Skip to main content
SpringerLink
Log in

Diagnosis and Treatment of Chronic Myeloid Leukemia

  • Chapter
  • First Online:
Book cover Neoplastic Diseases of the Blood

  • 2802 Accesses

Abstract

The original recognition of leukemia in the nineteenth century and the story of our progressive understanding of the biology and the development of treatment of chronic myeloid leukemia (CML) have been well reviewed in recent years [1, 2]. Today the diagnosis of CML usually presents few problems. In contrast, planning a therapeutic strategy for a patient who presents in chronic phase and monitoring a patient who starts treatment with a tyrosine kinase inhibitor (TKI) present a number of challenges. The same is true for a patient in chronic phase whose disease proves resistant to initial treatment with a TKI. Even more difficult may be the issue of how best to treat a patient presenting in or progressing to an advanced phase of CML. In this chapter, we will review some of the essentials of diagnosis of CML, which will be mostly self-evident to practicing hematologists, but the main focus will be on available treatment options, the results to date of using these various options, and guidance on therapeutic strategy.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 269.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Geary CG. The story of chronic myeloid leukaemia. Br J Haematol. 2000;110:2–11.

    Article  PubMed  CAS  Google Scholar 

  2. Goldman JM. Chronic myeloid leukemia: a historical perspective. Semin Hematol. 2010;47:302–11.

    Article  PubMed  CAS  Google Scholar 

  3. Fialkow PJ, Jacobson RJ, Papayannopoulou T. Chronic myelocytic leukemia: clonal origin in a stem cell common to the granulocyte, erythrocyte, platelet and monocyte/macrophage. Am J Med. 1977;63:125–30.

    Article  PubMed  CAS  Google Scholar 

  4. Nowell PC, Hungerford DA. A minute chromosome in human chronic granulocytic leukemia. Science. 1960;132:1497.

    Google Scholar 

  5. Whang-Peng J, Canellos GP, Carbone PP, Tjio JH. Clinical implications of cytogenetic variants in chronic myelocytic leukemia (CML). Blood. 1968;32:755–66.

    PubMed  CAS  Google Scholar 

  6. Ezdinli EZ, Sokal JE, Crosswhite L, Sandberg AA. Philadelphia-chromosome-positive and -negative chronic myelocytic leukemia. Ann Intern Med. 1970;72:175–82.

    PubMed  CAS  Google Scholar 

  7. Kurzrock R, Bueso-Ramos CE, Kantarjian H, et al. BCR rearrangement-negative chronic myelogenous leukemia revisited. J Clin Oncol. 2001;19:2915–26.

    PubMed  CAS  Google Scholar 

  8. Sokal JE, Cox EB, Baccarani M, et al. Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood. 1984;63:789–99.

    PubMed  CAS  Google Scholar 

  9. Savage DG, Szydlo RM, Goldman JM. Clinical features at diagnosis in 430 patients with chronic myeloid leukaemia seen at a referral centre over a 16-year period. Br J Haematol. 1997;96: 111–6.

    Article  PubMed  CAS  Google Scholar 

  10. Sokal JE, Baccarani M, Russo D, Tura S. Staging and prognosis in chronic myelogenous leukemia. Semin Hematol. 1988;25:49–61.

    PubMed  CAS  Google Scholar 

  11. Kantarjian HM, Dixon D, Keating MJ, et al. Characteristics of accelerated disease in chronic myelogenous leukemia. Cancer. 1988;61:1441–6.

    Article  PubMed  CAS  Google Scholar 

  12. Darte JM, Dacie JV, McSorley JG. Pelger-like leucocytes in chronic myeloid leukemia. Acta Haematol. 1954;12:117–24.

    Article  PubMed  CAS  Google Scholar 

  13. Shumak KH, Baker MA, Taub RN, Coleman MS. Myeloblastic and lymphoblastic markers in acute undifferentiated leukemia and chronic myelogenous leukemia in blast crisis. Cancer Res. 1980;40:4048–52.

    PubMed  CAS  Google Scholar 

  14. Forman EN, Padre-Mendoza T, Smith PS, Barker BE, Farnes P. Ph1-positive childhood leukemias: spectrum of lymphoid-myeloid expressions. Blood. 1977;49:549–58.

    PubMed  CAS  Google Scholar 

  15. Chan LC, Furley AJ, Ford AM, Yardumian DA, Greaves MF. Clonal rearrangement and expression of the T cell receptor beta gene and involvement of the breakpoint cluster region in blast crisis of CGL. Blood. 1986;67:533–6.

    PubMed  CAS  Google Scholar 

  16. Speed DE, Lawler SD. Chronic granuocytic leukaemia. The chromosomes and the disease. Lancet. 1964;1:403–8.

    Article  PubMed  CAS  Google Scholar 

  17. Mitelman F. The cytogenetic scenario of chronic myeloid leukemia. Leuk Lymphoma. 1993;11 Suppl 1:11–5.

    Article  PubMed  Google Scholar 

  18. Derderian PM, Kantarjian HM, Talpaz M, et al. Chronic myelogenous leukemia in the lymphoid blastic phase: characteristics, treatment response, and prognosis. Am J Med. 1993;94:69–74.

    Article  PubMed  CAS  Google Scholar 

  19. Kantarjian HM, Keating MJ, Talpaz M, et al. Chronic myelogenous leukemia in blast crisis. Analysis of 242 patients. Am J Med. 1987;83:445–54.

    Article  PubMed  CAS  Google Scholar 

  20. Stuppia L, Calabrese G, Peila R, et al. p53 loss and point mutations are associated with suppression of apoptosis and progression of CML into myeloid blastic crisis. Cancer Genet Cytogenet. 1997;98:28–35.

    Article  PubMed  CAS  Google Scholar 

  21. Ahuja H, Bar-Eli M, Advani SH, Benchimol S, Cline MJ. Alterations in the p53 gene and the clonal evolution of the blast crisis of chronic myelocytic leukemia. Proc Natl Acad Sci U S A. 1989;86:6783–7.

    Article  PubMed  CAS  Google Scholar 

  22. Mitelman F, Brandt L, Nilsson PG. Cytogenetic evidence for splenic origin of blastic transformation in chronic myeloid leukaemia. Scand J Haematol. 1974;13:87–92.

    Article  PubMed  CAS  Google Scholar 

  23. Stoll C, Oberling F, Flori E. Chromosome analysis of spleen and/or lymph nodes of patients with chronic myeloid leukemia (CML). Blood. 1978;52:828–38.

    PubMed  CAS  Google Scholar 

  24. Ej F, Thomas LB, Frei E, Fritz RD, Forkner CE. A distinctive type of intracerebral hemorrhage associated with “blastic crisis” in patients with leukemia. Cancer. 1960;13:146–54.

    Article  Google Scholar 

  25. Vernant JP, Brun B, Mannoni P, Dreyfus B. Respiratory distress of hyperleukocytic granulocytic leukemias. Cancer. 1979;44:264–8.

    Article  PubMed  CAS  Google Scholar 

  26. Neiman RS, Barcos M, Berard C, et al. Granulocytic sarcoma: a clinicopathologic study of 61 biopsied cases. Cancer. 1981;48:1426–37.

    Article  PubMed  CAS  Google Scholar 

  27. Schwartz JH, Canellos GP, Young RC, DeVita VTJ. Meningeal leukemia in the blastic phase of chronic granulocytic leukemia. Am J Med. 1975;59:819–28.

    Article  PubMed  CAS  Google Scholar 

  28. Hasford J, Pfirrmann M, Hehlmann R, et al. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst. 1998;90:850–8.

    Article  PubMed  CAS  Google Scholar 

  29. Gratwohl A, Hermans J, Goldman JM, et al. Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Lancet. 1998;352:1087–92.

    Article  PubMed  CAS  Google Scholar 

  30. Tura S, Baccarani M, Corbelli G. Staging of chronic myeloid leukaemia. Br J Haematol. 1981;47:105–19.

    Article  PubMed  CAS  Google Scholar 

  31. Cervantes F, Rozman C. A multivariate analysis of prognostic factors in chronic myeloid leukemia. Blood. 1982;60:1298–304.

    PubMed  CAS  Google Scholar 

  32. Hehlmann R, Heimpel H, Hasford J, et al. Randomized comparison of interferon-alpha with busulfan and hydroxyurea in chronic myelogenous leukemia. The German CML Study Group. Blood. 1994;84:4064–77.

    PubMed  CAS  Google Scholar 

  33. Thomas MJ, Irving JA, Lennard AL, Proctor SJ, Taylor PR. Validation of the Hasford score in a demographic study in chronic granulocytic leukaemia. J Clin Pathol. 2001;54:491–3.

    Article  PubMed  CAS  Google Scholar 

  34. Caplan SN, Coco FV, Berkman EM. Management of chronic myelocytic leukemia in pregnancy by cell pheresis. Transfusion. 1978;18:120–4.

    Article  PubMed  CAS  Google Scholar 

  35. Fitzgerald D, Rowe JM, Heal J. Leukapheresis for control of chronic myelogenous leukemia during pregnancy. Am J Hematol. 1986;22:213–8.

    Article  PubMed  CAS  Google Scholar 

  36. Kennedy BJ. Hydroxyurea therapy in chronic myelogenous leukemia. Cancer. 1972;29:1052–6.

    Article  PubMed  CAS  Google Scholar 

  37. Kolitz JE, Kempin SJ, Schluger A, et al. A phase II pilot trial of high-dose hydroxyurea in chronic myelogenous leukemia. Semin Oncol. 1992;19:27–33.

    PubMed  CAS  Google Scholar 

  38. Lugo TG, Pendergast AM, Muller AJ, Witte ON. Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science. 1990;247:1079–82.

    Article  PubMed  CAS  Google Scholar 

  39. Oda T, Tamura S, Matsuguchi T, Griffin JD, Druker BJ. The SH2 domain of ABL is not required for factor-independent growth induced by BCR-ABL in a murine myeloid cell line. Leukemia. 1995;9:295–301.

    PubMed  CAS  Google Scholar 

  40. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;2:561–6.

    Article  PubMed  CAS  Google Scholar 

  41. Druker BJ, Lydon NB. Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Invest. 2000;105:3–7.

    Article  PubMed  CAS  Google Scholar 

  42. Carroll M, Ohno-Jones S, Tamura S, et al. CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins. Blood. 1997;90:4947–52.

    PubMed  CAS  Google Scholar 

  43. Deininger MW, Goldman JM, Lydon N, Melo JV. The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. Blood. 1997;90:3691–8.

    PubMed  CAS  Google Scholar 

  44. Beran M, Cao X, Estrov Z, et al. Selective inhibition of cell proliferation and BCR-ABL phosphorylation in acute lymphoblastic leukemia cells expressing Mr 190,000 BCR-ABL protein by a tyrosine kinase inhibitor (CGP-57148). Clin Cancer Res. 1998;4:1661–72.

    PubMed  CAS  Google Scholar 

  45. Gambacorti-Passerini C, le Coutre P, Mologni L, et al. Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL  +  leukemic cells and induces apoptosis. Blood Cells Mol Dis. 1997;23:380–94.

    Article  PubMed  CAS  Google Scholar 

  46. 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;344:1031–7.

    Article  PubMed  CAS  Google Scholar 

  47. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001;344:1038–42.

    Article  PubMed  CAS  Google Scholar 

  48. 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;99:1928–37.

    Article  PubMed  CAS  Google Scholar 

  49. Sawyers CL, Hochhaus A, Feldman E, et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood. 2002;99:3530–9.

    Article  PubMed  CAS  Google Scholar 

  50. Kantarjian HM, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002;346:645–52.

    Article  PubMed  CAS  Google Scholar 

  51. Ottmann OG, Druker BJ, Sawyers CL, et al. A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood. 2002; 100:1965–71.

    Article  PubMed  CAS  Google Scholar 

  52. O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348: 994–1004.

    Article  PubMed  Google Scholar 

  53. Guilhot F, Chastang C, Michallet M, et al. Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. French Chronic Myeloid Leukemia Study Group. N Engl J Med. 1997;337:223–9.

    Article  PubMed  CAS  Google Scholar 

  54. Goldman JM, How I. treat chronic myeloid leukemia in the imatinib era. Blood. 2007;110:2828–37.

    Article  PubMed  CAS  Google Scholar 

  55. O’Brien SG, Guilhot F, Goldman JM, Hochhaus A, Hughes T, Radich J. International Randomized Study of Interferon versus STI571 (IRIS) 7-year follow-up: sustained survival, low rate of transformation and increased rate of major molecular response (MMR) in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib (IM). Blood. 2008;112:76. abstract 186.

    Google Scholar 

  56. Hochhaus A, O’Brien SG, Guilhot F, et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia. 2009;23:1054–61.

    Article  PubMed  CAS  Google Scholar 

  57. 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;355:2408–17.

    Article  PubMed  CAS  Google Scholar 

  58. Roy L, Guilhot J, Krahnke T, et al. Survival advantage from imatinib compared with the combination interferon-alpha plus cytarabine in chronic-phase chronic myelogenous leukemia: historical comparison between two phase 3 trials. Blood. 2006;108:1478–84.

    Article  PubMed  CAS  Google Scholar 

  59. Kantarjian HM, Talpaz M, O’Brien S, et al. Survival benefit with imatinib mesylate versus interferon-alpha-based regimens in newly diagnosed chronic-phase chronic myelogenous leukemia. Blood. 2006;108:1835–40.

    Article  PubMed  CAS  Google Scholar 

  60. de Lavallade H, Apperley JF, Khorashad JS, et al. Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol. 2008;26:3358–63.

    Article  PubMed  Google Scholar 

  61. Kantarjian HM, 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;103:2873–8.

    Article  PubMed  CAS  Google Scholar 

  62. Hughes TP, Branford S, White DL, et al. Impact of early dose intensity on cytogenetic and molecular responses in chronic-phase CML patients receiving 600 mg/day of imatinib as initial therapy. Blood. 2008;112:3965–73.

    Article  PubMed  CAS  Google Scholar 

  63. Millot F, Guilhot J, Nelken B, et al. Imatinib mesylate is effective in children with chronic myelogenous leukemia in late chronic and advanced phase and in relapse after stem cell transplantation. Leukemia. 2006;20:187–92.

    Article  PubMed  CAS  Google Scholar 

  64. Suttorp M. Innovative approaches of targeted therapy for CML of childhood in combination with paediatric haematopoietic SCT. Bone Marrow Transplant. 2008;42 Suppl 2:S40–6.

    Article  PubMed  CAS  Google Scholar 

  65. Suttorp M, Millot F. Treatment of pediatric chronic myeloid leukemia in the year 2010: use of tyrosine kinase inhibitors and stem-cell transplantation. Hematology Am Soc Hematol Educ Program. 2010;2010:368–76.

    Article  PubMed  Google Scholar 

  66. Marin D, Marktel S, Bua M, et al. The use of imatinib (STI571) in chronic myelod leukemia: some practical considerations. Haematologica. 2002;87:979–88.

    PubMed  CAS  Google Scholar 

  67. Deininger MW, O’Brien SG, Ford JM, Druker BJ. Practical management of patients with chronic myeloid leukemia receiving imatinib. J Clin Oncol. 2003;21:1637–47.

    Article  PubMed  CAS  Google Scholar 

  68. Kaeda J, Chase A, Goldman JM. Cytogenetic and molecular monitoring of residual disease in chronic myeloid leukaemia. Acta Haematol. 2002;107:64–75.

    Article  PubMed  CAS  Google Scholar 

  69. Hughes T, Branford S. Molecular monitoring of BCR-ABL as a guide to clinical management in chronic myeloid leukaemia. Blood Rev. 2006;20:29–41.

    Article  PubMed  CAS  Google Scholar 

  70. Hughes TP, Kaeda J, Branford S, et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med. 2003;349:1423–32.

    Article  PubMed  CAS  Google Scholar 

  71. Reinhold U, Hennig E, Leiblein S, Niederwieser D, Deininger MW. FISH for BCR-ABL on interphases of peripheral blood neutrophils but not of unselected white cells correlates with bone marrow cytogenetics in CML patients treated with imatinib. Leukemia. 2003;17:1925–9.

    Article  PubMed  CAS  Google Scholar 

  72. 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.

    Article  PubMed  CAS  Google Scholar 

  73. Cross NC, Hughes TP, Hochhaus A, Goldman JM. International standardisation of quantitative real-time RT-PCR for BCR-ABL. Leuk Res. 2008;32:505–6.

    Article  PubMed  CAS  Google Scholar 

  74. Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108:1809–20.

    Article  PubMed  CAS  Google Scholar 

  75. White HE, Matejtschuk P, Rigsby P, et al. Establishment of the first World Health Organization International Genetic Reference Panel for quantitation of BCR-ABL mRNA. Blood. 2010;116:e111–7.

    Article  PubMed  CAS  Google Scholar 

  76. Bartley PA, Ross DM, Latham S, et al. Sensitive detection and quantification of minimal residual disease in chronic myeloid leukaemia using nested quantitative PCR for BCR-ABL DNA. Int J Lab Hematol. 2010;32:e222–8.

    Article  PubMed  CAS  Google Scholar 

  77. White D, Saunders V, Lyons AB, et al. In vitro sensitivity to imatinib-induced inhibition of ABL kinase activity is predictive of molecular response in patients with de novo CML. Blood. 2005;106:2520–6.

    Article  PubMed  CAS  Google Scholar 

  78. Thomas J, Wang L, Clark RE, Pirmohamed M. Active transport of imatinib into and out of cells: implications for drug resistance. Blood. 2004;104:3739–45.

    Article  PubMed  CAS  Google Scholar 

  79. Mahon FX, Belloc F, Lagarde V, et al. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood. 2003;101:2368–73.

    Article  PubMed  CAS  Google Scholar 

  80. Radich JP, Dai H, Mao M, et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci U S A. 2006;103:2794–9.

    Article  PubMed  CAS  Google Scholar 

  81. Picard S, Titier K, Etienne G, et al. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood. 2007;109:3496–9.

    Article  PubMed  CAS  Google Scholar 

  82. Larson RA, Druker BJ, Guilhot F, et al. Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood. 2008;111:4022–8.

    Article  PubMed  CAS  Google Scholar 

  83. Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009;27:6041–51.

    Article  PubMed  CAS  Google Scholar 

  84. Jabbour E, Kantarjian HM, Jones D, et al. Imatinib mesylate dose escalation is associated with durable responses in patients with chronic myeloid leukemia after cytogenetic failure on standard-dose imatinib therapy. Blood. 2009;113:2154–60.

    Article  PubMed  CAS  Google Scholar 

  85. Tam CS, Kantarjian H, Garcia-Manero G, et al. Failure to achieve a major cytogenetic response by 12 months defines inadequate response in patients receiving nilotinib or dasatinib as second or subsequent line therapy for chronic myeloid leukemia. Blood. 2008;112:516–8.

    Article  PubMed  CAS  Google Scholar 

  86. Milojkovic D, Nicholson E, Apperley JF, et al. Early prediction of success or failure of treatment with second-generation tyrosine kinase inhibitors in patients with chronic myeloid leukemia. Haematologica. 2010;95:224–31.

    Article  PubMed  CAS  Google Scholar 

  87. Marin D, Milojkovic D, Olavarria E, et al. European LeukemiaNet criteria for failure or suboptimal response reliably identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor. Blood. 2008;112:4437–44.

    Article  PubMed  CAS  Google Scholar 

  88. Lombardo LJ, Lee FY, Chen P, et al. Discovery of N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem. 2004;47:6658–61.

    Article  PubMed  CAS  Google Scholar 

  89. Fricker J. Tyrosine kinase inhibitors: the next generation. Lancet Oncol. 2006;7:621.

    Article  PubMed  Google Scholar 

  90. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354:2531–41.

    Article  PubMed  CAS  Google Scholar 

  91. Kantarjian HM, Pasquini R, Hamerschlak N, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood. 2007;109:5143–50.

    Article  PubMed  CAS  Google Scholar 

  92. Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell. 2005;7:129–41.

    Article  PubMed  CAS  Google Scholar 

  93. Kantarjian HM, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006;354:2542–51.

    Article  PubMed  Google Scholar 

  94. Kantarjian HM, Giles FJ, Bhalla KN, et al. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood. 2011;117:1141–5.

    Article  PubMed  CAS  Google Scholar 

  95. Kantarjian HM, Giles F, Gattermann N, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007;110:3540–6.

    Article  PubMed  CAS  Google Scholar 

  96. Golas JM, Arndt K, Etienne C, et al. SKI-606, a 4-anilino-3-­quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice. Cancer Res. 2003;63:375–81.

    PubMed  CAS  Google Scholar 

  97. Puttini M, Coluccia AM, Boschelli F, et al. In vitro and in vivo activity of SKI-606, a novel Src-Abl inhibitor, against imatinib-resistant Bcr-Abl  +  neoplastic cells. Cancer Res. 2006;66:11314–22.

    Article  PubMed  CAS  Google Scholar 

  98. Redaelli S, Piazza R, Rostagno R, et al. Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. [letter]. J Clin Oncol. 2009;27(3):469–71.

    Article  PubMed  CAS  Google Scholar 

  99. O’Hare T, Shakespeare WC, Zhu X, et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009;16:401–12.

    Article  PubMed  CAS  Google Scholar 

  100. O’Hare T, Deininger MW, Eide CA, Clackson T, Druker BJ. Targeting the BCR-ABL signaling pathway in therapy-resistant Philadelphia chromosome-positive leukemia. Clin Cancer Res. 2011;17:212–21.

    Article  PubMed  Google Scholar 

  101. Bonifazi F, de Vivo A, Rosti G, et al. Chronic myeloid leukemia and interferon-alpha: a study of complete cytogenetic responders. Blood. 2001;98:3074–81.

    Article  PubMed  CAS  Google Scholar 

  102. Rousselot P, Huguet F, Rea D, et al. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood. 2007;109:58–60.

    Article  PubMed  CAS  Google Scholar 

  103. Goh HG, Kim YJ, Kim DW, et al. Previous best responses can be re-achieved by resumption after imatinib discontinuation in patients with chronic myeloid leukemia: implication for intermittent imatinib therapy. Leuk Lymphoma. 2009;50:944–51.

    Article  PubMed  CAS  Google Scholar 

  104. Mahon FX, Rea D, Guilhot J, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010;11:1029–35.

    Article  PubMed  CAS  Google Scholar 

  105. Pye SM, Cortes J, Ault P, et al. The effects of imatinib on pregnancy outcome. Blood. 2008;111:5505–8.

    Article  PubMed  CAS  Google Scholar 

  106. Preudhomme C, Guilhot J, Nicolini FE, et al. Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med. 2010;363:2511–21.

    Article  PubMed  CAS  Google Scholar 

  107. Deenik W, van der Holt B, Verhoef GE, et al. Dose-finding study of imatinib in combination with intravenous cytarabine: feasibility in newly diagnosed patients with chronic myeloid leukemia. Blood. 2008;111:2581–8.

    Article  PubMed  CAS  Google Scholar 

  108. Copland M, Pellicano F, Richmond L, et al. BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergizes with tyrosine kinase inhibitors. Blood. 2008;111:2843–53.

    Article  PubMed  CAS  Google Scholar 

  109. Shah NP, Skaggs BJ, Branford S, et al. Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency. J Clin Invest. 2007;117:2562–9.

    Article  PubMed  CAS  Google Scholar 

  110. Kantarjian HM, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362:2260–70.

    Article  PubMed  CAS  Google Scholar 

  111. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362:2251–9.

    Article  PubMed  CAS  Google Scholar 

  112. Ottmann OG, Pfeifer H. First-line treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia in adults. Curr Opin Oncol. 2009;21 Suppl 1:S43–6.

    Article  PubMed  CAS  Google Scholar 

  113. Talpaz M, McCredie K, Kantarjian H, Trujillo J, Keating M, Gutterman J. Chronic myelogenous leukaemia: haematological remissions with alpha interferon. Br J Haematol. 1986;64:87–95.

    Article  PubMed  CAS  Google Scholar 

  114. Guilhot F, Lacotte-Thierry L. Interferon-alpha: mechanisms of action in chronic myelogenous leukemia in chronic phase. Hematol Cell Ther. 1998;40:237–9.

    PubMed  CAS  Google Scholar 

  115. Chronic Myeloid Leukemia Trialists’ Collaborative Group. Interferon alfa versus chemotherapy for chronic myeloid leukemia a meta-analysis of seven randomized trials. J Natl Cancer Inst. 1997;89:1616–20.

    Article  Google Scholar 

  116. Kantarjian HM, O’Brien S, Smith TL, et al. Treatment of Philadelphia chromosome-positive early chronic phase chronic myelogenous leukemia with daily doses of interferon alpha and low-dose cytarabine. J Clin Oncol. 1999;17:284–92.

    PubMed  CAS  Google Scholar 

  117. Talpaz M. Interferon-alfa-based treatment of chronic myeloid leukemia and implications of signal transduction inhibition. Semin Hematol. 2001;38:22–7.

    Article  PubMed  CAS  Google Scholar 

  118. Peters DG, Hoover RR, Gerlach MJ, et al. Activity of the farnesyl protein transferase inhibitor SCH66336 against BCR/ABL-induced murine leukemia and primary cells from patients with chronic myeloid leukemia. Blood. 2001;97:1404–12.

    Article  PubMed  CAS  Google Scholar 

  119. Karp JE, Lancet JE, Kaufmann SH, et al. Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial. Blood. 2001;97:3361–9.

    Article  PubMed  CAS  Google Scholar 

  120. O’Brien S, Kantarjian H, Keating M, et al. Homoharringtonine therapy induces responses in patients with chronic myelogenous leukemia in late chronic phase. Blood. 1995;86:3322–6.

    PubMed  Google Scholar 

  121. O’Brien S, Kantarjian H, Koller C, et al. Sequential homoharringtonine and interferon-alpha in the treatment of early chronic phase chronic myelogenous leukemia. Blood. 1999;93:4149–53.

    PubMed  Google Scholar 

  122. Kantarjian HM, O’Brien SM, Keating M, et al. Results of decitabine therapy in the accelerated and blastic phases of chronic myelogenous leukemia. Leukemia. 1997;11:1617–20.

    Article  PubMed  CAS  Google Scholar 

  123. Sacchi S, Kantarjian HM, O’Brien S, et al. Chronic myelogenous leukemia in nonlymphoid blastic phase: analysis of the results of first salvage therapy with three different treatment approaches for 162 patients. Cancer. 1999;86:2632–41.

    Article  PubMed  CAS  Google Scholar 

  124. Pavlu J, Kew AK, Taylor-Roberts B, et al. Optimizing patient selection for myeloablative allogeneic hematopoietic cell transplantation in chronic myeloid leukemia in chronic phase. Blood. 2010;115:4018–20.

    Article  PubMed  CAS  Google Scholar 

  125. Clift RA, Anasetti C. Allografting for chronic myeloid leukaemia. Baillieres Clin Haematol. 1997;10:319–36.

    Article  PubMed  CAS  Google Scholar 

  126. Goldman JM, Majhail NS, Klein JP, et al. Relapse and late mortality in 5-year survivors of myeloablative allogeneic hematopoietic cell transplantation for chronic myeloid leukemia in first chronic phase. J Clin Oncol. 2010;28:1888–95.

    Article  PubMed  Google Scholar 

  127. Storb R. Reduced-intensity conditioning transplantation in myeloid malignancies. Curr Opin Oncol. 2009;21 Suppl 1:S3–5.

    Article  PubMed  Google Scholar 

  128. McSweeney PA, Niederwieser D, Shizuru JA, et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood. 2001;97:3390–400.

    Article  PubMed  CAS  Google Scholar 

  129. Kolb HJ, Mittermuller J, Clemm C, et al. Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood. 1990;76:2462–5.

    PubMed  CAS  Google Scholar 

  130. Porter DL, Roth MS, McGarigle C, Ferrara JL, Antin JH. Induction of graft-versus-host disease as immunotherapy for relapsed chronic myeloid leukemia. N Engl J Med. 1994;330:100–6.

    Article  PubMed  CAS  Google Scholar 

  131. Olavarria E, Parker S, Craddock C, et al. Collection of Ph-negative progenitor cells from interferon responsive patients with chronic myeloid leukemia: effect of granulocyte-colony-stimulating factor mobilization. Haematologica. 2000;85:647–52.

    PubMed  CAS  Google Scholar 

  132. McGlave PB, De Fabritiis P, Deisseroth A, et al. Autologous transplants for chronic myelogenous leukaemia: results from eight transplant groups. Lancet. 1994;343:1486–8.

    Article  PubMed  CAS  Google Scholar 

  133. Cullis JO, Jiang YZ, Schwarer AP, Hughes TP, Barrett AJ, Goldman JM. Donor leukocyte infusions for chronic myeloid leukemia in relapse after allogeneic bone marrow transplantation. Blood. 1992;79:1379–81.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to acknowledge Dr. Annette J. Neylon’s contribution to earlier versions of this chapter.

Author information

Authors and Affiliations

  1. Northern Institute for Cancer Research, Newcastle University Medical School, Newcastle University, Newcastle Hospitals NHS Foundation Trust, Newcastle, NE2 4HH, UK

    Stephen G. O’Brien B.Sc.(Hons), Ph.D., M.B.Ch.B., F.C.R.P., M.R.C.Path

  2. Department of Hematology, Imperial College of London, London, W12 0NN, UK

    John M. Goldman D.M., F.R.C.P., F.Med.Sci.

Authors
  1. Stephen G. O’Brien B.Sc.(Hons), Ph.D., M.B.Ch.B., F.C.R.P., M.R.C.Path
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John M. Goldman D.M., F.R.C.P., F.Med.Sci.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stephen G. O’Brien B.Sc.(Hons), Ph.D., M.B.Ch.B., F.C.R.P., M.R.C.Path .

Editor information

Editors and Affiliations

  1. Beth Israel Hospital, Cancer Center, St. Lukes-Roosevelt Hospital Center, 10th Avenue 1000, New York, 10019, New York, USA

    Peter H. Wiernik

  2. , Department of Hematology, Imperial College of London, Du Cane Road 150, London, W12 0NN, United Kingdom

    John M. Goldman

  3. Continuum Cancer Centers, Department of Medicine, St. Luke's-Roosevelt Hospital Center, 10th Avenue 1000, New York, 10019, New York, USA

    Janice P. Dutcher

  4. , Division of Hematology, Mayo Clinic, First Street SW. 200, Rochester, 55905, Minnesota, USA

    Robert A. Kyle

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

O’Brien, S.G., Goldman, J.M. (2013). Diagnosis and Treatment of Chronic Myeloid Leukemia. In: Wiernik, P., Goldman, J., Dutcher, J., Kyle, R. (eds) Neoplastic Diseases of the Blood. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-3764-2_5

Download citation

  • DOI: https://doi.org/10.1007/978-1-4614-3764-2_5

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4614-3763-5

  • Online ISBN: 978-1-4614-3764-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation