloid leukemia and other hematologic malignancies. Blood 101:1692–1697PubMedGoogle Scholar
  22. Cortes J, Giles F, O’Brien SM et al (2003c) Phase II study of bortezomib (Velcade, formerly PS341) for patients with imatinib-refractory chronic myeloid leukemia in chronic or accelerated phase. Blood 102:312b, abstract 4971Google Scholar
  23. Cortes J, O’Brien S, Kantarjian HM (2004a) Discontinuation of imatinib therapy after achieving a molecular response. Blood 104:2204–2205PubMedGoogle Scholar
  24. Cortes J, O’Brien S, Verstovsek S et al (2004b) Phase I study of lonafarnib (SCH66336) in combination with imatinib for patients (pts) with chronic myeloid leukemia (CML) after failure to imatinib. Blood 104:288a, abstract 1009Google Scholar
  25. Cortes JE, O’Brien SM, Giles F et al (2004c) Investigational strategies in chronic myelogenous leukemia. Hematol Oncol Clin N Am 18:619–639Google Scholar
  26. Cortes J, Kim DW, Rosti G et al (2006) Dasatinib in patients with chronic myeloid leukemia in myeloid blast crisis who are resistant or intolerant to imatinib: results of the CA1800006’ sTART-B’ Study. J Clin Oncol 24:18S, abstract 6529Google Scholar
  27. Coutre S, Martinelli G, Dombret H et al (2006) Dasatinib in patients with chronic myeloid leukemia in lymphoid blast crisis or Ph-chromosome positive acute lymphoblastic leukemia (Ph+ALL) who are imatinib-resistant or intolerant: Results of the CA180015’ sTART-L’ study. J Clin Oncol 24:18S, abstract 6528Google Scholar
  28. Dazzi F, Szydlo RM, Cross NC et al (2000) Durability of responses following donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Blood 96:2712–2716PubMedGoogle Scholar
  29. Deininger MWN (2005a) Can we afford to let sleeping dogs lie? Blood 105:1840–1841PubMedGoogle Scholar
  30. Deininger M, Buchdunger E, Druker BJ (2005b) The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 105:2640–2653PubMedGoogle Scholar
  31. Druker BJ, Lyndon NB (2000) Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myeloid leukemia. J Clin Invest 105:3–7PubMedGoogle Scholar
  32. Druker BJ, Tamura S, Buchdunger E et al (1996) Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of BCR-ABL positive cells. Nat Med 2:561–566PubMedGoogle Scholar
  33. Druker BJ, Talpaz M, Resta DJ et al (2001) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344:1031–1037PubMedGoogle Scholar
  34. Druker BJ, Guilhot F, O’Brien S et al (2006) Five-year follow-up of imatinib therapy for newly diagnosed chronic myeloid leukemia in chronic-phase shows sustained responses and high overall survival. New Engl J Med, in pressGoogle Scholar
  35. Du Y, Wang K, Fang H et al (2006) Coordination of intrinsic, extrinsic, and endoplasmic reticulum-mediated apoptosis by imatinib mesylate combined with arsenic trioxide in chronic myeloid leukemia. Blood 107:1582–1590PubMedGoogle Scholar
  36. Eaves AC, Barnett MJ, Ponchio L et al (1998) Differences between normal and CML stem cells: potential targets for clinical exploitation. Stem Cells 16(Suppl 1):77–83PubMedGoogle Scholar
  37. Ebonether M, Stentoft J, Ford J, Buhl L, Gratwohl A (2002) Cerebral edema as a possible complication of treatment with imatinib. Lancet 359:1751–1752Google Scholar
  38. Eisterer W, Jiang X, Christ O et al (2005) Different subsets of primary chronic myeloid leukemia stem cells engraft immunodeficient mice and produce a model of human disease. Leukemia 19:435–411PubMedGoogle Scholar
  39. El Ouriaghli F, Sloand E, Mainwaring L et al (2003) Clonal dominance in chronic myelogenous leukemia is associated with diminished sensitivity to the antiproliferative effects of neutrophil elastase. Blood 102:3786–3792PubMedGoogle Scholar
  40. Fialkow PJ, Martin PJ, Najfeld, V et al (1981) Multistep origin of chronic myelogenous leukemia. Blood 58:158–163PubMedGoogle Scholar
  41. Goldman JM, Marin D (2003) Management decisions in chronic myeloid leukemia. Semin Hematol 40:97–103PubMedGoogle Scholar
  42. Goldman JM, Gordon MY (2006) Why do stem CML cells survive allogeneic stem cell transplantation or imatinib? Does it really matter? Leuk Lymphoma 47:1–8PubMedGoogle Scholar
  43. Goldman JM, Hughes T, Radich J et al (2005) Continuing reduction in level of residual disease after 4 years in patients with CML in chronic phase responding to first-line imatinib (IM) in the IRIS study. Blood 106:51a, abstract 163Google Scholar
  44. Goodell MA, Rosenzweig M, Kim H et al (1997) Dye efflux studies suggest that stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species. Nat Med 3:1337–1345PubMedGoogle Scholar
  45. Gordon MY, Marley SB, Lewis JL et al (1998) Treatment with interferon-a preferentially reduces the capacity for amplification of granulocyte-macrophage progenitors (CFU-GM) from patients with chronic myeloid leukemia but spares normal CFU-GM. J Clin Invest 102:710–715PubMedGoogle Scholar
  46. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL (2001) Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293:876–880PubMedGoogle Scholar
  47. Gotlib J, Mauro MJ, O’Dwyer M et al (2003) Tipifarnib (Zarnestra) and imatinib (Gleevec) combination therapy in patients with advanced chronic myelogenous leukemia (CML): Preliminary results of a phase I study. Blood 102:909a, abstract 3384Google Scholar
  48. Gratwohl A, Passweg J, Baldomero H et al (2001) Hematopoietic stem cell transplantation activity in Europe. Bone Marrow Transplant 27:899–916PubMedGoogle Scholar
  49. Gratwohl A et al (2005) Does early stem cell transplant have a role in chronic myeloid leukaemia? Lancet Oncol 6:722–724Google Scholar
  50. Griffin JD (2002) Resistance to targeted therapy in leukaemia. Lancet 359:458–459PubMedGoogle Scholar
  51. Gumireddy K, Baker SJ, Cosenza SC, John P, Kang AD, Robell KA, Reddy MVR, Reddy EP (2005) A non-ATP-competitive inhibitor of BCR-ABL overrides imatinib resistance. Proc Nat Acad Sci USA 102:1992–1997PubMedGoogle Scholar
  52. Guo Y, Lubbert M, Engelhardt M (2003) CD34-hematopoietic stem cells: current concepts. Stem Cells 21:15–20PubMedGoogle Scholar
  53. Hochhaus A, Kantrajian H, Baccarani M et al (2006) Dasatinib in patients with chronic phase chronic myeloid leukemia who are resistant or intolerant to imatinib: Results of the CA180013’ sTART-C’ study. J Clin Oncol 24:18S, abstract 6526Google Scholar
  54. Holyoake T, Jiang X, Eaves C, Eaves A (1999) Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. Blood 94:2056–2064PubMedGoogle Scholar
  55. Hoover RR, Mahon FX, Melo JV, Daley GQ (2002) Overcoming STI571 resistance with farnesyl transferase inhibitor SCH66336. Blood 100:1068–1071PubMedGoogle Scholar
  56. Hughes TP, Kaeda J, Branford S et al (2003) Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed patients with chronic myeloid leukemia. N Engl J Med 349:1423–1432PubMedGoogle Scholar
  57. Hughes TP, Deininger M, Hochhaus A et al (2006) Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: Review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 168:28–37Google Scholar
  58. Huntly BJ, Gilliland DG (2005) Leukemia stem cells and the evolution of cancer-stem cell research. Nat Rev Cancer 5:311–321PubMedGoogle Scholar
  59. Issa J-P, Gharibyan V, Cortes J et al (2005) Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate. J Clin Oncol 23:3948–3956PubMedGoogle Scholar
  60. Jabbour E, Kantarjian H, O’Brien S et al (2006) Sudden blastic transformation in patients with chronic myeloid leukemia treated with imatinib mesylate. Blood 107:480–482PubMedGoogle Scholar
  61. Jamieson CH, Ailles LE, Dylla SJ et al (2004) Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 351:657–667PubMedGoogle Scholar
  62. Kaeda J, O’Shea D, Szydlo RM et al (2006) Serial measurements BCR-ABL transcripts in the peripheral blood after allogeneic stem cell transplant for chronic myeloid leukemia: An attempt to define patients who may not require further therapy. Blood 102:4121–4126Google Scholar
  63. Kantarjian HM, Cortes J, O’Brien S et al (2002) Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukaemia in blast phase. Blood 99:3547–3553PubMedGoogle Scholar
  64. Kantarjian HM, Talpaz M, O’Brien S et al (2003a) Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood 101:473–475PubMedGoogle Scholar
  65. Kantarjian HM, O’Brien S, Cortes J et al (2003b) Results of decitabine (5-aza-2′deoxycytidine) therapy in 130 patients with chronic myelogenous leukemia. Cancer 98:522–528PubMedGoogle Scholar
  66. Kantarjian H, Talpaz M, O’Brien S et al (2004a) High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia. Blood 103:2873–2878PubMedGoogle Scholar
  67. Kantarjian HM, Cortes JE, O’Brien S et al (2004b) Long-term survival benefit and improved complete cytogenetic and molecular response rates with imatinib mesylate in Philadelphia chromosome-positive chronic myeloid leukemia after failure of interferon-a. Blood 104:1979–1988PubMedGoogle Scholar
  68. Kantarjian HM, Giles F, Wunderle L et al (2006a) Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 354:2531–2541PubMedGoogle Scholar
  69. Kantarjian HM, Gatterman N, O’Brien S et al (2006b) A phase II study of AMN107, a novel inhibitor of bcr-abl, administered to imatinib resistant and intolerant patients with chronic myelogenous leukemia in chronic phase. J Clin Oncol 24:18S, abstract 6534Google Scholar
  70. Kornblith AB, Herndon JE, Silverman LR et al (2000) Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: A cancer and Leukemia Group B study. J Clin Oncol 18:956–962Google Scholar
  71. Kreuzer KA, Kluhs C, Baskaynak G et al (2004) Filgrastim-induced stem cell mobilization in chronic myeloid leukaemia patients during imatinib therapy: safety, feasibility and evidence for an efficient in vivo purging. Br J Haematol 124:195–199PubMedGoogle Scholar
  72. Kuci S, Wessels JT, Buhring H-J et al (2003) Identification of a novel class of human adherent CD34-stem cells that give rise to SCID-repopulating cells. Blood 101:869–876PubMedGoogle Scholar
  73. Kurbegov D, Molldrem JL (2004) Immunity to chronic myelogenous leukemia. Hematol Oncol Clin North Am 18:733–752PubMedGoogle Scholar
  74. Lange T, Bumm T, Mueller M et al (2005) Durability of molecular remission in chronic myeloid leukemia patients treated with imatinib vs stem cell transplantation. Leukemia 19:1262–1265PubMedGoogle Scholar
  75. Li Z, Qiao Y, Laska E et al (2003) Combination of imatinib mesylate with autologous leukocyte-derived heat shock protein 70 vaccine for chronic myelogenous leukemia. Proc Am Soc Clin Onc 14:664Google Scholar
  76. Loriaux M, Deininger M (2004) Clonal abnormalities in Philadelphia chromosome negative cells in chronic myeloid leukemia patients treated with imatinib. Leuk Lymph 45:2197–2203Google Scholar
  77. Ly C, Arechiga AF, Melo JV, Walsh C, Ong ST (2003) Bcr-Abl kinase modulates the transplantation regulators ribosomal protein S6 and 4EBP1 in chronic myelogenous leukemia cells via the mammalian target of rapamycin. Cancer Res 63:5716–5722PubMedGoogle Scholar
  78. Mahon FX, Deininger MWN, Schultheis B et al (2000) Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood 96:1070–1079PubMedGoogle Scholar
  79. Marin D, Kaeda JS, Andreasson C et al (2005) Phase I/II trial of adding semisynthetic homoharringtonine in chronic myeloid leukemia patients who have achieved partial or complete cytogenetic response on imatinib. Cancer 103:1850–1855PubMedGoogle Scholar
  80. Marley SB, Gordon MY (2005) Chronic myeloid leukemia: stem cell derived but progenitor cell driven. Clin Sci (London) 109:13–25PubMedGoogle Scholar
  81. Marley SB, Deininger MW, Davidson RJ et al (2000) The tyrosine kinase inhibitor STI571, like interferon-a, preferentially reduces the capacity for amplification of granulocyte-macrophage progenitors from patients with chronic myeloid leukemia. Exp Hematol 28:551–557PubMedGoogle Scholar
  82. Marley SB, Davidson RJ, Lewis JL et al (2001) Progenitor cells from patients with advanced phase chronic myeloid leukemia respond to ST571 in vitro. Leuk Res 25:997–1002PubMedGoogle Scholar
  83. Martine G, Philippe R, Michel T et al (2002) Imatinib (Gleevec) and cytarabine (Ara-C) is an effective regimen in Philadelphia-positive chronic myelogenous leukemia chronic phase patients. Blood 100:95 a, abstract 351Google Scholar
  84. Mauro MJ, Deininger MWN, O’Dwyer ME et al (2002) Phase I/II study of arsenic trioxide (trisenox) in combination with imatinib mesylate (Gleevec, STI571) in patients with Gleevec-resistant chronic myelogenous leukemia in chronic phase. Blood 100, abstract 3090Google Scholar
  85. Mayerhofer M, Aichberger KJ, Florian S et al (2005) Identification of mTOR as a novel bifunctional target in chronic myeloid leukemia: dissection of growth-inhibitory and VEGF-suppressive effects of rapamycin in leukemic cells. FASEB J 19:960–962PubMedGoogle Scholar
  86. Mestan J, Brueggen J, Fabbro D et al (2005) In vivo activity of AMN107, as selective Bcr-Abl kinase inhibitor, in murine leukemia models. J Clin Oncol 23:565s, abstract 6522Google Scholar
  87. Michor F, Hughes TP, Iwasa Y et al (2005) Dynamics of chronic myeloid leukaemia. Nature 435:1267–1270PubMedGoogle Scholar
  88. Mohi MG, Boulton C, Gu T-L et al (2004) Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proc Natl Acad Sci USA 101:3130–3135PubMedGoogle Scholar
  89. Molldrem J, Dermime S, Parker K et al (1996) Targeted T-cell therapy for human leukemia: cytotoxic T lymphocytes specific for a peptide derived from proteinase 3 preferentially lyse human myeloid leukemia cells. Blood 88:2450–2457PubMedGoogle Scholar
  90. Molldrem JJ, Lee PP, Wang C et al (2000) Evidence that specific T lymphocytes may participate in the elimination of chronic myelogenous leukemia. Nat Med 6:1018–1023PubMedGoogle Scholar
  91. Mughal TI, Goldman JM (2001) Chronic myeloid leukaemia: STI571 magnifies the therapeutic dilemma. Eur J Cancer 37:561–568PubMedGoogle Scholar
  92. Mughal TI, Goldman JM (2003) Chronic myeloid leukemia: The value of tyrosine kinase inhibition. Am J Cancer 2:305–311Google Scholar
  93. Mughal TI, Goldman JM (2004) Chronic myeloid leukemia: Current status and controversies. Oncology 18:837–847PubMedGoogle Scholar
  94. Mughal TI, Goldman JM (2006a) Molecularly targeted treatment of chronic myeloid leukemia: Beyond the imatinib era. Front Biosci 1:209–220Google Scholar
  95. Mughal TI, Goldman JM (2006b) Chronic myeloid leukemia: Why does it evolve from chronic phase to blast transformation? Front Biosci 1:198–208Google Scholar
  96. Mughal TI, Hoyle C, Goldman JM (1994) Autografting for patients with chronic myeloid leukemia — the Hammersmith Experience. Stem Cell 11:20–22Google Scholar
  97. Mughal TI, Yong A, Szydlo RM et al (2001) The probability of long-term leukaemia-free survival for patients in molecular remission 5 years after allogeneic stem cell transplantation for chronic myeloid leukaemia in chronic phase. Br J Haematol 115:569–574PubMedGoogle Scholar
  98. Mow BM, Chandra J, Svingen PA et al (2002) Effects of the Bcr/abl kinase inhibitors STI571 and adaphostin (NSC 680410) on chronic myelogenous leukemia cells in vitro, Blood, 99:664–671PubMedGoogle Scholar
  99. Nimmanapalli R, O’Bryan E, Bhalla K (2001) Geldanamycin and its analogue 17-allylamino-17-demethoxygeldanamycin lowers Bcr-Abl levels and induces apoptosis and differentiation of Bcr-Abl-positive human leukemic blasts. Cancer Res 61:1799–1804PubMedGoogle Scholar
  100. Nimmanapalli R, Fuino L, Bali P et al (2003) Histone deacetylase inhibitor LAQ824 both lowers expression and promotes proteasomal degradation of Bcr-Abl and induces apoptosis of imatinib mesylate-sensitive or-refractory chronic myelogenous leukemia-blast crisis cells. Cancer Res 63:5126–5135PubMedGoogle Scholar
  101. O’Brien S, Kantarjian H, Keating M et al (1995) Homoharringtonine therapy induces responses in patients with chronic myelogenous leukemia in late chronic phase. Blood 86:3322–3326PubMedGoogle Scholar
  102. O’Brien SG, Guilhot F, Larson RA et al (2003a) Imatinib compared with interferon and low dose cytarabine for newly diagnosed chronicphase chronic myeloid leukemia. N Engl J Med 348:994–1004PubMedGoogle Scholar
  103. O’Brien S, Giles F, Talpaz M et al (2003b) Results of triple therapy with interferon-alfa, cytarabine, and homoharringtonine, and the impact of adding imatinib to treatment sequence in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in early chronic phase. Cancer 98:888–893PubMedGoogle Scholar
  104. O’Dwyer ME, Mauro MJ, Kurilik G et al (2002) The impact of clonal evolution on response to imatinib mesylate (STI571) in accelerated phase CML. Blood 100:1628–1633PubMedGoogle Scholar
  105. Ogawa M, Fried J, Sakai A, Clarkson BD (1970) Studies of cellular proliferation in human leukemia. IV. The proliferative activity, generation time and emergence time of neutrophilic granulocytes in chronic granulocytic leukemia. Cancer 25:1031–1049PubMedGoogle Scholar
  106. Oka Y, Tsuboi A, Taguchi T et al (2004) Induction of WTI (Wilms tumor gene)-specific cytotoxic T lymphocytes by WTI peptide vaccine and the resultant cancer regression. PNAS 101:13885–13890PubMedGoogle Scholar
  107. Pardal R, Clark MF, Morrison SJ (2003) Applying the principles of stemcell biology to cancer. Nat Rev Cancer 3:895–902PubMedGoogle Scholar
  108. Perseghin P, Gambacorti-Passerini C, Tornaghi L et al (2005) Peripheral blood progenitor cell collection in chronic myeloid leukemia patients with complete cytogenetic response after treatment with imatinib mesylate. Transfusion 45:1214–1220PubMedGoogle Scholar
  109. Pockley AG (2003) Heat shock proteins as regulators of the immune response. Lancet 362:469–476PubMedGoogle Scholar
  110. Preffer FI, Dombkowski D, Sykes M et al (2002) Lineage-negative side-population with restricted hematopoietic capacity circulate in normal adult blood: Immunophenoptypic and functional characterization. Stem Cells 20:417–427PubMedGoogle Scholar
  111. Press RD, Love Z, Tronnes AA et al (2006) BCR-ABL mRNA levels at and after the time of complete cytogenetic response (CCR) predict the duration of CCR in imatinib-treated patients with CML. Blood 102:4250–4256Google Scholar
  112. Radich J, Dai HD, Mao M et al (2006) Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci USA 103:2794–2799PubMedGoogle Scholar
  113. Ravandi-Kashani F, Ridgeway J, Nishimura S et al (2003) Pilot study of combination of imatinib mesylate and Trisenox (As2O3) in patients with accelerated and blast phase CML. Blood 102:314b, abstract 4977Google Scholar
  114. Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer and cancer stem cells. Nature 414:105–111PubMedGoogle Scholar
  115. Rousselot O, Huguet F, Rea D et al (2006) Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood, DOI 10.1882/blood-2006-03-011239Google Scholar
  116. Sattler M, Mohi MG, Pride YB et al (2002) Critical role for Gab2 in transformation by BCR/ABL. Cancer Cell 1:479–492PubMedGoogle Scholar
  117. Savani BN, Rezvani K, Mielke S et al (2006) Factors associated with early molecular remission after T cell-depleted allogeneic stem cell transplantation for chronic myelogenous leukemia. Blood 107:1688–1695PubMedGoogle Scholar
  118. Sawyers CL, Hochhaus A, Feldman E et al (2002) Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 99:3530–3539PubMedGoogle Scholar
  119. Shah NP, Tran C, Lee FY et al (2004) Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305:399–401PubMedGoogle Scholar
  120. Simonsson B for the IRIS study group (2005) Beneficial effects of cytogenetic and molecular response on long-term outcome in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib (IM): Update from the IRIS study. Blood 106:52 a, abstract 166Google Scholar
  121. Srivastava PK (2000) Immunotherapy of human cancer: lessons from mice. Nat Immunol 1:363–366PubMedGoogle Scholar
  122. Srivastava PK (2002) Roles of heat-shock proteins in innate and adaptive immunity. Nat Rev Immunol 2:185–194PubMedGoogle Scholar
  123. Suto R, Srivastava PK (1995) A mechanism for the specific immunogenicity of heat shock protein-chaperoned peptides. Science 269:1585–1588PubMedGoogle Scholar
  124. Talpaz M, Rousselot P, Kim DW et al (2005) A phase II study of dasatinib in patients with chronic myeloid leukemia (CML) in myeloid blast crisis who are resistant or intolerant to imatinib: First results of the CA180006’ sTART-B’ study. Blood 106:16a, abstract 40Google Scholar
  125. Talpaz M, Shah NP, Kantarjian H et al (2006a) Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 354:2531–2541PubMedGoogle Scholar
  126. Talpaz M, Apperley JF, Kim DW et al (2006b) Dasatinib in patients with accelerated phase chronic myeloid leukemia who are resistant or intolerant to imatinib: Results of the CA1800006’ sTART-B’ study. J Clin Oncol 24:18S, abstract 6526Google Scholar
  127. Tipping AJ, Mahon FX, Zafiridis G et al (2002) Drug responses of imatinib mesylate-resistant cells: synergism of imatinib with other chemotherapeutic agents. Leukemia 16:2349–2357PubMedGoogle Scholar
  128. Uchida N, Fujisaki T, Eaves AC, Eaves CJ (2001) Transplantable hematopoietic stem cells in human fetal liver have a CD34+ side population (SP) phenotype. J Clin Invest 108:1071–1077PubMedGoogle Scholar
  129. Udomsakdi C, Eaves C, Swolin B et al (1992) Rapid decline of chronic myeloid leukemia cells in long term culture due to a defect at the leukemic stem cell level. Proc Nat Acad Sci USA 89:6192–6196PubMedGoogle Scholar
  130. Uno K, Inukai T, Kayagaki N et al (2003) TNF-related apoptosis-inducing ligand (TRAIL) frequently induces apoptosis in Philadelphia chromosome-positive leukemia cells. Blood 101:3658–3667PubMedGoogle Scholar
  131. Verstovsek S, Lunin S, Kantarjian H et al (2003) Clinical relevance of VEGF receptors 1 and 2 in patients with chronic myeloid leukemia. Leuk Res 27:661–669PubMedGoogle Scholar
  132. Vickers M (1996) Estimation of the number of mutations necessary to cause chronic myeloid leukaemia from epidemiological data. Br J Haematol 94:1–4PubMedGoogle Scholar
  133. Wang JCY, Lapidot T, Cashman JD et al (1998) High level engraftment of NOD/SCID mice by primitive normal and leukemic hematopoietic cells from patients with chronic myeloid leukemia in chronic phase. Blood 91:2406–2414PubMedGoogle Scholar
  134. Weisberg E, Manley PW, Breitenstein W et al (2005) Characterization of AMN 107, a selective inhibitor of native and mutant Bcr-Ab l. Cancer Cell 7:129–141PubMedGoogle Scholar
  135. Weisdorf DJ, Anasetti C, Antin JH et al (2002) Allogeneic bone marrow transplantation for chronic myelogenous leukemia: comparative analysis of unrelated versus matched sibling donor transplantation. Blood 99:1971–1977PubMedGoogle Scholar
  136. Wolff NC, Veach DR, Tong WP et al (2005) PD166326, a novel tyrosine kinase inhibitor, has greater antileukemic activity than imatinib mesylate in a murine model of chronic myelogenous leukemia. Blood 105:3995–4003PubMedGoogle Scholar
  137. Xue S-A, Gao L, Hart D et al (2005) Elimination of human leukemia cells in NOD/SCID mice by WT1-TCR gene transduced human T cells. Blood 106:3062–3067PubMedGoogle Scholar
  138. Yong ASM, Szydlo RM, Goldman JM et al (2005) Molecular profiling of CD34+ cells identifies low expression of CD7 with high expression of proteinase 3 or elastase as predictors for longer survival in CML patients. Blood 107:205–212PubMedGoogle Scholar
  139. Young MA, Shah NP, Chao LH et al (2006) Structure of the kinase domain of an imatinib-resistant Abl mutant in complex with the Aurora kinase inhibitor VX-680. Cancer Res 66:1007–1014PubMedGoogle Scholar
  140. Yu C, Krystal G, Dent P et al (2002) Flavopiridol potentiates STI571-induced mitochondrial damage and apoptosis in BCR-ABL-positive human leukemia cells. Clin Cancer Res 8:2976–2984PubMedGoogle Scholar
  141. Yu C, Rahmani M, Conrad D, Subler M, Dent P, Grant S (2003) The proteasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl+ cells sensitive and resistant to STI571. Blood 102:3765–3774PubMedGoogle Scholar
  142. Zeng Y, Graner MW, Thompson S et al (2005) Induction of BCR-ABL-specific immunity following vaccination with chaperone rich lysates from BCR-ABL+ tumor cells. Blood 105:2016–2022PubMedGoogle Scholar
  143. Zhou S, Schuetz JD, Bunting KD et al (2001) The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med 7:1028–1034PubMedGoogle Scholar

Copyright information

© Springer Berlin Heidelberg 2007

Authors and Affiliations

  • Tariq I Mughal
    • 1
  • John M Goldman
    • 2
  1. 1.Division of Hematology and Stem Cell TransplantationUniversity of Texas, Southwestern School of MedicineDallasUSA
  2. 2.Hematology Branch, National Heart, Lung and Blood InstituteNational Institutes of HealthBethesdaUSA

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