Seminars in Hematology
Volume 44 , Pages 4-14 , January 2007

The Biology of Chronic Myelogenous Leukemia: Implications for Imatinib Therapy

  • Ricardo H. Alvarez

      Affiliations

    • Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX.
    • ,
  • Hagop Kantarjian

      Affiliations

    • Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX.
    • ,
  • Jorge E. Cortes

      Affiliations

    • Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX.
    • Corresponding Author InformationAddress correspondence to Jorge E. Cortes, MD, Professor of Medicine, Department of Leukemia, Unit 428, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-4009.

References 

  1. In:  Ries LAG,  Eisner MP,  Kosary CL, et al. editor. SEER Cancer Statistics Review, 1975-2002. Bethesda, MD: National Cancer Institute; 2004;Available at: http://seer.cancer.gov/statfacts/html/cmyl.html?statfacts_page=cmyl.html&x=11&y=17
  2. Cortes J, Silver RT, Kantarjian H. Chronic myeloid leukemia. In:  Kufe D,  Bast R,  Hait W, et al. editor. Holland-Frei Cancer Medicine. (ed 7).. Hamilton, Ontario, Canada: Decker; 2006;p. 1761–1771
  3. Bizzozero OJ, Johnson KG, Ciocco A, Kawasaki S, Toyoda S. Radiation-related leukemia in Hiroshima and Nagasaki 1946-1964 (II). Ann Intern Med. 1967;66:522–530
  4. Cortes J. Natural history and staging of chronic myelogenous leukemia. Hemat Oncol Clin North Am. 2004;18:569–584
  5. Cortes JE, Talpaz M, Kantarjian H. Chronic myelogenous leukemia: a review. Am J Med. 1996;100:555–570
  6. Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002;100:2292–2302
  7. Cortes JE, Talpaz M, O’Brien S, et al. Staging of chronic myeloid leukemia in the imatinib era: An evaluation of the World Health Organization proposal. Cancer. 2006;106:1306–1315
  8. Sokal JE, Baccarani M, Russo D, Tura S. Staging and prognosis in chronic myelogenous leukemia. Semin Hematol. 1988;25:49–61
  9. Cortes J, Kantarjian H. Advanced-phase chronic myeloid leukemia. Semin Hematol. 2003;40:79–86
  10. Speck B, Bortin MM, Champlin R, et al. Allogeneic bone-marrow transplantation for chronic myelogenous leukaemia. Lancet. 1984;1:665–668
  11. Kantarjian HM, Dixon D, Keating MJ, et al. Characteristics of accelerated disease in chronic myelogenous leukemia. Cancer. 1988;61:1441–1446
  12. Anastasi J, Feng J, Le Beau MM, Larson RA, Rolwey JD, Vardiman JW. The relationship between secondary chromosomal abnormalities and blast transformation in chronic myeloid leukemia. Leukemia. 1995;9:628–633
  13. Swolin B, Weinfeld A, Westing J, Waldenström J, Magnusson BP. Karyotypic evolution in Ph-positive chronic myeloid leukemia in relation to management and disease progression. Cancer Genet Cytogenet. 1985;18:65–79
  14. Cortes JE, Talpaz M, Giles F, et al. Prognostic significance of cytogenetic clonal evolution in patients with chronic myelogenous leukemia on imatinib mesylate therapy. Blood. 2003;101:3794–3800
  15. Cramer E, Auclair C, Hakim J, et al. Metabolic activity of phagocytosing granulocytes in chronic granulocytic leukemia: ultrastructural observation of a degranulation defect. Blood. 1977;50:93–106
  16. Cortes JE, Silver R, Kantarjian H: Chronic Myelogenous Leukemia in Cancer Management: A Multidisciplinary Approach. By Pazdur et al: CMP 2005-2006 Edition. Darien, CT, CMP Healthcare Media Group, Chapter 33, pp 797-810.
  17. Castro-Malaspina H, Moore MA. Pathophysiological mechanisms operating in the development of myelofibrosis: Role of megakaryocytes. Nouv Rev Fr Hematol. 1982;24:221–226
  18. Aguayo A, Kantarjian H, Manshouri T, et al. Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes. Blood. 2000;96:2240–2245
  19. Tefferi A. Myelofibrosis with myeloid metaplasia. N Engl J Med. 2000;342:1255–1265
  20. Goldman JM, Melo JV. Chronic myeloid leukemia—Advances in biology and new approaches to treatment. N Engl J Med. 2003;349:1451–1464
  21. Faderl S, Talpaz M, Estrov Z, O’Brien S, Kurzrock R, Kantarjian HM. The biology of chronic myeloid leukemia. N Engl J Med. 1999;341:164–172
  22. Faderl S, Hochhaus A, Hughes T. Monitoring of minimal residual disease in chronic myeloid leukemia. Hematol Oncol Clin North Am. 2004;18:657–670
  23. Daley GQ, van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the p210bcr/abl gene of the Philadelphia chromosome. Science. 1990;247:824–830
  24. Voncken JW, Kaartinen V, Pattengale PK, Germeraad WTV, Groffen J, Heisterkamp N. BCR/ABL p210 and p190 cause distinct leukemia in transgenic mice. Blood. 1995;86:4603–4611
  25. McWhirter JR, Wang JYJ. Activation of tyrosine kinase and microfilament-binding functions of c-abl by bcr sequences in bcr/abl fusion proteins. Mol Cell Biol. 1991;13:1553–1563
  26. Cortez D, Kadlec L, Pendergast AM. Structural and signaling requirements for BCR/ABL-mediated transformation and inhibition of apoptosis. Mol Cell Biol. 1995;15:5531–5541
  27. Puil L, Liu J, Gish G, et al. Bcr-Abl oncoproteins bind directly to activators of the Ras signalling pathway. EMBO J. 1994;13:764–773
  28. Sattler M, Mohi MG, Pride YB, et al. Critical role for Gab2 in transformation by BCR/ABL. Cancer Cell. 2002;1:479–492
  29. Cahill MA, Janknecht R, Nordheim A. Signalling pathways: Jack of all cascades. Curr Biol. 1996;6:16–19
  30. Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov. 2005;4:988–1004
  31. Jain SK, Susa M, Keeler ML, Carlesso N, Druker B, Varticovski L. PI3-kinase activation in BCR/abl-transformed hematopoietic cells does not require the interaction of p85 SH2 domains with p210 BCR/abl. Blood. 1996;88:1542–1550
  32. Myers MP, Pass I, Batty IH, et al. The lipid phosphatase activity of PTEN is critical for its tumor suppressor function. Proc Natl Acad Sci U S A. 1998;95:13513–13518
  33. Zhou BP, Liao Y, Xu W, Zou Y, Spohn B, Hung MC. HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nat Cell Biol. 2001;3:973–982
  34. Sellers WR, Fisher DE. Apoptosis and cancer drug targeting. J Clin Invest. 1999;104:1655–1661
  35. Datta SR, Dudek H, Tao X, et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997;91:231–241
  36. Silverman N, Maniatis T. NF-κB signaling pathways in mammalian and insect innate immunity. Genes Dev. 2001;15:2321–2342
  37. Gesbert F, Sellers WR, Signoretti S, Loda M, Griffin JD. BCR/ABL regulates expression of the cyclin-dependent kinase inhibitor p27 Kip1 through the prosphatidylinositol 3-kinase/AKT pathway. J Biol Chem. 2000;275:39223–39230
  38. Frank DA, Varticovski L. BCR/abl leads to the constitutive activation of Stat proteins and shares an epitope with tyrosine phosphorylated Stats. Leukemia. 1996;10:1724–1730
  39. Klejman A, Schreiner SJ, Nieborowska-Skorska M, et al. The Src family kinase Hck couples BCR/ABL to STAT5 activation in myeloid leukemia cells. EMBO J. 2002;21:5766–5774
  40. Horita M, Andrew EJ, Benito A, et al. Blockade of the BCR/ABL kinase activity induces apoptosis of chronic myelogenous leukemia cells by suppressing signal transducer and activator of transcription 5-dependent expression of Bcl-XL. J Exp Med. 2000;191:977–984
  41. Melo JV, Deininger MW. Biology of chronic myelogenous leukemia—Signaling pathways of initiation and transformation. Hematol Oncol Clin North Am. 2004;18:545–568
  42. Verfaillie CM, Hurley R, Zhao RC, Prosper F, Delforge M, Bhatia R. Pathophysiology of CML: Do defects in integrin function contribute to the premature circulation and massive expansion of the BCR/ABL positive clone?. J Lab Clin Med. 1997;129:584–591
  43. Lewis JM, Baskaran R, Taagepera S, Schwartz MA, Wang JYJ. Integrin regulation of c-Abl tyrosine kinase activity and cytoplasmatic–nuclear transport. Proc Natl Acad Sci U S A. 1996;93:15174–15179
  44. Sokal JE, Cox EB, Baccarani M, et al. Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood. 1984;63:789–799
  45. Ohnishi K, Ohno R, Tomonaga M, et al. The Kouseisho Leukemia Study Group A randomized trial comparing interferon-α with busulfan for newly diagnosed chronic myelogenous leukemia in chronic phase. Blood. 1995;86:906–916
  46. Hasford J, Pfirrmann M, Hehlmann R, et al. Writing Committee for the Collaborative CML Prognostic Factors Project Group A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. J Natl Cancer Inst. 1998;90:850–858
  47. Gratwohl A, Hermans J, Niederwieser D, et al. Chronic Leukemia Working Party of the European Group for Bone Marrow Transplantation Bone marrow transplantation for chronic myeloid leukemia: Long-term results. Bone Marrow Transplant. 1993;12:509–516
  48. Thomas ED, Clift RA, Fefer A, et al. Marrow transplantation for the treatment of chronic myelogenous leukemia. Ann Intern Med. 1986;104:155–163
  49. Kantarjian HM, O’Brien S, Cortes JE, et al. Complete cytogenetic and molecular responses to interferon-α-based therapy for chronic myelogenous leukemia are associated with excellent long-term prognosis. Cancer. 2003;97:1033–1041
  50. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase of the growth of Bcr-Abl positive cells. Nat Med. 1996;2:561–566
  51. Beran M, Cao X, Estrov Z, et al. Selective inhibition of cell proliferation and BCR-ABL phosphorylation in acute lymphoblastic leukemia expressing Mr190,000 BCR-ABL protein by a tyrosine kinase inhibitor (CGP-57148). Clin Cancer Res. 1998;4:1661–1672
  52. Buchdunger E, Zimmermann J, Mett H, et al. Selective inhibition of the platelet-derived growth factor signal transduction pathway by a protein-tyrosine kinase inhibitor of the 2-phenylaminopyrimidine class. Proc Natl Acad Sci U S A. 1995;92:2558–2562
  53. Buchdunger E, Zimmermann J, Mett H, et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res. 1996;56:100–104
  54. Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J. Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase. Science. 2000;289:1938–1942
  55. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1031–1037
  56. Kantarjian H, Sawyers C, Hochhaus A, et al. International STI51 CML Study Group Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002;346:645–652
  57. Silver RT, Talpaz M, Sawyers CL, et al. Four years of follow-up of 1027 patients with late chronic phase (L-CP), accelerated phase (AP), or blast crisis (BC) chronic myelogenous leukemia (CML) treated with imatinib in three large phase II trials. Blood. 2004;104:11a;(abstr)
  58. Kantarjian HM, Cortes JE, O’Brien S, et al. Long-term survival benefit and improved complete cytogenetic and molecular response rates with imatinib mesylate in Philadelphia chromosome–positive chronic-phase chronic myeloid leukemia after failure of interferon-α. Blood. 2004;104:1979–1988
  59. Cervantes F, Hernandez-Boluda JC, Steegmann JL, et al. Imatinib mesylate therapy of chronic phase chronic myeloid leukemia resistant or intolerant to interferon: results and prognostic factors for response and progression-free survival in 150 patients. Haematologica. 2003;88:1117–1122
  60. O’Brien SG, Guilhot F, Larson RA, et al. IRIS Investigators Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994–1004
  61. Druker BJ, Guilhot F, O’Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408–2417
  62. Hughes T, Deininger M, Hochhaus A, et al. 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. 2006;108:28–37
  63. Talpaz M, Silver RT, Druker BJ, et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: Results of a phase 2 study. Blood. 2002;99:1928–1937
  64. Cortes J, Giles F, O’Brien S, et al. Result of high-dose imatinib mesylate in patients with Philadelphia chromosome–positive chronic myeloid leukemia after failure of interferon-α. Blood. 2003;102:83–86
  65. Kantarjian H, Talpaz M, O’Brien S, et al. High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome–positive chronic phase chronic myeloid leukemia. Blood. 2004;103:2873–2878
  66. Aoki E, Kantarjian H, O’Brien S, et al. High-dose imatinib mesylate treatment in patients with untreated early chronic phase (CP) chronic myeloid leukemia (CML): 2.5-year follow-up. J Clin Oncol. 2006;24:6535;(suppl, abstr)
  67. Hughes TP, Branford S, Matthews J, et al. Trial of higher dose imatinib with selective intensification in newly diagnosed CML patients in the chronic phase. Blood. 2003;102:31a, (abstr)
  68. Cortes J, Giles F, Salvado A, et al. High-dose imatinib in patients with previously untreated chronic myeloid leukemia in early chronic phase: preliminary results of a multicenter community based trial. J Clin Oncol. 2005;23:564s;(suppl, abstr)
  69. Rosti G, Martinelli G, Castagnetti F, et al. Imatinib 800 mg: Preliminary results of a phase II trial of the GIMEMA CML Working Party in intermediate Sokal risk patients and status-of-the-art of an ongoing multinational, prospective randomized trial of imatinib standard dose (400 mg daily) vs. high dose (800 mg daily) in high Sokal risk patients. Blood. 2005;106:320a;(abstr 1098)
  70. Cortes J, Talpaz M, O’Brien S, et al. Molecular responses in patients with chronic myelogenous leukemia in chronic phase treated with imatinib mesylate. Clin Cancer Res. 2005;11:3425–3432
  71. Hughes TP, Branford S, Reynolds J, et al. Maintenance of imatinib dose intensity in the first six months of therapy for newly diagnosed patients with CML is predictive of molecular response, independent of the ability to increase dose at a later point. Blood. 2005;106:51a;(abstr 164)
  72. Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myelogenous leukemia: Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108:1809–1820
  73. Graham SM, Jørgensen HG, Allan E, et al. Primitive quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood. 2002;99:319–325
  74. Cortes J, O’Brien S, Kantarjian H. Discontinuation of imatinib therapy after achieving a molecular response. Blood. 2004;104:2204–2205
  75. Sneed TB, Kantarjian HM, Talpaz M, et al. The significance of myelosuppression during therapy with imatinib mesylate in patients with chronic myelogenous leukemia in chronic phase. Cancer. 2004;100:116–121
  76. Cashen A, DiPersio JF, Khoury H. Does early imatinib-induced myelosuppression predict hematologic responses in patients with advanced-phase chronic myeloid leukemia?. J Clin Oncol. 2003;21:4255–4256
  77. Deininger MWN, O’Brien SG, Ford JM, Druker BJ. Practical management of patients with chronic myeloid leukemia receiving imatinib. J Clin Oncol. 2003;21:1637–1647
  78. Quintas-Cardama A, Kantarjian H, O’Brien S, et al. Granulocyte–colony-stimulating factor (filgrastim) may overcome imatinib-induced neutropenia in patients with chronic-phase chronic myelogenous leukemia. Cancer. 2004;100:2592–2597
  79. Mauro MJ, Kurilik G, Balleisen S, et al. Myeloid growth factors for neutropenia during imatinib mesylate therapy for CML: preliminary evidence of safety and efficacy. Blood. 2001;98:139a;(abstr)
  80. Marin D, Marktel S, Foot N, et al. G-CSF reverses cytopenia and may increase cytogenetic responses in patients with CML treated with imatinib mesylate. Blood. 2002;100:782a;(abstr)
  81. Ault P, Kantarjian H, Welch MA, Giles F, Rios MB, Cortes J. Interleukin 11 may improve thrombocytopenia associated with imatinib mesylate therapy in chronic myelogenous leukemia. Leuk Res. 2004;28:613–618
  82. Cortes J, O’Brien S, Quintas A, et al. Erythropoietin is effective in improving the anemia induced by imatinib mesylate therapy in patients with chronic myeloid leukemia in chronic phase. Cancer. 2004;100:2396–2402
  83. Mauro MJ, Blasdel C, O’Dwyer ME, et al. Erythropoietin for anemia during imatinib mesylate (STI571) therapy for CML: Preliminary evidence of safety and efficacy. J Clin Oncol. 2002;21:27a;(abstr 106)
  84. Ault P, Kantarjian H, O’Brien S, Garcia-Manero G, Rios MB, Cortes JE. Use of darbepoetin alfa for the treatment of anemia occurring during imatinib therapy for CML: Preliminary evidence of safety and efficacy. Proc Am Soc Clin Oncol. 2003;22:613a;(abstr 2467)
  85. Lahaye T, Riehm B, Berger U, et al. Response and resistance in 300 patients with BCR-ABL–positive leukemias treated with imatinib in a single center. Cancer. 2005;103:1659–1669
  86. Kantarjian HM, Talpaz M, O’Brien S, et al. Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood. 2004;101:473–475
  87. Zonder JA, Pemberton P, Brandt H, Mohamed AN, Schiffer CA. The effect of dose increase of imatinib mesylate in patients with chronic or accelerated phase chronic myelogenous leukemia with inadequate hematologic or cytogenetic response to initial treatment. Clin Cancer Res. 2003;9:2092–2097

PII: S0037-1963(06)00260-5

doi: 10.1053/j.seminhematol.2006.12.007

Seminars in Hematology
Volume 44 , Pages 4-14 , January 2007

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