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Leukemia and Related Disorders pp 97–147Cite as

Chronic Myeloid Leukemia (CML)

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Part of the book series: Contemporary Hematology ((CH))

Abstract

Chronic myeloid leukemia (CML) is a relatively rare form of leukemia, comprising ∼15% of all leukemia cases. According to the National Cancer Institute’s Surveillance Epidemiology and End Result (SEER) Cancer Statistics database, an estimated 2,800 men and 2,070 women will be diagnosed with CML in 2010. Among these patients, 440 men and women are expected to die. Mortality did not change between 1975 and 1984, decreased slightly between 1984 and 1997, but decreased significantly after the introduction of the ABL-targeted tyrosine kinase inhibitor (TKI) imatinib mesylate (IM). The prevalence of CML in the USA could increase to 200,000 or more cases over the next 20 years.

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References

  1. O’Brien S, Berman E, Borghaei H, et al. NCCN clinical practice guidelines in oncology: chronic myelogenous leukemia. J Natl Compr Canc Netw. 2009;7(9):984–1023.

    PubMed  Google Scholar 

  2. Altekruse SF, Kosary CL, Krapcho M, et al. SEER Cancer Statistics Review, 1975–2007. National Cancer Institute. 2010. Accessed 07/20/2010. seer.cancer.gov/csr/1975_2008/.

  3. Jabbour E, Cortes J, Kantarjian H. Optimal first-line treatment of chronic myeloid leukemia. How to use imatinib and what role for newer drugs. Oncology (Williston Park). 2007;21(6):653–62; discussion 663–4, 667–8.

    Google Scholar 

  4. 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(35):6041–51. doi:10.1200/JCO.2009.25.0779.

    PubMed  CAS  Google Scholar 

  5. Baccarani M, Castagnetti F, Gugliotta G, Palandri F, Soverini S. Response definitions and European Leukemianet Management recommendations. Best Pract Res Clin Haematol. 2009;22(3):331–41. doi:10.1016/j.beha.2009.10.001.

    PubMed  Google Scholar 

  6. 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(6):1809–20. doi:10.1182/blood-2006-02-005686.

    PubMed  CAS  Google Scholar 

  7. O’Brien S, Berman E, Moore JO, et al. NCCN Task Force report: tyrosine kinase inhibitor therapy selection in the management of patients with chronic myelogenous leukemia. J Natl Compr Canc Netw. 2011;9 Suppl 2:S1–25.

    PubMed  Google Scholar 

  8. Fialkow PJ, Gartler SM, Yoshida A. Clonal origin of chronic myelocytic leukemia in man. Proc Natl Acad Sci USA. 1967;58(4):1468–71.

    PubMed  CAS  Google Scholar 

  9. Knudson AG. Two genetic hits (more or less) to cancer. Nat Rev Cancer. 2001;1(2):157–62. doi:10.1038/35101031.

    PubMed  CAS  Google Scholar 

  10. Deininger MW, Goldman JM, Melo JV. The molecular biology of chronic myeloid leukemia. Blood. 2000;96(10):3343–56.

    PubMed  CAS  Google Scholar 

  11. Melo JV, Barnes DJ. Chronic myeloid leukaemia as a model of disease evolution in human cancer. Nat Rev Cancer. 2007;7(6):441–53. doi:10.1038/nrc2147.

    PubMed  CAS  Google Scholar 

  12. Quintas-Cardama A, Cortes J. Molecular biology of bcr-abl1-positive chronic myeloid leukemia. Blood. 2009;113(8):1619–30. doi:10.1182/blood-2008-03-144790.

    PubMed  CAS  Google Scholar 

  13. Verma D, Kantarjian HM, Jones D, et al. Chronic myeloid leukemia (CML) with P190 BCR-ABL: analysis of characteristics, outcomes, and prognostic significance. Blood. 2009;114(11): 2232–5. doi:10.1182/blood-2009-02-204693.

    PubMed  CAS  Google Scholar 

  14. Sokal JE, Baccarani M, Russo D, Tura S. Staging and prognosis in chronic myelogenous ­leukemia. Semin Hematol. 1988;25(1):49–61.

    PubMed  CAS  Google Scholar 

  15. Savage DG, Szydlo RM, Chase A, Apperley JF, Goldman JM. Bone marrow transplantation for chronic myeloid leukaemia: the effects of differing criteria for defining chronic phase on probabilities of survival and relapse. Br J Haematol. 1997;99(1):30–5.

    PubMed  CAS  Google Scholar 

  16. Kantarjian HM, Deisseroth A, Kurzrock R, Estrov Z, Talpaz M. Chronic myelogenous leukemia: a concise update. Blood. 1993;82(3):691–703.

    PubMed  CAS  Google Scholar 

  17. Swerdlow SH, Campo E, Harris NL, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed., Vol 2. Lyon: IARC Press; 2008.

    Google Scholar 

  18. Johansson B, Fioretos T, Mitelman F. Cytogenetic and molecular genetic evolution of chronic myeloid leukemia. Acta Haematol. 2002;107(2):76–94.

    PubMed  CAS  Google Scholar 

  19. Sokal JE, Cox EB, Baccarani M, et al. Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood. 1984;63(4):789–99.

    PubMed  CAS  Google Scholar 

  20. Hasford J, Ansari H, Pfirrmann M, Hehlmann R. Analysis and validation of prognostic factors for CML. German CML Study Group. Bone Marrow Transplant. 1996;17 Suppl 3:S49–54.

    PubMed  Google Scholar 

  21. Hasford J, Pfirrmann M, Shepherd P, et al. The impact of the combination of baseline risk group and cytogenetic response on the survival of patients with chronic myeloid leukemia treated with interferon alpha. Haematologica. 2005;90(3):335–40.

    PubMed  Google Scholar 

  22. 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(15):1423–32. doi:10.1056/NEJMoa030513.

    PubMed  CAS  Google Scholar 

  23. 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(11):994–1004. doi:10.1056/NEJMoa022457.

    PubMed  Google Scholar 

  24. 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(23):2408–17. doi:10.1056/NEJMoa062867.

    PubMed  CAS  Google Scholar 

  25. Hasford J, Baccarani M, Hoffmann V, et al. Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score. Blood. 2011;118(3):686–92. doi:10.1182/blood-2010-12-319038. www.refworks.com.

    PubMed  CAS  Google Scholar 

  26. Sandberg AA. Chromosomes and causation of human cancer and leukemia: XL. The Ph1 and other translocations in CML. Cancer. 1980;46(10):2221–6.

    PubMed  CAS  Google Scholar 

  27. Heim S, Billstrom R, Kristoffersson U, Mandahl N, Strombeck B, Mitelman F. Variant Ph translocations in chronic myeloid leukemia. Cancer Genet Cytogenet. 1985;18(3):215–27.

    PubMed  CAS  Google Scholar 

  28. Fisher AM, Strike P, Scott C, Moorman AV. Breakpoints of variant 9;22 translocations in chronic myeloid leukemia locate preferentially in the CG-richest regions of the genome. Genes Chromosomes Cancer. 2005;43(4):383–9. doi:10.1002/gcc.20196.

    PubMed  CAS  Google Scholar 

  29. Huntly BJ, Bench A, Green AR. Double jeopardy from a single translocation: deletions of the derivative chromosome 9 in chronic myeloid leukemia. Blood. 2003;102(4):1160–8. doi:10.1182/blood-2003-01-0123.

    PubMed  CAS  Google Scholar 

  30. Kim DH, Popradi G, Sriharsha L, et al. No significance of derivative chromosome 9 deletion on the clearance kinetics of BCR/ABL fusion transcripts, cytogenetic or molecular response, loss of response, or treatment failure to imatinib mesylate therapy for chronic myeloid leukemia. Cancer. 2008;113(4):772–81. doi:10.1002/cncr.23607.

    PubMed  CAS  Google Scholar 

  31. Quintas-Cardama A, Kantarjian H, Talpaz M, et al. Imatinib mesylate therapy may overcome the poor prognostic significance of deletions of derivative chromosome 9 in patients with chronic myelogenous leukemia. Blood. 2005;105(6):2281–6. doi:10.1182/blood-2004-06-2208.

    PubMed  CAS  Google Scholar 

  32. Quintás-Cardama A, Kantarjian H, Shan J, et al. Prognostic impact of deletions of derivative chromosome 9 in patients with chronic myelogenous leukemia treated with nilotinib or dasatinib. Cancer. 2011;117(22):5085–93. doi:10.1002/cncr.26147.

    Google Scholar 

  33. Kirstetter P, Schuster MB, Bereshchenko O, et al. Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells. Cancer Cell. 2008;13(4):299–310. doi:10.1016/j.ccr.2008.02.008.

    PubMed  CAS  Google Scholar 

  34. Marcucci G, Radmacher MD, Maharry K, et al. MicroRNA expression in cytogenetically ­normal acute myeloid leukemia. N Engl J Med. 2008;358(18):1919–28. doi:10.1056/NEJMoa074256.

    PubMed  CAS  Google Scholar 

  35. Figueroa ME, Lugthart S, Li Y, et al. DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell. 2010;17(1):13–27. doi:10.1016/j.ccr.2009.11.020.

    PubMed  CAS  Google Scholar 

  36. Delhommeau F, Dupont S, DellaValle V, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;360(22):2289–301. doi:10.1056/NEJMoa0810069.

    PubMed  Google Scholar 

  37. Abdel-Wahab O, Mullally A, Hedvat C, et al. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood. 2009;114(1):144–7. doi:10.1182/blood-2009-03-210039.

    PubMed  CAS  Google Scholar 

  38. Tiu RV, Gondek LP, O’Keefe CL, et al. Prognostic impact of SNP array karyotyping in myelodysplastic syndromes and related myeloid malignancies. Blood. 2011;117(17):4552–60. doi:10.1182/blood-2010-07-295857.

    PubMed  CAS  Google Scholar 

  39. Mardis ER, Ding L, Dooling DJ, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009;361(11):1058–66. doi:10.1056/NEJMoa0903840.

    PubMed  CAS  Google Scholar 

  40. Ley TJ, Ding L, Walter MJ, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010;363(25):2424–33. doi:10.1056/NEJMoa1005143.

    PubMed  CAS  Google Scholar 

  41. Kim DH, Lee ST, Won HH, et al. A genome-wide association study identifies novel loci associated with susceptibility to chronic myeloid leukemia. Blood. 2011;117(25):6906–11. doi:10.1182/blood-2011-01-329797.

    PubMed  CAS  Google Scholar 

  42. Bruns I, Czibere A, Fischer JC, et al. The hematopoietic stem cell in chronic phase CML is characterized by a transcriptional profile resembling normal myeloid progenitor cells and reflecting loss of quiescence. Leukemia. 2009;23(5):892–9. doi:10.1038/leu.2008.392.

    PubMed  CAS  Google Scholar 

  43. Graham SM, Vass JK, Holyoake TL, Graham GJ. Transcriptional analysis of quiescent and proliferating CD34+ human hemopoietic cells from normal and chronic myeloid leukemia sources. Stem Cells. 2007;25(12):3111–20. doi:10.1634/stemcells.2007-0250.

    PubMed  CAS  Google Scholar 

  44. Zheng C, Li L, Haak M, et al. Gene expression profiling of CD34+ cells identifies a molecular signature of chronic myeloid leukemia blast crisis. Leukemia. 2006;20(6):1028–34. doi:10.1038/sj.leu.2404227.

    PubMed  CAS  Google Scholar 

  45. Yong AS, Szydlo RM, Goldman JM, Apperley JF, Melo JV. Molecular profiling of CD34+ cells identifies low expression of CD7, along with high expression of proteinase 3 or elastase, as predictors of longer survival in patients with CML. Blood. 2006;107(1):205–12. doi:10.1182/blood-2005-05-2155.

    PubMed  CAS  Google Scholar 

  46. Radich JP, Dai H, Mao M, et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci USA. 2006;103(8):2794–9. doi:10.1073/pnas.0510423103.

    PubMed  CAS  Google Scholar 

  47. Oehler VG, Guthrie KA, Cummings CL, et al. The preferentially expressed antigen in melanoma (PRAME) inhibits myeloid differentiation in normal hematopoietic and leukemic progenitor cells. Blood. 2009;114(15):3299–308. doi:10.1182/blood-2008-07-170282.

    PubMed  CAS  Google Scholar 

  48. McWeeney SK, Pemberton LC, Loriaux MM, et al. A gene expression signature of CD34+ cells to predict major cytogenetic response in chronic-phase chronic myeloid leukemia patients treated with imatinib. Blood. 2010;115(2):315–25. doi:10.1182/blood-2009-03-210732.

    PubMed  CAS  Google Scholar 

  49. Goldman JM, Melo JV. BCR-ABL in chronic myelogenous leukemia – how does it work? Acta Haematol. 2008;119(4):212–7. doi:10.1159/000140633.

    PubMed  CAS  Google Scholar 

  50. Van Etten RA. Mechanisms of transformation by the BCR-ABL oncogene: new perspectives in the post-imatinib era. Leuk Res. 2004;28 Suppl 1:S21–8. doi:10.1016/j.leukres.2003.10.005.

    PubMed  Google Scholar 

  51. Ren R. Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer. 2005;5(3):172–83. doi:10.1038/nrc1567.

    PubMed  CAS  Google Scholar 

  52. Cortes J, Rousselot P, Kim DW, et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood. 2007;109(8):3207–13. doi:10.1182/blood-2006-09-046888.

    PubMed  CAS  Google Scholar 

  53. Fleming A, Noda T, Yoshimori T, Rubinsztein DC. Chemical modulators of autophagy as biological probes and potential therapeutics. Nat Chem Biol. 2011;7(1):9–17. doi:10.1038/nchembio.500.

    PubMed  CAS  Google Scholar 

  54. Gordon MY, Dowding CR, Riley GP, Goldman JM, Greaves MF. Altered adhesive interactions with marrow stroma of haematopoietic progenitor cells in chronic myeloid leukaemia. Nature. 1987;328(6128):342–4. doi:10.1038/328342a0.

    PubMed  CAS  Google Scholar 

  55. Verfaillie CM, McCarthy JB, McGlave PB. Mechanisms underlying abnormal trafficking of malignant progenitors in chronic myelogenous leukemia. Decreased adhesion to stroma and fibronectin but increased adhesion to the basement membrane components laminin and collagen type IV. J Clin Invest. 1992;90(4):1232–41. doi:10.1172/JCI115985.

    PubMed  CAS  Google Scholar 

  56. Salgia R, Li JL, Ewaniuk DS, et al. BCR/ABL induces multiple abnormalities of cytoskeletal function. J Clin Invest. 1997;100(1):46–57. doi:10.1172/JCI119520.

    PubMed  CAS  Google Scholar 

  57. Salgia R, Quackenbush E, Lin J, et al. The BCR/ABL oncogene alters the chemotactic response to stromal-derived factor-1alpha. Blood. 1999;94(12):4233–46.

    PubMed  CAS  Google Scholar 

  58. Bhatia R, McCarthy JB, Verfaillie CM. Interferon-alpha restores normal beta 1 integrin-mediated inhibition of hematopoietic progenitor proliferation by the marrow microenvironment in chronic myelogenous leukemia. Blood. 1996;87(9):3883–91.

    PubMed  CAS  Google Scholar 

  59. Geay JF, Buet D, Zhang Y, et al. p210BCR-ABL inhibits SDF-1 chemotactic response via alteration of CXCR4 signaling and down-regulation of CXCR4 expression. Cancer Res. 2005;65(7):2676–83. doi:10.1158/0008-5472.CAN-04-2152.

    PubMed  CAS  Google Scholar 

  60. Peled A, Hardan I, Trakhtenbrot L, et al. Immature leukemic CD34  +  CXCR4+ cells from CML patients have lower integrin-dependent migration and adhesion in response to the chemokine SDF-1. Stem Cells. 2002;20(3):259–66. doi:10.1634/stemcells.20-3-259.

    PubMed  CAS  Google Scholar 

  61. Jin L, Tabe Y, Konoplev S, et al. CXCR4 up-regulation by imatinib induces chronic myelogenous leukemia (CML) cell migration to bone marrow stroma and promotes survival of quiescent CML cells. Mol Cancer Ther. 2008;7(1):48–58. doi:10.1158/1535-7163.MCT-07-0042.

    PubMed  CAS  Google Scholar 

  62. Zeng Z, Shi YX, Samudio IJ, et al. Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML. Blood. 2009;113(24):6215–24. doi:10.1182/blood-2008-05-158311.

    PubMed  CAS  Google Scholar 

  63. Gaiger A, Henn T, Horth E, et al. Increase of bcr-abl chimeric mRNA expression in tumor cells of patients with chronic myeloid leukemia precedes disease progression. Blood. 1995;86(6):2371–8.

    PubMed  CAS  Google Scholar 

  64. Elmaagacli AH, Beelen DW, Opalka B, Seeber S, Schaefer UW. The amount of BCR-ABL fusion transcripts detected by the real-time quantitative polymerase chain reaction method in patients with Philadelphia chromosome positive chronic myeloid leukemia correlates with the disease stage. Ann Hematol. 2000;79(8):424–31.

    PubMed  CAS  Google Scholar 

  65. Barnes DJ, Schultheis B, Adedeji S, Melo JV. Dose-dependent effects of Bcr-Abl in cell line models of different stages of chronic myeloid leukemia. Oncogene. 2005;24(42):6432–40. doi:10.1038/sj.onc.1208796.

    PubMed  CAS  Google Scholar 

  66. Jamieson CH, Ailles LE, Dylla SJ, et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med. 2004;351(7):657–67. doi:10.1056/NEJMoa040258.

    PubMed  CAS  Google Scholar 

  67. Melo JV, Chuah C. Resistance to imatinib mesylate in chronic myeloid leukaemia. Cancer Lett. 2007;249(2):121–32. doi:10.1016/j.canlet.2006.07.010.

    PubMed  CAS  Google Scholar 

  68. Penserga ET, Skorski T. Fusion tyrosine kinases: a result and cause of genomic instability. Oncogene. 2007;26(1):11–20. doi:10.1038/sj.onc.1209756.

    PubMed  CAS  Google Scholar 

  69. Huang P, Feng L, Oldham EA, Keating MJ, Plunkett W. Superoxide dismutase as a target for the selective killing of cancer cells. Nature. 2000;407(6802):390–5. doi:10.1038/35030140.

    PubMed  CAS  Google Scholar 

  70. Sattler M, Verma S, Shrikhande G, et al. The BCR/ABL tyrosine kinase induces production of reactive oxygen species in hematopoietic cells. J Biol Chem. 2000;275(32):24273–8. doi:10.1074/jbc.M002094200.

    PubMed  CAS  Google Scholar 

  71. Skorski T. BCR/ABL, DNA damage and DNA repair: implications for new treatment concepts. Leuk Lymphoma. 2008;49(4):610–4. doi:10.1080/03093640701859089.

    PubMed  CAS  Google Scholar 

  72. Koptyra M, Cramer K, Slupianek A, Richardson C, Skorski T. BCR/ABL promotes accumulation of chromosomal aberrations induced by oxidative and genotoxic stress. Leukemia. 2008;22(10):1969–72. doi:10.1038/leu.2008.78.

    PubMed  CAS  Google Scholar 

  73. Stoklosa T, Poplawski T, Koptyra M, et al. BCR/ABL inhibits mismatch repair to protect from apoptosis and induce point mutations. Cancer Res. 2008;68(8):2576–80. doi:10.1158/0008-5472.CAN-07-6858.

    PubMed  CAS  Google Scholar 

  74. Neviani P, Santhanam R, Trotta R, et al. The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein. Cancer Cell. 2005;8(5):355–68. doi:10.1016/j.ccr.2005.10.015.

    PubMed  CAS  Google Scholar 

  75. Mullighan CG, Miller CB, Radtke I, et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature. 2008;453(7191):110–4. doi:10.1038/nature06866.

    PubMed  CAS  Google Scholar 

  76. Keeshan K, Santilli G, Corradini F, Perrotti D, Calabretta B. Transcription activation function of C/EBPalpha is required for induction of granulocytic differentiation. Blood. 2003;102(4):1267–75. doi:10.1182/blood-2003-02-0477.

    PubMed  CAS  Google Scholar 

  77. Nakahara F, Sakata-Yanagimoto M, Komeno Y, et al. Hes1 immortalizes committed progenitors and plays a role in blast crisis transition in chronic myelogenous leukemia. Blood. 2010;115(14):2872–81. doi:10.1182/blood-2009-05-222836.

    PubMed  CAS  Google Scholar 

  78. Branford S, Rudzki Z, Harper A, et al. Imatinib produces significantly superior molecular responses compared to interferon alfa plus cytarabine in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Leukemia. 2003;17(12):2401–9. doi:10.1038/sj.leu.2403158.

    PubMed  CAS  Google Scholar 

  79. Branford S, Rudzki Z, Parkinson I, et al. Real-time quantitative PCR analysis can be used as a primary screen to identify patients with CML treated with imatinib who have BCR-ABL kinase domain mutations. Blood. 2004;104(9):2926–32. doi:10.1182/blood-2004-03-1134.

    PubMed  CAS  Google Scholar 

  80. Canitrot Y, Falinski R, Louat T, et al. p210 BCR/ABL kinase regulates nucleotide excision repair (NER) and resistance to UV radiation. Blood. 2003;102(7):2632–7. doi:10.1182/blood-2002-10-3207.

    PubMed  CAS  Google Scholar 

  81. Graham SM, Jorgensen 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(1):319–25.

    PubMed  CAS  Google Scholar 

  82. Copland M, Hamilton A, Elrick LJ, et al. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood. 2006;107(11):4532–9. doi:10.1182/blood-2005-07-2947.

    PubMed  CAS  Google Scholar 

  83. Zhao C, Chen A, Jamieson CH, et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature. 2009;458(7239):776–9. doi:10.1038/nature07737.

    PubMed  CAS  Google Scholar 

  84. Dierks C, Beigi R, Guo GR, et al. Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell. 2008;14(3):238–49. doi:10.1016/j.ccr.2008.08.003.

    PubMed  CAS  Google Scholar 

  85. Zhang B, Strauss AC, Chu S, et al. Effective targeting of quiescent chronic myelogenous leukemia stem cells by histone deacetylase inhibitors in combination with imatinib mesylate. Cancer Cell. 2010;17(5):427–42. doi:10.1016/j.ccr.2010.03.011.

    PubMed  Google Scholar 

  86. Noens L, van Lierde MA, De Bock R, et al. Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: the ADAGIO study. Blood. 2009;113(22):5401–11. doi:10.1182/blood-2008-12-196543.

    PubMed  CAS  Google Scholar 

  87. Ibrahim AR, Eliasson L, Apperley JF, et al. Poor adherence is the main reason for loss of CCyR and imatinib failure for chronic myeloid leukemia patients on long-term therapy. Blood. 2011;117(14):3733–6. doi:10.1182/blood-2010-10-309807.

    PubMed  CAS  Google Scholar 

  88. 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(12):4437–44. doi:10.1182/blood-2008-06-162388.

    PubMed  CAS  Google Scholar 

  89. Wang YL, Bagg A, Pear W, Nowell PC, Hess JL. Chronic myelogenous leukemia: laboratory diagnosis and monitoring. Genes Chromosomes Cancer. 2001;32(2):97–111.

    PubMed  CAS  Google Scholar 

  90. Landstrom AP, Tefferi A. Fluorescent in situ hybridization in the diagnosis, prognosis, and treatment monitoring of chronic myeloid leukemia. Leuk Lymphoma. 2006;47(3):397–402. doi:10.1080/10428190500353133.

    PubMed  CAS  Google Scholar 

  91. Roth MS, Antin JH, Ash R, et al. Prognostic significance of Philadelphia chromosome-positive cells detected by the polymerase chain reaction after allogeneic bone marrow transplant for chronic myelogenous leukemia. Blood. 1992;79(1):276–82.

    PubMed  CAS  Google Scholar 

  92. Hughes TP, Morgan GJ, Martiat P, Goldman JM. Detection of residual leukemia after bone marrow transplant for chronic myeloid leukemia: role of polymerase chain reaction in predicting relapse. Blood. 1991;77(4):874–8.

    PubMed  CAS  Google Scholar 

  93. Radich JP, Gehly G, Gooley T, et al. Polymerase chain reaction detection of the BCR-ABL fusion transcript after allogeneic marrow transplantation for chronic myeloid leukemia: results and implications in 346 patients. Blood. 1995;85(9):2632–8.

    PubMed  CAS  Google Scholar 

  94. Radich JP, Gooley T, Bryant E, et al. The significance of bcr-abl molecular detection in chronic myeloid leukemia patients “late,” 18 months or more after transplantation. Blood. 2001;98(6):1701–7.

    PubMed  CAS  Google Scholar 

  95. Olavarria E, Kanfer E, Szydlo R, et al. Early detection of BCR-ABL transcripts by quantitative reverse transcriptase-polymerase chain reaction predicts outcome after allogeneic stem cell transplantation for chronic myeloid leukemia. Blood. 2001;97(6):1560–5.

    PubMed  CAS  Google Scholar 

  96. Branford S, Hughes TP, Rudzki Z. Monitoring chronic myeloid leukaemia therapy by real-time quantitative PCR in blood is a reliable alternative to bone marrow cytogenetics. Br J Haematol. 1999;107(3):587–99.

    PubMed  CAS  Google Scholar 

  97. Lin F, van Rhee F, Goldman JM, Cross NC. Kinetics of increasing BCR-ABL transcript numbers in chronic myeloid leukemia patients who relapse after bone marrow transplantation. Blood. 1996;87(10):4473–8.

    PubMed  CAS  Google Scholar 

  98. Mensink E, van de Locht A, Schattenberg A, et al. Quantitation of minimal residual disease in Philadelphia chromosome positive chronic myeloid leukaemia patients using real-time quantitative RT-PCR. Br J Haematol. 1998;102(3):768–74.

    PubMed  CAS  Google Scholar 

  99. Branford S, Seymour JF, Grigg A, et al. BCR-ABL messenger RNA levels continue to decline in patients with chronic phase chronic myeloid leukemia treated with imatinib for more than 5 years and approximately half of all first-line treated patients have stable undetectable BCR-ABL using strict sensitivity criteria. Clin Cancer Res. 2007;13(23):7080–5. doi:10.1158/1078-0432.CCR-07-0844.

    PubMed  CAS  Google Scholar 

  100. 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(9):3425–32. doi:10.1158/1078-0432.CCR-04-2139.

    PubMed  CAS  Google Scholar 

  101. Hughes TP, Hochhaus A, Branford S, et al. Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS). Blood. 2010;116(19):3758–65. doi:10.1182/blood-2010-03-273979.

    PubMed  CAS  Google Scholar 

  102. Stock W, Yu D, Karrison T, et al. Quantitative real-time RT-PCR monitoring of BCR-ABL in chronic myelogenous leukemia shows lack of agreement in blood and bone marrow samples. Int J Oncol. 2006;28(5):1099–103.

    PubMed  CAS  Google Scholar 

  103. Branford S, Fletcher L, Cross NCP, Müller MC, Hochhaus A, Kim DW. Desirable performance characteristics for BCR-ABL measurement on an international reporting scale to allow consistent interpretation of individual patient response and comparison of response rates between clinical trials. Blood. 2008;112:3330–8.

    PubMed  CAS  Google Scholar 

  104. Hughes TP, Hochhaus A, Branford S, et al. Reduction of BCR-ABL transcript levels at 6, 12, and 18 months (mo) correlates with long-term outcomes on imatinib (IM) at 72 Mo: an analysis from the international randomized study of interferon versus STI571 (IRIS) in patients (pts) with chronic phase chronic myeloid leukemia (CML-CP). ASH Annu Meeting Abstr. 2008;112(11):334. http://abstracts.hematologylibrary.org/cgi/content/abstract/ashmtg;112/11/334.

    Google Scholar 

  105. Muller MC, Hanfstein B, Erben P, et al. Molecular response to first line imatinib therapy is predictive for long term event free survival in patients with chronic phase chronic myelogenous leukemia – an interim analysis of the randomized German CML study IV. ASH Annu Meeting Abstr. 2008;112(11):333. http://abstracts.hematologylibrary.org/cgi/content/abstract/ashmtg;112/11/333.

    Google Scholar 

  106. 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(4):223–9.

    PubMed  CAS  Google Scholar 

  107. Kantarjian HM, Smith TL, O’Brien S, Beran M, Pierce S, Talpaz M. Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon-alpha therapy. The Leukemia Service. Ann Intern Med. 1995;122(4):254–61.

    PubMed  CAS  Google Scholar 

  108. Kantarjian HM, O’Brien S, Cortes JE, et al. Complete cytogenetic and molecular responses to interferon-alpha-based therapy for chronic myelogenous leukemia are associated with excellent long-term prognosis. Cancer. 2003;97(4):1033–41. doi:10.1002/cncr.11223.

    PubMed  CAS  Google Scholar 

  109. Bonifazi F, de Vivo A, Rosti G, et al. Chronic myeloid leukemia and interferon-alpha: a study of complete cytogenetic responders. Blood. 2001;98(10):3074–81.

    PubMed  CAS  Google Scholar 

  110. Mahon FX, Delbrel X, Cony-Makhoul P, et al. Follow-up of complete cytogenetic remission in patients with chronic myeloid leukemia after cessation of interferon alfa. J Clin Oncol. 2002;20(1):214–20.

    PubMed  CAS  Google Scholar 

  111. Essers MA, Offner S, Blanco-Bose WE, et al. IFNalpha activates dormant haematopoietic stem cells in vivo. Nature. 2009;458(7240):904–8. doi:10.1038/nature07815.

    PubMed  CAS  Google Scholar 

  112. Sato T, Onai N, Yoshihara H, Arai F, Suda T, Ohteki T. Interferon regulatory factor-2 protects quiescent hematopoietic stem cells from type I interferon-dependent exhaustion. Nat Med. 2009;15(6):696–700. doi:10.1038/nm.1973.

    PubMed  CAS  Google Scholar 

  113. Dowding C, Gordon M, Guo AP, et al. Potential mechanisms of action of interferon-alpha in CML. Leuk Lymphoma. 1993;11 Suppl 1:185–91.

    PubMed  Google Scholar 

  114. Guilhot F, Roy L, Saulnier PJ, Guilhot J. Interferon in chronic myeloid leukaemia: past and future. Best Pract Res Clin Haematol. 2009;22(3):315–29. doi:10.1016/j.beha.2009.10.005.

    PubMed  CAS  Google Scholar 

  115. 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(5486):1938–42.

    PubMed  CAS  Google Scholar 

  116. Kantarjian HM, Cortes J, O’Brien S, et al. Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase. Blood. 2002;99(10):3547–53.

    PubMed  CAS  Google Scholar 

  117. 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(6):1928–37.

    PubMed  CAS  Google Scholar 

  118. Kantarjian HM, Talpaz M, O’Brien S, et al. Imatinib mesylate for Philadelphia chromosome-positive, chronic-phase myeloid leukemia after failure of interferon-alpha: follow-up results. Clin Cancer Res. 2002;8(7):2177–87.

    PubMed  CAS  Google Scholar 

  119. 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(10):3530–9.

    PubMed  CAS  Google Scholar 

  120. 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-alpha. Blood. 2003;102(1):83–6. doi:10.1182/blood-2003-01-0025.

    PubMed  CAS  Google Scholar 

  121. 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(6):1054–61. doi:10.1038/leu.2009.38.

    PubMed  CAS  Google Scholar 

  122. Deininger M, O’Brien SG, Guilhot F, et al. International randomized study of interferon Vs STI571 (IRIS) 8-year follow up: sustained survival and Low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib. Blood (ASH Annu Meeting Abstr). 2009;114(22):1126. http://abstracts.hematologylibrary.org/cgi/content/abstract/ashmtg;114/22/1126.

    Google Scholar 

  123. Bhatia R, Holtz M, Niu N, et al. Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood. 2003;101(12):4701–7. doi:10.1182/blood-2002-09-2780.

    PubMed  CAS  Google Scholar 

  124. Bocchia M, Ippoliti M, Gozzetti A, et al. CD34+/Ph  +  cells are still detectable in chronic myeloid leukemia patients with sustained and prolonged complete cytogenetic remission ­during treatment with imatinib mesylate. Leukemia. 2008;22(2):426–8. doi:10.1038/sj.leu.2404893.

    PubMed  CAS  Google Scholar 

  125. 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(11):1029–35. doi:10.1016/S1470-2045(10), 70233-3.

    PubMed  CAS  Google Scholar 

  126. Kantarjian H, 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(12):5143–50. doi:10.1182/blood-2006-11-056028.

    PubMed  CAS  Google Scholar 

  127. Hochhaus A, Kantarjian HM, Baccarani M, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood. 2007;109(6):2303–9. doi:10.1182/blood-2006-09-047266.

    PubMed  CAS  Google Scholar 

  128. Hazarika M, Jiang X, Liu Q, et al. Tasigna for chronic and accelerated phase Philadelphia chromosome – positive chronic myelogenous leukemia resistant to or intolerant of imatinib. Clin Cancer Res. 2008;14(17):5325–31. doi:10.1158/1078-0432.CCR-08-0308.

    PubMed  CAS  Google Scholar 

  129. Cortes JE, Jones D, O’Brien S, et al. Nilotinib as front-line treatment for patients with chronic myeloid leukemia in early chronic phase. J Clin Oncol. 2010;28(3):392–7. doi:10.1200/JCO.2009.25.4896.

    PubMed  CAS  Google Scholar 

  130. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362(24):2251–9. doi:10.1056/NEJMoa0912614.

    PubMed  CAS  Google Scholar 

  131. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362(24):2260–70. doi:10.1056/NEJMoa1002315.

    PubMed  CAS  Google Scholar 

  132. Alvarado Y, Kantarjian H, O’Brien S, et al. Significance of suboptimal response to imatinib, as defined by the European LeukemiaNet, in the long-term outcome of patients with early chronic myeloid leukemia in chronic phase. Cancer. 2009;115(16):3709–18. doi:10.1002/cncr.24418.

    PubMed  CAS  Google Scholar 

  133. Mauro MJ, Deininger MW. Management of drug toxicities in chronic myeloid leukaemia. Best Pract Res Clin Haematol. 2009;22(3):409–29. doi:10.1016/j.beha.2009.06.001.

    PubMed  CAS  Google Scholar 

  134. Thomas J, Wang L, Clark RE, Pirmohamed M. Active transport of imatinib into and out of cells: implications for drug resistance. Blood. 2004;104(12):3739–45. doi:10.1182/blood-2003-12-4276.

    PubMed  CAS  Google Scholar 

  135. Jordanides NE, Jorgensen HG, Holyoake TL, Mountford JC. Functional ABCG2 is overexpressed on primary CML CD34+ cells and is inhibited by imatinib mesylate. Blood. 2006;108(4):1370–3. doi:10.1182/blood-2006-02-003145.

    PubMed  CAS  Google Scholar 

  136. White DL, Saunders VA, Dang P, et al. OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib. Blood. 2006;108(2):697–704. doi:10.1182/blood-2005-11-4687.

    PubMed  CAS  Google Scholar 

  137. White DL, Saunders VA, Dang P, et al. Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: higher doses of imatinib may overcome the negative impact of low OCT-1 activity. Blood. 2007;110(12):4064–72. doi:10.1182/blood-2007-06-093617.

    PubMed  CAS  Google Scholar 

  138. 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(8):4022–8. doi:10.1182/blood-2007-10-116475.

    PubMed  CAS  Google Scholar 

  139. 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(8):3496–9. doi:10.1182/blood-2006-07-036012.

    PubMed  CAS  Google Scholar 

  140. Mahon FX, Belloc F, Lagarde V, et al. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood. 2003;101(6):2368–73. doi:10.1182/blood.V101.6.2368.

    PubMed  CAS  Google Scholar 

  141. Jiang X, Zhao Y, Smith C, et al. Chronic myeloid leukemia stem cells possess multiple unique features of resistance to BCR-ABL targeted therapies. Leukemia. 2007;21(5):926–35. doi:10.1038/sj.leu.2404609.

    PubMed  CAS  Google Scholar 

  142. Hatziieremia S, Jordanides NE, Holyoake TL, Mountford JC, Jorgensen HG. Inhibition of MDR1 does not sensitize primitive chronic myeloid leukemia CD34+ cells to imatinib. Exp Hematol. 2009;37(6):692–700. doi:10.1016/j.exphem.2009.02.006.

    PubMed  CAS  Google Scholar 

  143. Wang L, Giannoudis A, Lane S, Williamson P, Pirmohamed M, Clark RE. Expression of the uptake drug transporter hOCT1 is an important clinical determinant of the response to imatinib in chronic myeloid leukemia. Clin Pharmacol Ther. 2008;83(2):258–64. doi:10.1038/sj.clpt.6100268.

    PubMed  CAS  Google Scholar 

  144. Gorre ME, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001;293(5531):876–80. doi:10.1126/science.1062538.

    PubMed  CAS  Google Scholar 

  145. Hochhaus A, Kreil S, Corbin AS, et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia. 2002;16(11):2190–6. doi:10.1038/sj.leu.2402741.

    PubMed  CAS  Google Scholar 

  146. Hu Y, Liu Y, Pelletier S, et al. Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia. Nat Genet. 2004;36(5):453–61. doi:10.1038/ng1343.

    PubMed  CAS  Google Scholar 

  147. Donato NJ, Wu JY, Stapley J, et al. BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood. 2003;101(2):690–8. doi:10.1182/blood.V101.2.690.

    PubMed  CAS  Google Scholar 

  148. Wu J, Meng F, Lu H, et al. Lyn regulates BCR-ABL and Gab2 tyrosine phosphorylation and c-Cbl protein stability in imatinib-resistant chronic myelogenous leukemia cells. Blood. 2008;111(7):3821–9. doi:10.1182/blood-2007-08-109330.

    PubMed  CAS  Google Scholar 

  149. Wu J, Meng F, Kong LY, et al. Association between imatinib-resistant BCR-ABL mutation-negative leukemia and persistent activation of LYN kinase. J Natl Cancer Inst. 2008;100(13):926–39. doi:10.1093/jnci/djn188.

    PubMed  CAS  Google Scholar 

  150. 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(27):6658–61. doi:10.1021/jm049486a.

    PubMed  CAS  Google Scholar 

  151. Mahon FX, Hayette S, Lagarde V, et al. Evidence that resistance to nilotinib may be due to BCR-ABL, Pgp, or Src kinase overexpression. Cancer Res. 2008;68(23):9809–16. doi:10.1158/0008-5472.CAN-08-1008.

    PubMed  CAS  Google Scholar 

  152. O’Hare T, Eide CA, Deininger MW. Persistent LYN signaling in imatinib-resistant, BCR-ABL-independent chronic myelogenous leukemia. J Natl Cancer Inst. 2008;100(13):908–9. doi:10.1093/jnci/djn204.

    PubMed  Google Scholar 

  153. 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(10):3794–800. doi:10.1182/blood-2002-09-2790.

    PubMed  CAS  Google Scholar 

  154. O’Dwyer ME, Mauro MJ, Blasdel C, et al. Clonal evolution and lack of cytogenetic response are adverse prognostic factors for hematologic relapse of chronic phase CML patients treated with imatinib mesylate. Blood. 2004;103(2):451–5. doi:10.1182/blood-2003-02-0371.

    PubMed  Google Scholar 

  155. Andersen MK, Pedersen-Bjergaard J, Kjeldsen L, Dufva IH, Brondum-Nielsen K. Clonal Ph-negative hematopoiesis in CML after therapy with imatinib mesylate is frequently characterized by trisomy 8. Leukemia. 2002;16(7):1390–3. doi:10.1038/sj.leu.2402634.

    PubMed  CAS  Google Scholar 

  156. Bumm T, Muller C, Al-Ali HK, et al. 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. 2003;101(5):1941–9. doi:10.1182/blood-2002-07-2053.

    PubMed  CAS  Google Scholar 

  157. O’Dwyer ME, Gatter KM, Loriaux M, et al. Demonstration of Philadelphia chromosome negative abnormal clones in patients with chronic myelogenous leukemia during major ­cytogenetic responses induced by imatinib mesylate. Leukemia. 2003;17(3):481–7. doi:10.1038/sj.leu.2402848.

    PubMed  Google Scholar 

  158. 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: a 4.5-year follow-up. Cancer. 2005;103(8):1659–69. doi:10.1002/cncr.20922.

    PubMed  Google Scholar 

  159. Hagemeijer A, Smit EM, Lowenberg B, Abels J. Chronic myeloid leukemia with permanent disappearance of the Ph1 chromosome and development of new clonal subpopulations. Blood. 1979;53(1):1–14.

    PubMed  CAS  Google Scholar 

  160. Fayad L, Kantarjian H, O’Brien S, et al. Emergence of new clonal abnormalities following interferon-alpha induced complete cytogenetic response in patients with chronic myeloid leukemia: report of three cases. Leukemia. 1997;11(5):767–71.

    PubMed  CAS  Google Scholar 

  161. Chee YL, Vickers MA, Stevenson D, Holyoake TL, Culligan DJ. Fatal myelodysplastic syndrome developing during therapy with imatinib mesylate and characterised by the emergence of complex Philadelphia negative clones. Leukemia. 2003;17(3):634–5. doi:10.1038/sj.leu.2402842.

    PubMed  CAS  Google Scholar 

  162. Kovitz C, Kantarjian H, Garcia-Manero G, Abruzzo LV, Cortes J. Myelodysplastic syndromes and acute leukemia developing after imatinib mesylate therapy for chronic myeloid leukemia. Blood. 2006;108(8):2811–3. doi:10.1182/blood-2006-04-017400.

    PubMed  CAS  Google Scholar 

  163. Deininger MW, Cortes J, Paquette R, et al. The prognosis for patients with chronic myeloid leukemia who have clonal cytogenetic abnormalities in Philadelphia chromosome-negative cells. Cancer. 2007;110(7):1509–19. doi:10.1002/cncr.22936.

    PubMed  Google Scholar 

  164. Jabbour E, Kantarjian HM, Abruzzo LV, et al. Chromosomal abnormalities in Philadelphia chromosome negative metaphases appearing during imatinib mesylate therapy in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Blood. 2007;110(8):2991–5. doi:10.1182/blood-2007-01-070045.

    PubMed  CAS  Google Scholar 

  165. Fabarius A, Haferlach C, Muller MC, et al. Dynamics of cytogenetic aberrations in Philadelphia chromosome positive and negative hematopoiesis during dasatinib therapy of chronic myeloid leukemia patients after imatinib failure. Haematologica. 2007;92(6):834–7.

    PubMed  CAS  Google Scholar 

  166. Shah NP, Nicoll JM, Nagar B, et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell. 2002;2(2):117–25.

    PubMed  CAS  Google Scholar 

  167. Azam M, Latek RR, Daley GQ. Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL. Cell. 2003;112(6):831–43.

    PubMed  CAS  Google Scholar 

  168. Branford S, Rudzki Z, Walsh S, et al. High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance. Blood. 2002;99(9):3472–5.

    PubMed  CAS  Google Scholar 

  169. Branford S, Rudzki Z, Walsh S, et al. Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood. 2003;102(1):276–83. doi:10.1182/blood-2002-09-2896.

    PubMed  CAS  Google Scholar 

  170. Corm S, Nicollini F, Borie D, et al. Mutation status of imatinib mesylate-resistants CML patients and clinical outcomes: a French multicenter retrospective study for the fiLMC Group. ASH Annu Meeting Abstr. 2004;104(11):275. http://abstracts.hematologylibrary.org/cgi/content/abstract/ashmtg;104/11/275.

    Google Scholar 

  171. Willis SG, Lange T, Demehri S, et al. High-sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic evolution but not response to therapy. Blood. 2005;106(6):2128–37. doi:10.1182/blood-2005-03-1036.

    PubMed  CAS  Google Scholar 

  172. Gruber FX, Ernst T, Kiselev Y, Hochhaus A, Mikkola I. Detection of drug-resistant clones in chronic myelogenous leukemia patients during dasatinib and nilotinib treatment. Clin Chem. 2010;56(3):469–73. doi:10.1373/clinchem.2009.133843.

    PubMed  CAS  Google Scholar 

  173. Nardi V, Raz T, Cao X, et al. Quantitative monitoring by polymerase colony assay of known mutations resistant to ABL kinase inhibitors. Oncogene. 2008;27(6):775–82. doi:10.1038/sj.onc.1210698.

    PubMed  CAS  Google Scholar 

  174. Branford S, Melo JV, Hughes TP. Selecting optimal second-line tyrosine kinase inhibitor therapy for chronic myeloid leukemia patients after imatinib failure: does the BCR-ABL mutation status really matter? Blood. 2009;114(27):5426–35. doi:10.1182/blood-2009-08-215939.

    PubMed  CAS  Google Scholar 

  175. Sherbenou DW, Hantschel O, Kaupe I, et al. BCR-ABL SH3-SH2 domain mutations in chronic myeloid leukemia patients on imatinib. Blood. 2010;116(17):3278–85. doi:10.1182/blood-2008-10-183665.

    PubMed  CAS  Google Scholar 

  176. Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell. 2005;7(2):129–41. doi:10.1016/j.ccr.2005.01.007.

    PubMed  CAS  Google Scholar 

  177. O’Hare T, Eide CA, Deininger MW. Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood. 2007;110(7):2242–9. doi:10.1182/blood-2007-03-066936.

    PubMed  Google Scholar 

  178. Tokarski JS, Newitt JA, Chang CY, et al. The structure of Dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. Cancer Res. 2006;66(11):5790–7. doi:10.1158/0008-5472.CAN-05-4187.

    PubMed  CAS  Google Scholar 

  179. Manley PW, Cowan-Jacob SW, Fendrich G, et al. Bcr-Abl binding modes of dasatinib, imatinib and nilotinib: an NMR study. ASH Annu Meeting Abstr. 2006;108(11):747. http://abstracts.hematologylibrary.org/cgi/content/abstract/ashmtg;108/11/747.

    Google Scholar 

  180. Soverini S, Martinelli G, Rosti G, et al. ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia. J Clin Oncol. 2005;23(18):4100–9. doi:10.1200/JCO.2005.05.531.

    PubMed  CAS  Google Scholar 

  181. Nicolini FE, Corm S, Le QH, et al. Mutation status and clinical outcome of 89 imatinib mesylate-resistant chronic myelogenous leukemia patients: a retrospective analysis from the French intergroup of CML (Fi(phi)-LMC GROUP). Leukemia. 2006;20(6):1061–6. doi:10.1038/sj.leu.2404236.

    PubMed  CAS  Google Scholar 

  182. Apperley JF. Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol. 2007;8(11):1018–29. doi:10.1016/S1470-2045(07)70342-X.

    PubMed  CAS  Google Scholar 

  183. Apperley JF. Part II: management of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol. 2007;8(12):1116–28. doi:10.1016/S1470-2045(07), 70379-0.

    PubMed  CAS  Google Scholar 

  184. Redaelli S, Piazza R, Rostagno R, et al. Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. J Clin Oncol. 2009;27(3):469–71. doi:10.1200/JCO.2008.19.8853.

    PubMed  CAS  Google Scholar 

  185. Press RD, Willis SG, Laudadio J, Mauro MJ, Deininger MW. Determining the rise in BCR-ABL RNA that optimally predicts a kinase domain mutation in patients with chronic myeloid leukemia on imatinib. Blood. 2009;114(13):2598–605. doi:10.1182/blood-2008-08-173674.

    PubMed  CAS  Google Scholar 

  186. Quintas-Cardama A, Cortes JE, O’Brien S, et al. Dasatinib early intervention after cytogenetic or hematologic resistance to imatinib in patients with chronic myeloid leukemia. Cancer. 2009;115(13):2912–21. doi:10.1002/cncr.24325.

    PubMed  CAS  Google Scholar 

  187. 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(8):2873–8. doi:10.1182/blood-2003-11-3800.

    PubMed  CAS  Google Scholar 

  188. 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(10):3965–73. doi:10.1182/blood-2008-06-161737.

    PubMed  CAS  Google Scholar 

  189. Cortes JE, Kantarjian HM, Goldberg SL, et al. High-dose imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: high rates of rapid cytogenetic and molecular responses. J Clin Oncol. 2009;27(28):4754–9. doi:10.1200/JCO.2008.20.3869.

    PubMed  CAS  Google Scholar 

  190. Baccarani M, Rosti G, Castagnetti F, et al. Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of high-risk, Philadelphia-positive chronic myeloid leukemia: a European LeukemiaNet Study. Blood. 2009;113(19):4497–504. doi:10.1182/blood-2008-12-191254.

    PubMed  CAS  Google Scholar 

  191. Cortes JE, Baccarani M, Guilhot F, et al. Phase III, randomized, open-label study of daily imatinib mesylate 400 mg versus 800 mg in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase using molecular end points: tyrosine kinase inhibitor optimization and selectivity study. J Clin Oncol. 2010;28(3):424–30. doi:10.1200/JCO.2009.25.3724.

    PubMed  CAS  Google Scholar 

  192. Hehlmann R, Jung-Munkwitz S, Lauseker M, et al. Randomized comparison of imatinib 800 Mg Vs. Imatinib 400 Mg +/− IFN in newly diagnosed BCR/ABL positive chronic phase CML: analysis of molecular remission at 12 months; the German CML-study IV. ASH Annu Meeting Abstr. 2009;114(22):339. http://abstracts.hematologylibrary.org/cgi/content/abstract/ashmtg;114/22/339.

    Google Scholar 

  193. Preudhomme C, Guilhot J, Nicolini FE, et al. Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med. 2010;363(26):2511–21. doi:10.1056/NEJMoa1004095.

    PubMed  CAS  Google Scholar 

  194. Brave M, Goodman V, Kaminskas E, et al. Sprycel for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of imatinib mesylate. Clin Cancer Res. 2008;14(2):352–9. doi:10.1158/1078-0432.CCR-07-4175.

    PubMed  CAS  Google Scholar 

  195. Hantschel O, Rix U, Superti-Furga G. Target spectrum of the BCR-ABL inhibitors imatinib, nilotinib and dasatinib. Leuk Lymphoma. 2008;49(4):615–9. doi:10.1080/10428190801896103.

    PubMed  CAS  Google Scholar 

  196. Soverini S, Colarossi S, Gnani A, et al. Resistance to dasatinib in Philadelphia-positive leukemia patients and the presence or the selection of mutations at residues 315 and 317 in the BCR-ABL kinase domain. Haematologica. 2007;92(3):401–4.

    PubMed  CAS  Google Scholar 

  197. Quintas-Cardama A, Cortes JE. The next generation of therapies for chronic myeloid leukemia. Clin Lymphoma Myeloma. 2009;9 Suppl 4:S395–403. doi:10.3816/CLM.2009.s.040.

    PubMed  CAS  Google Scholar 

  198. Baccarani M, Rosti G, Saglio G, et al. Dasatinib time to and durability of major and complete cytogenetic response (MCyR and CCyR) in patients with chronic myeloid leukemia in chronic phase (CML-CP). ASH Annu Meeting Abstr. 2008;112(11):450. http://abstracts.hematologylibrary.org/cgi/content/abstract/ashmtg;112/11/450.

    Google Scholar 

  199. Hochhaus A, Muller MC, Radich J, et al. Dasatinib-associated major molecular responses are rapidly achieved in patients with chronic myeloid leukemia in chronic phase (CML-CP) following resistance, suboptimal response, or intolerance on imatinib. ASH Annu Meeting Abstr. 2008;112(11):1095. http://abstracts.hematologylibrary.org/cgi/content/abstract/ashmtg;112/11/1095.

    Google Scholar 

  200. Shah NP, Kantarjian HM, Kim DW, et al. Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol. 2008;26(19):3204–12. doi:10.1200/JCO.2007.14.9260.

    PubMed  CAS  Google Scholar 

  201. Jabbour E, Bahceci E, Zhu C, Lambert A, Cortes J. Predictors of long-term cytogenetic response following dasatinib therapy of patients with chronic-phase chronic myeloid leukemia (CML-CP). ASH Annu Meeting Abstr. 2009;114(22):3296. http://abstracts.hematologylibrary.org/cgi/content/abstract/ashmtg;114/22/3296.

    Google Scholar 

  202. 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(10):3540–6. doi:10.1182/blood-2007-03-080689.

    PubMed  CAS  Google Scholar 

  203. 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(4):1141–5. doi:10.1182/blood-2010-03-277152.

    PubMed  CAS  Google Scholar 

  204. Branford S, Kim D, Soverini S, et al. Molecular response at 3 months on nilotinib therapy predicts response and long-term outcomes in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in chronic phase (CML-CP). ASH Annu Meeting Abstr. 2009;114(22):3292. http://abstracts.hematologylibrary.org/cgi/content/abstract/ashmtg;114/22/3292.

    Google Scholar 

  205. Kantarjian HM, Jabbour E, Giles FJ, et al. Prognostic factors for progression-free survival in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in chronic phase (CML-CP) treated with nilotinib based on 24 month data. ASH Annu Meeting Abstr. 2009;114(22):3298. http://abstracts.hematologylibrary.org/cgi/content/abstract/ashmtg;114/22/3298.

    Google Scholar 

  206. Hughes T, Saglio G, Branford S, et al. Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase. J Clin Oncol. 2009;27(25):4204–10. doi:10.1200/JCO.2009.21.8230.

    PubMed  CAS  Google Scholar 

  207. Soverini S, Gnani A, Colarossi S, et al. Philadelphia-positive patients who already harbor imatinib-resistant Bcr-Abl kinase domain mutations have a higher likelihood of developing additional mutations associated with resistance to second- or third-line tyrosine kinase inhibitors. Blood. 2009;114(10):2168–71. doi:10.1182/blood-2009-01-197186.

    PubMed  CAS  Google Scholar 

  208. Griswold IJ, MacPartlin M, Bumm T, et al. Kinase domain mutants of Bcr-Abl exhibit altered transformation potency, kinase activity, and substrate utilization, irrespective of sensitivity to imatinib. Mol Cell Biol. 2006;26(16):6082–93. doi:10.1128/MCB.02202-05.

    PubMed  CAS  Google Scholar 

  209. 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(9):2562–9. doi:10.1172/JCI30890.

    PubMed  CAS  Google Scholar 

  210. Cortes J, Jabbour E, Kantarjian H, et al. Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors. Blood. 2007;110(12):4005–11. doi:10.1182/blood-2007-03-080838.

    PubMed  CAS  Google Scholar 

  211. Jabbour E, Kantarjian HM, Jones D, et al. Characteristics and outcome of chronic myeloid leukemia patients with F317L BCR-ABL kinase domain mutation after therapy with tyrosine kinase inhibitors. Blood. 2008;112(13):4839–42. doi:10.1182/blood-2008-04-149948.

    PubMed  CAS  Google Scholar 

  212. Muller MC, Cortes JE, Kim DW, et al. Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations. Blood. 2009;114(24):4944–53. doi:10.1182/blood-2009-04-214221.

    PubMed  Google Scholar 

  213. Jabbour E, Cortes JE, Kantarjian H. Second-line therapy and beyond resistance for the treatment of patients with chronic myeloid leukemia post imatinib failure. Clin Lymphoma Myeloma. 2009;9 Suppl 3:S272–9. doi:10.3816/CLM.2009.s.023.

    PubMed  CAS  Google Scholar 

  214. Shah N, Bahceci E, Lambert A, Ploughman L, Radich J. Resistance, outcome and the development of mutations with dasatinib in patients with chronic-phase chronic myeloid leukemia (CML-CP). ASH Annu Meeting Abstr. 2009;114(22):1122. http://abstracts.hematologylibrary.org/cgi/content/abstract/ashmtg;114/22/1122.

    Google Scholar 

  215. Ray A, Cowan-Jacob SW, Manley PW, Mestan J, Griffin JD. Identification of BCR-ABL point mutations conferring resistance to the Abl kinase inhibitor AMN107 (nilotinib) by a random mutagenesis study. Blood. 2007;109(11):5011–5. doi:10.1182/blood-2006-01-015347.

    PubMed  CAS  Google Scholar 

  216. Garg RJ, Kantarjian H, O’Brien S, et al. The use of nilotinib or dasatinib after failure to 2 prior tyrosine kinase inhibitors: long-term follow-up. Blood. 2009;114(20):4361–8. doi:10.1182/blood-2009-05-221531.

    PubMed  CAS  Google Scholar 

  217. Sawyers CL. Chronic myeloid leukemia. N Engl J Med. 1999;340(17):1330–40.

    PubMed  CAS  Google Scholar 

  218. Faderl S, Talpaz M, Estrov Z, Kantarjian HM. Chronic myelogenous leukemia: biology and therapy. Ann Intern Med. 1999;131(3):207–19.

    PubMed  CAS  Google Scholar 

  219. Palandri F, Castagnetti F, Alimena G, et al. The long-term durability of cytogenetic responses in patients with accelerated phase chronic myeloid leukemia treated with imatinib 600 mg: the GIMEMA CML Working Party experience after a 7-year follow-up. Haematologica. 2009;94(2):205–12. doi:10.3324/haematol.13529.

    PubMed  CAS  Google Scholar 

  220. Apperley JF, Cortes JE, Kim DW, et al. Dasatinib in the treatment of chronic myeloid leukemia in accelerated phase after imatinib failure: the START a trial. J Clin Oncol. 2009;27(21):3472–9. doi:10.1200/JCO.2007.14.3339.

    PubMed  CAS  Google Scholar 

  221. Kantarjian H, Cortes J, Kim DW, et al. Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up. Blood. 2009;113(25):6322–9. doi:10.1182/blood-2008-11-186817.

    PubMed  CAS  Google Scholar 

  222. le Coutre P, Ottmann OG, Giles F, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood. 2008;111(4):1834–9. doi:10.1182/blood-2007-04-083196.

    PubMed  Google Scholar 

  223. Goldman JM. Initial treatment for patients with CML. Hematology. 2009;2009(1):453–60. doi:10.1182/asheducation-2009.1.453. http://asheducationbook.hematologylibrary.org/cgi/content/abstract/bloodbook;2009/1/453.

    Google Scholar 

  224. Silver RT. The blast phase of chronic myeloid leukaemia. Best Pract Res Clin Haematol. 2009;22(3):387–94. doi:10.1016/j.beha.2009.07.006.

    PubMed  Google Scholar 

  225. Fava C, Kantarjian HM, Jabbour E, et al. Failure to achieve a complete hematologic response at the time of a major cytogenetic response with second-generation tyrosine kinase inhibitors is associated with a poor prognosis among patients with chronic myeloid leukemia in accelerated or blast phase. Blood. 2009;113(21):5058–63. doi:10.1182/blood-2008-10-184960.

    PubMed  CAS  Google Scholar 

  226. Cortes J, Kim DW, Raffoux E, et al. Efficacy and safety of dasatinib in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blast phase. Leukemia. 2008;22(12):2176–83. doi:10.1038/leu.2008.221.

    PubMed  CAS  Google Scholar 

  227. Shah NP. Advanced CML: therapeutic options for patients in accelerated and blast phases. J Natl Compr Canc Netw. 2008;6 Suppl 2:S31–6.

    PubMed  CAS  Google Scholar 

  228. Giles FJ, DeAngelo DJ, Baccarani M, et al. Optimizing outcomes for patients with advanced disease in chronic myelogenous leukemia. Semin Oncol. 2008;35(1 Suppl 1):S1–17; quiz S18-20. 10.1053/j.seminoncol.2007.12.002.

    PubMed  CAS  Google Scholar 

  229. Palandri F, Castagnetti F, Testoni N, et al. Chronic myeloid leukemia in blast crisis treated with imatinib 600 mg: outcome of the patients alive after a 6-year follow-up. Haematologica. 2008;93(12):1792–6. doi:10.3324/haematol.13068.

    PubMed  CAS  Google Scholar 

  230. Ottmann OG, Wassmann B. Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2005:118–122. 10.1182/asheducation-2005.1.118.

  231. Kondo T, Tasaka T, Sano F, et al. Philadelphia chromosome-positive acute myeloid leukemia (Ph  +  AML) treated with imatinib mesylate (IM): a report with IM plasma concentration and bcr-abl transcripts. Leuk Res. 2009;33(9):e137–8. doi:10.1016/j.leukres.2009.03.017.

    PubMed  CAS  Google Scholar 

  232. Thomas ED, Clift RA, Fefer A, et al. Marrow transplantation for the treatment of chronic myelogenous leukemia. Ann Intern Med. 1986;104(2):155–63.

    PubMed  CAS  Google Scholar 

  233. Gratwohl A, Heim D. Current role of stem cell transplantation in chronic myeloid leukaemia. Best Pract Res Clin Haematol. 2009;22(3):431–43. doi:10.1016/j.beha.2009.05.002.

    PubMed  Google Scholar 

  234. Radich JP, Gooley T, Bensinger W, et al. HLA-matched related hematopoietic cell transplantation for chronic-phase CML using a targeted busulfan and cyclophosphamide preparative regimen. Blood. 2003;102(1):31–5. doi:10.1182/blood-2002-08-2619.

    PubMed  CAS  Google Scholar 

  235. Clift RA, Buckner CD, Thomas ED, et al. Marrow transplantation for patients in accelerated phase of chronic myeloid leukemia. Blood. 1994;84(12):4368–73.

    PubMed  CAS  Google Scholar 

  236. Hansen JA, Gooley TA, Martin PJ, et al. Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med. 1998;338(14):962–8. doi:10.1056/NEJM199804023381405.

    PubMed  CAS  Google Scholar 

  237. Pasquini MC, Wang Z. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR Summary Slides. 2010. CIBMTR Web site. www.cibmtr.org. Updated 2010. Accessed 1 June 2011.

  238. Radich J. Stem cell transplant for chronic myeloid leukemia in the imatinib era. Semin Hematol. 2010;47(4):354–61. doi:10.1053/j.seminhematol.2010.06.008.

    PubMed  CAS  Google Scholar 

  239. Venepalli N, Rezvani K, Mielke S, Savani BN. Role of allo-SCT for CML in 2010. Bone Marrow Transplant. 2010;45(11):1579–86. doi:10.1038/bmt.2010.138.

    PubMed  CAS  Google Scholar 

  240. Cortes J, Talpaz M, Bixby D, et al. A phase 1 trial of oral ponatinib (AP24534) in patients with refractory chronic myelogenous leukemia (CML) and other hematologic malignancies: emerging safety and clinical response findings. Blood (ASH Annu Meeting Abstr). 2010;116(21):210. http://abstracts.hematologylibrary.org/cgi/content/abstract/ashmtg;116/21/210.

    Google Scholar 

  241. Oehler VG, Gooley T, Snyder DS, et al. The effects of imatinib mesylate treatment before allogeneic transplantation for chronic myeloid leukemia. Blood. 2007;109(4):1782–9. doi:10.1182/blood-2006-06-031682.

    PubMed  CAS  Google Scholar 

  242. Lee SJ, Kukreja M, Wang T, et al. Impact of prior imatinib mesylate on the outcome of hematopoietic cell transplantation for chronic myeloid leukemia. Blood. 2008;112(8):3500–7. doi:10.1182/blood-2008-02-141689.

    PubMed  CAS  Google Scholar 

  243. Shimoni A, Leiba M, Schleuning M, et al. Prior treatment with the tyrosine kinase inhibitors dasatinib and nilotinib allows stem cell transplantation (SCT) in a less advanced disease phase and does not increase SCT toxicity in patients with chronic myelogenous leukemia and Philadelphia positive acute lymphoblastic leukemia. Leukemia. 2009;23(1):190–4. doi:10.1038/leu.2008.160.

    PubMed  CAS  Google Scholar 

  244. Weisser M, Schleuning M, Haferlach C, Schwerdtfeger R, Kolb HJ. Allogeneic stem-cell transplantation provides excellent results in advanced stage chronic myeloid leukemia with major cytogenetic response to pre-transplant imatinib therapy. Leuk Lymphoma. 2007;48(2):295–301. doi:10.1080/10428190601078464.

    PubMed  CAS  Google Scholar 

  245. Deininger M, Schleuning M, Greinix H, et al. The effect of prior exposure to imatinib on transplant-related mortality. Haematologica. 2006;91(4):452–9.

    PubMed  CAS  Google Scholar 

  246. 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(9134):1087–92.

    PubMed  CAS  Google Scholar 

  247. Passweg JR, Walker I, Sobocinski KA, et al. Validation and extension of the EBMT risk score for patients with chronic myeloid leukaemia (CML) receiving allogeneic haematopoietic stem cell transplants. Br J Haematol. 2004;125(5):613–20. doi:10.1111/j.1365-2141.2004.04955.x.

    PubMed  Google Scholar 

  248. Clift RA, Buckner CD, Appelbaum FR, et al. Allogeneic marrow transplantation in patients with chronic myeloid leukemia in the chronic phase: a randomized trial of two irradiation regimens. Blood. 1991;77(8):1660–5.

    PubMed  CAS  Google Scholar 

  249. Kerbauy FR, Storb R, Hegenbart U, et al. Hematopoietic cell transplantation from HLA-identical sibling donors after low-dose radiation-based conditioning for treatment of CML. Leukemia. 2005;19(6):990–7. doi:10.1038/sj.leu.2403730.

    PubMed  CAS  Google Scholar 

  250. Or R, Shapira MY, Resnick I, et al. Nonmyeloablative allogeneic stem cell transplantation for the treatment of chronic myeloid leukemia in first chronic phase. Blood. 2003;101(2):441–5. doi:10.1182/blood-2002-02-0535.

    PubMed  CAS  Google Scholar 

  251. Crawley C, Szydlo R, Lalancette M, et al. Outcomes of reduced-intensity transplantation for chronic myeloid leukemia: an analysis of prognostic factors from the Chronic Leukemia Working Party of the EBMT. Blood. 2005;106(9):2969–76. doi:10.1182/blood-2004-09-3544.

    PubMed  CAS  Google Scholar 

  252. Bensinger WI, Martin PJ, Storer B, et al. Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med. 2001;344(3):175–81. doi:10.1056/NEJM200101183440303.

    PubMed  CAS  Google Scholar 

  253. Couban S, Simpson DR, Barnett MJ, et al. A randomized multicenter comparison of bone marrow and peripheral blood in recipients of matched sibling allogeneic transplants for myeloid malignancies. Blood. 2002;100(5):1525–31. doi:10.1182/blood-2002-01-0048.

    PubMed  CAS  Google Scholar 

  254. Oehler VG, Radich JP, Storer B, et al. Randomized trial of allogeneic related bone marrow transplantation versus peripheral blood stem cell transplantation for chronic myeloid leukemia. Biol Blood Marrow Transplant. 2005;11(2):85–92. doi:10.1016/j.bbmt.2004.09.010.

    PubMed  Google Scholar 

  255. Sanz J, Sanz GF. Umbilical cord blood transplantation from unrelated donors in adult patients with chronic myeloid leukaemia. Best Pract Res Clin Haematol. 2010;23(2):217–22. doi:10.1016/j.beha.2010.05.001.

    PubMed  Google Scholar 

  256. Olavarria E, Siddique S, Griffiths MJ, et al. Posttransplantation imatinib as a strategy to postpone the requirement for immunotherapy in patients undergoing reduced-intensity allografts for chronic myeloid leukemia. Blood. 2007;110(13):4614–7. doi:10.1182/blood-2007-04-082990.

    PubMed  CAS  Google Scholar 

  257. DeAngelo DJ, Hochberg EP, Alyea EP, et al. Extended follow-up of patients treated with imatinib mesylate (Gleevec) for chronic myelogenous leukemia relapse after allogeneic transplantation: durable cytogenetic remission and conversion to complete donor chimerism without graft-versus-host disease. Clin Cancer Res. 2004;10(15):5065–71. doi:10.1158/1078-0432.CCR-03-0580.

    PubMed  CAS  Google Scholar 

  258. Hess G, Bunjes D, Siegert W, et al. Sustained complete molecular remissions after treatment with imatinib-mesylate in patients with failure after allogeneic stem cell transplantation for chronic myelogenous leukemia: results of a prospective phase II open-label multicenter study. J Clin Oncol. 2005;23(30):7583–93. doi:10.1200/JCO.2005.01.3110.

    PubMed  CAS  Google Scholar 

  259. Kolb HJ, Schattenberg A, Goldman JM, et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood. 1995;86(5):2041–50.

    PubMed  CAS  Google Scholar 

  260. Savani BN, Montero A, Kurlander R, Childs R, Hensel N, Barrett AJ. Imatinib synergizes with donor lymphocyte infusions to achieve rapid molecular remission of CML relapsing after allogeneic stem cell transplantation. Bone Marrow Transplant. 2005;36(11):1009–15. doi:10.1038/sj.bmt.1705167.

    PubMed  CAS  Google Scholar 

  261. Silver RT, Cortes J, Waltzman R, Mone M, Kantarjian H. Sustained durability of responses and improved progression-free and overall survival with imatinib treatment for accelerated phase and blast crisis chronic myeloid leukemia: long-term follow-up of the STI571 0102 and 0109 trials. Haematologica. 2009;94(5):743–4. doi:10.3324/haematol.2009.006999.

    PubMed  Google Scholar 

  262. Novartis Pharmaceuticals Corporation. Gleevec (imatinib mesylate): prescribing information (online). http://www.pharma.us.novartis.com/product/pi/pdf/gleevec_tabs.pdf. Accessed 26 May 2011.

  263. Novartis Pharmaceuticals Corporation. Tasigna (nilotinib): prescribing information (online). http://www.pharma.us.novartis.com/product/pi/pdf/tasigna.pdf. Accessed 27 May 2011.

  264. Bristol Myers Squibb Corporation. Sprycel (dasatinib): prescribing information (online). http://packageinserts.bms.com/pi/pi_sprycel.pdf. Accessed 25 May 2011.

  265. Ramar K, Potti A, Mehdi SA. Uncommon syndromes and treatment manifestations of malignancy: Case 4. Periorbital edema and imatinib mesylate therapy for chronic myelogenous leukemia. J Clin Oncol. 2003;21(1):172–3.

    PubMed  Google Scholar 

  266. Porkka K, Khoury HJ, Paquette RL, Matloub Y, Sinha R, Cortes JE. Dasatinib 100 mg once daily minimizes the occurrence of pleural effusion in patients with chronic myeloid leukemia in chronic phase and efficacy is unaffected in patients who develop pleural effusion. Cancer. 2010;116(2):377–86. doi:10.1002/cncr.24734.

    PubMed  CAS  Google Scholar 

  267. Quintas-Cardama A, Kantarjian H, O’Brien S, et al. Pleural effusion in patients with chronic myelogenous leukemia treated with dasatinib after imatinib failure. J Clin Oncol. 2007;25(25):3908–14. doi:10.1200/JCO.2007.12.0329.

    PubMed  CAS  Google Scholar 

  268. Deininger MW, O’Brien SG, Ford JM, Druker BJ. Practical management of patients with chronic myeloid leukemia receiving imatinib. J Clin Oncol. 2003;21(8):1637–47. doi:10.1200/JCO.2003.11.143.

    PubMed  CAS  Google Scholar 

  269. Deremer DL, Ustun C, Natarajan K. Nilotinib: a second-generation tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia. Clin Ther. 2008;30(11):1956–75. doi:10.1016/j.clinthera.2008.11.014.

    PubMed  CAS  Google Scholar 

  270. Cortes JE, Hochhaus A, le Coutre PD, et al. Minimal cross-intolerance with nilotinib in patients with chronic myeloid leukemia in chronic or accelerated phase who are intolerant to imatinib. Blood. 2011;117(21):5600–6. http://bloodjournal.hematologylibrary.org/content/early/2011/04/04/blood-2010-11-318949.abstract. 10.1182/blood-2010-11–318949.

  271. Keller G, Schafhausen P, Brummendorf TH. Bosutinib. Recent Results Cancer Res. 2010;184:119–27. doi:10.1007/978-3-642-01222-8_9.

    PubMed  CAS  Google Scholar 

  272. Quintas-Cardama A, Kantarjian H, Cortes J. Imatinib and beyond – exploring the full potential of targeted therapy for CML. Nat Rev Clin Oncol. 2009;6(9):535–43. doi:10.1038/nrclinonc.2009.112.

    PubMed  CAS  Google Scholar 

  273. Quintas-Cardama A, Kantarjian H, Cortes J. Homoharringtonine, omacetaxine mepesuccinate, and chronic myeloid leukemia circa 2009. Cancer. 2009;115(23):5382–93. doi:10.1002/cncr.24601.

    PubMed  CAS  Google Scholar 

  274. Konig H, Hartel N, Schultheis B, et al. Enhanced Bcr-Abl-specific antileukemic activity of arsenic trioxide (Trisenox) through glutathione-depletion in imatinib-resistant cells. Haematologica. 2007;92(6):838–41.

    PubMed  CAS  Google Scholar 

  275. Cortes-Franco J, Dombret H, Schafhausen P, et al. Danusertib hydrochloride (PHA-739358), a multi-kinase aurora inhibitor, elicits clinical benefit in advanced chronic myeloid leukemia and Philadelphia chromosome positive acute lymphoblastic leukemia. Blood (ASH Annu Meeting Abstr). 2009;114(22):864. http://abstracts.hematologylibrary.org/cgi/content/abstract/ashmtg;114/22/864.

    Google Scholar 

  276. Irvine DA, Zhang B, Allan EK, et al. Combination of the hedgehog pathway inhibitor LDE225 and nilotinib eliminates chronic myeloid leukemia stem and progenitor cells. Blood. 2009;114(22):1428. http://abstracts.hematologylibrary.org/cgi/content/abstract/ashmtg;114/22/1428.

    Google Scholar 

  277. Van Etten RA, Chan WW, Zaleskas VM, et al. Switch pocket inhibitors of the ABL tyrosine kinase: distinct kinome inhibition profiles and in vivo efficacy in mouse models of CML and B-lymphoblastic leukemia induced by BCR-ABL T315I. Blood. 2008;112(11):576. http://abstracts.hematologylibrary.org/cgi/content/abstract/ashmtg;112/11/576.

    Google Scholar 

  278. Lapenna S, Giordano A. Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009;8(7):547–66. doi:10.1038/nrd2907.

    PubMed  CAS  Google Scholar 

  279. Zhang J, Adrian FJ, Jahnke W, et al. Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature. 2010;463(7280):501–6. doi:10.1038/nature08675.

    PubMed  CAS  Google Scholar 

  280. 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(9):3322–6.

    PubMed  Google Scholar 

  281. 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(12):4149–53. http://bloodjournal.hematologylibrary.org/cgi/content/abstract/bloodjournal;93/12/4149.

    PubMed  Google Scholar 

  282. 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(5):401–12. doi:10.1016/j.ccr.2009.09.028.

    PubMed  Google Scholar 

  283. Talpaz M, Cortes JE, Deininger MW, et al. Phase I trial of AP24534 in patients with refractory chronic myeloid leukemia (CML) and hematologic malignancies. ASCO Meeting Abstr. 2010;28(15):6511. http://meeting.ascopubs.org/cgi/content/abstract/28/15_suppl/6511.

    Google Scholar 

  284. 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(5):401–12. doi:10.1016/j.ccr.2009.09.028.

    PubMed  Google Scholar 

  285. Milojkovic D, Nicholson E, Apperly 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(2):224–231. 10.3324/haematol. 2009.012781.

    Google Scholar 

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Authors and Affiliations

  1. Division of Medical Oncology, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA

    Andrew Coveler M.D. (Assistant Professor)

  2. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Andrew Coveler M.D. (Assistant Professor) & Vivian G. Oehler M.D. (Assistant Member)

  3. Division of Hematology, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA

    Vivian G. Oehler M.D. (Assistant Member)

Authors
  1. Andrew Coveler M.D.
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  2. Vivian G. Oehler M.D.
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Correspondence to Vivian G. Oehler M.D. .

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Editors and Affiliations

  1. Univ of Washington School of Medicine, Member,, Professor of Med, Division of Hematology, Attending Physician, Seattle Cancer Care Alliance, Seattle, 98109-1024, Washington, USA

    Elihu H. Estey

  2. Director, Clinical Research Division,, Fred Hutchinson Cancer Research Center, Professor of Medicine; Head of Oncology, Seattle Cancer Care Alliance, Univ of Washington Sch of Med, Seattle, 98109-1024, Washington, USA

    Fred R. Appelbaum

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Coveler, A., Oehler, V.G. (2012). Chronic Myeloid Leukemia (CML). In: Estey, E., Appelbaum, F. (eds) Leukemia and Related Disorders. Contemporary Hematology. Springer, New York, NY. https://doi.org/10.1007/978-1-60761-565-1_4

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