Seminars in Oncology
Volume 35 , Pages S1-S17 , February 2008

Optimizing Outcomes for Patients With Advanced Disease in Chronic Myelogenous Leukemia

  • Francis J. Giles

      Affiliations

    • Professor of Medicine, and Chief, Division of Hematology and Medical Oncology, University of Texas Health Science Center at San Antonio; and Director of CTRC Institute for Drug Development, San Antonio, TX.
    • These authors contributed equally to the development of this manuscript.
    • Corresponding Author InformationAddress correspondence to Francis J. Giles, MB, MD, FRCPI, FRCPath, Division of Hematology and Medical Oncology, University of Texas Health Science Center at San Antonio, Director of CTRC Institute for Drug Development, 7979 Wurzbach Road, Suite 400, San Antonio, TX 78229.
  • ,
  • Daniel J. DeAngelo

      Affiliations

    • Dana-Farber Cancer Institute, Boston, MA.
    • These authors contributed equally to the development of this manuscript.
  • ,
  • Michele Baccarani

      Affiliations

    • University of Bologna, Bologna, Italy.
  • ,
  • Michael Deininger

      Affiliations

    • Oregon Health & Science University, Portland, OR.
  • ,
  • François Guilhot

      Affiliations

    • Clinical Investigational Center INSERM, CHU de Poitiers, Poitiers, France.
  • ,
  • Timothy Hughes

      Affiliations

    • Institute of Medical and Veterinary Science, Adelaide, Australia.
  • ,
  • Michael Mauro

      Affiliations

    • Oregon Health & Science University, Portland, OR.
  • ,
  • Jerald Radich

      Affiliations

    • Fred Hutchinson Cancer Research Center, Seattle, WA.
  • ,
  • Oliver Ottmann

      Affiliations

    • Johann Wolfgang Goethe Universität, Frankfurt, Germany.
  • ,
  • Jorge Cortes

      Affiliations

    • Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX.
    • These authors contributed equally to the development of this manuscript.

References 

  1. Sokal JE, Baccarani M, Russo D, et al. Staging and prognosis in chronic myelogenous leukemia. Semin Hematol. 1988;25:49–61
  2. Clift RA, Buckner CD, Thomas ED, et al. Marrow transplantation for patients in accelerated phase of chronic myeloid leukemia. Blood. 1994;84:4368–4373
  3. Kantarjian HM, Dixon D, Keating MJ, et al. Characteristics of accelerated disease in chronic myelogenous leukemia. Cancer. 1988;61:1441–1446
  4. Speck B, Bortin MM, Champlin R, et al. Allogeneic bone-marrow transplantation for chronic myelogenous leukaemia. Lancet. 1984;1:665–668
  5. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia. http://www.nccn.org/professionals/physician_gls/PDF/cml.pdfaccessed December 2007
  6. Cortes J, Talpaz M, O’Brien S, et al. Suppression of cytogenetic clonal evolution with interferon alfa therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia. J Clin Oncol. 1998;16:3279–3285
  7. Majlis A, Smith TL, Talpaz M, et al. Significance of cytogenetic clonal evolution in chronic myelogenous leukemia. J Clin Oncol. 1996;14:196–203
  8. Kurzrock R, Gutterman JU, Talpaz M. The molecular genetics of Philadelphia chromosome-positive leukemias. N Engl J Med. 1988;319:990–998
  9. 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;103:2794–2799
  10. Druker BJ, Guilhot F, O’Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408–2417
  11. 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
  12. Gleevec Package insert. East Hanover, NJ. Novartis Pharmaceuticals Corporation
  13. Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002;346:645–652
  14. Kerkela R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med. 2006;12:908–916
  15. Atallah E, Durand J-B, Kantarjian H, et al. Congestive heart failure is a rare event in patients receiving imatinib therapy. Blood. 2007;110:1233–1237
  16. 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;108:1809–1820
  17. 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;86:2632–2641
  18. Giles FJ, Cortes JE, Kantarjian HM, et al. Accelerated and blastic phases of chronic myelogenous leukemia. Hematol Oncol Clin North Am. 2004;18:753–774xii
  19. Karbasian Esfahani M, Moris EL, Dutcher JP, et al. Blastic phase of chronic myelogenous leukemia. Curr Treat Options Oncol. 2006;7:189–199
  20. Deininger M, Schleuning M, Greinix H, et al. The effect of prior exposure to imatinib on transplant-related mortality. Haematologica. 2006;91:452–459
  21. Talpaz M, Silver RT, Druker BJ, et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: Results of a phase 2 study. Blood. 2002;99:1928–1937
  22. Kantarjian H, Talpaz M, O’Brien S, et al. Survival benefit with imatinib mesylate therapy in patients with accelerated-phase chronic myelogenous leukemia–Comparison with historic experience. Cancer. 2005;103:2099–2108
  23. 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;99:3530–3539
  24. 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;100:1965–1971
  25. 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;103:1659–1669
  26. Cortes J, Kantarjian H. New targeted approaches in chronic myeloid leukemia. J Clin Oncol. 2005;23:6316–6324
  27. Sawyers CL. Chronic myeloid leukemia. N Engl J Med. 1999;340:1330–1340
  28. Elrick LJ, Jorgensen HG, Mountford JC, et al. Punish the parent not the progeny. Blood. 2005;105:1862–1866
  29. 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;293:876–880
  30. Roumiantsev S, Shah NP, Gorre ME, et al. Clinical resistance to the kinase inhibitor STI-571 in chronic myeloid leukemia by mutation of Tyr-253 in the Abl kinase domain P-loop. Proc Natl Acad Sci U S A. 2002;99:10700–10705
  31. Kantarjian HM, Talpaz M, O’Brien S, et al. Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood. 2003;101:473–475
  32. Olsson-Stromberg U, Aleskog A, Bjornberg A, et al. Imatinib activity in vitro in tumor cells from patients with chronic myeloid leukemia in chronic phase and blast crisis. Anticancer Drugs. 2006;17:631–639
  33. Hehlmann R, Heimpel H, Hasford J German CML Study Group. Randomized comparison of interferon-alpha with busulfan and hydroxyurea in chronic myelogenous leukemia. Blood. 1994;84:4064–4477
  34. Allan NC, Richards SM, Shepherd PC. UK Medical Research Council randomised, multicentre trial of interferon-alpha n1 for chronic myeloid leukaemia: Improved survival irrespective of cytogenetic response (The UK Medical Research Council’s Working Parties for Therapeutic Trials in Adult Leukaemia). Lancet. 1995;345:1392–1397
  35. Parmar S, Platanias LC. Interferons: Mechanisms of action and clinical applications. Curr Opin Oncol. 2003;15:431–439
  36. Dowding C, Guo AP, Osterholz J, et al. Interferon-alpha overrides the deficient adhesion of chronic myeloid leukemia primitive progenitor cells to bone marrow stromal cells. Blood. 1991;78:499–505
  37. 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;87:3883–3891
  38. Cortes J, Fayad L, Kantarjian H, et al. Association of HLA phenotype and response to interferon-alpha in patients with chronic myelogenous leukemia. Leukemia. 1998;12:455–462
  39. Deng M, Daley GQ. Expression of interferon consensus sequence binding protein induces potent immunity against BCR/ABL-induced leukemia. Blood. 2001;97:3491–3497
  40. Oka T, Sastry KJ, Nehete P, et al. Evidence for specific immune response against P210 BCR-ABL in long-term remission CML patients treated with interferon. Leukemia. 1998;12:155–163
  41. Baccarani M, Martinelli G, Rosti G, et al. Imatinib and pegylated human recombinant interferon-alpha2b in early chronic-phase chronic myeloid leukemia. Blood. 2004;104:4245–4251
  42. Quintas-Cardama A, Kantarjian HM, Ravandi F, et al. Immune modulation of minimal residual disease (MRD) in patients (pts) with chronic myelogenous leukemia (CML) in early chronic phase (CP): A randomized trial of frontline high-dose (HS) imatinib mesylate (IM) with or without pegylated-interferon (PEG-IFN) and GM-CSF. Blood. 2006;11:626a;(abstr 2207)
  43. Dauer M, Schmad K, Junkmann J, et al. IFN-alpha promotes definitive maturation of dendritic cells generated by short-term culture of monocytes with GM-CSF and IL-4. J Leukoc Biol. 2006;80:278–286
  44. Guerci A, Nicolini F, Maloisel F, et al. Randomized comparison of imatinib with imatinib combination therapies in newly diagnosed chronic myelogenous leukemia patients in chronic phase: Design and first interim analysis of a phase III trial from the French CML Group. Blood. 2005;11:53a;(abstr 168)
  45. Guilhot F, Chastang C, Michallet M French Chronic Myeloid Leukemia Study Group. Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. N Engl J Med. 1997;337:223–229
  46. Quintas-Cardama A, Kantarjian H, Ravandi F, et al. A pilot trial of imatinib, low-dose cytarabine (ara-C) and idarubicin (Ida) in patients (pts) with chronic myeloid leukemia (CML) in myeloid blastic phase (BP). Blood. 2005;11:290a;(abstr 4840)
  47. Heidel F, Cortes J, Ruecker F, et al. Results of a multicenter phase II trial for older patients with c-Kit positive acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (HR-MDS) using low-dose ara-C (LDAC) and imatinib. Blood. 2005;11:527a;(abstr 1853)
  48. Carvajal RD, Tse A, Schwartz GK. Aurora kinases: New targets for cancer therapy. Clin Cancer Res. 2006;12:6869–6875
  49. Harrington EA, Bebbington D, Moore J, et al. VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nat Med. 2004;10:262–267
  50. Cheetham GM, Charlton PA, Golec JM, et al. Structural basis for potent inhibition of the Aurora kinases and a T315I multi-drug resistant mutant form of Abl kinase by VX-680. Cancer Lett. 2007;251:323–329
  51. Giles FJ, Cortes JE, Jones D, et al. MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation. Blood. 2006;11:556a;(abstr 1967)
  52. Hoover RR, Harding MW. Synergistic activity of the aurora kinase inhibitor MK-0457 (VX-680) with idarubicin, ara-C, and inhibitors of BCR-ABL. Blood. 2006;11:403a;(abstr 1384)
  53. 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;86:3322–3326
  54. Visani G, Russo D, Ottaviani E, et al. Effects of homoharringtonine alone and in combination with alpha interferon and cytosine arabinoside on ‘in vitro’ growth and induction of apoptosis in chronic myeloid leukemia and normal hematopoietic progenitors. Leukemia. 1997;11:624–628
  55. O’Brien S, Giles F, Talpz M, et al. Results of triple therapy with interferon-alpha, cytarabine, and homoharringtonine, and the impact of adding imatinib to the treatment sequence in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in early chronic phase. Cancer. 2003;98:888–893
  56. Scappini B, Onida F, Kantarjian HM, et al. In vitro effects of STI 571-containing drug combinations on the growth of Philadelphia-positive chronic myelogenous leukemia cells. Cancer. 2002;94:2653–2662
  57. Tipping AJ, Mahon FX, Zafirides G, et al. Drug responses of imatinib mesylate-resistant cells: synergism of imatinib with other chemotherapeutic drugs. Leukemia. 2002;16:2349–2357
  58. Quintás-Cardama A, Kantarrjian H, Garcia-Manero G, et al. Phase I/II study of subcutaneous homoharringtonine in patients with chronic myeloid leukemia who have failed prior therapy. Cancer. 2007;109:1701–1707
  59. Quintas-Cardama A, Kantarjian HM, Wierda W, et al. A phase II study of intravenous (IV) homoharringtonine (HHT) and imatinib (IM) in patients (pts) with chronic myeloid leukemia (CML). Blood. 2006;11:616a;(abstr 2174)
  60. Porosnicu M, Nimmanapalli R, Nguyen D, et al. Co-treatment with As2O3 enhances selective cytotoxic effects of STI-571 against Brc-Abl-positive acute leukemia cells. Leukemia. 2001;15:772–778
  61. Yang D, Zhang R, Shen Y, et al. Comparison of combination therapy of imatinib with trisenox versus imatinib monotherapy for chronic myeloid leukemia patients in chronic phase. Blood. 2006;11:612a;(abstr 2159)
  62. Schnier J, Schwelberger HG, Smit-McBride Z, et al. Translation initiation factor 5A and its hypusine modification are essential for cell viability in the yeast Saccharomyces cerevisiae. Mol Cell Biol. 1991;11:3105–3114
  63. Balabanov S, Gontarewicz A, Ziegler P, et al. Hypusination of eukaryotic initiation factor 5A (EIF-5A): A novel therapeutic target in BCR-ABL-positive leukemias identified by a proteomics approach. Blood. 2007;109:1701–1707
  64. Cortes JE, O’Brien SM, Giles F, et al. Investigational strategies in chronic myelogenous leukemia. ix Hematol Oncol Clin North Am. 2004;18:619–639
  65. Fiskus W, Pranpat M, Bali P, et al. Combined effects of novel tyrosine kinase inhibitor AMN107 and histone deacetylase inhibitor LBH589 against Bcr-Abl-expressing human leukemia cells. Blood. 2006;108:645–652
  66. George P, Bali P, Annavarapu S, et al. Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3. Blood. 2005;105:1768–1776
  67. Kano Y, Akutsu M, Tsunoda S, et al. Cytotoxic effects of histone deacetylase inhibitor FK228 (depsipeptide, formally named FR901228) in combination with conventional anti-leukemia/lymphoma agents against human leukemia/lymphoma cell lines. Invest New Drugs. 2007;25:31–40
  68. Stover EH, Chen J, Lee BH, et al. The small molecule tyrosine kinase inhibitor AMN107 inhibits TEL-PDGFRbeta and FIP1L1-PDGFRalpha in vitro and in vivo. Blood. 2005;106:3206–3213
  69. Garcia-Manero G, Yang H, Bueso-Ramos C, et al. Phase I study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) in patients with advanced leukemias and myelodysplastic syndromes. Blood. 2008;111:1060–1066
  70. Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature. 2006;441:424–430
  71. Cortes J, Jabbour E, Daley GQ, et al. Phase 1 study of lonafarnib (SCH 66336) and imatinib mesylate in patients with chronic myeloid leukemia who have failed prior single-agent therapy with imatinib. Cancer. 2007;110:1295–1302
  72. Isaacs JS, Xu W, Neckers L. Heat shock protein 90 as a molecular target for cancer therapeutics. Cancer Cell. 2003;3:213–217
  73. George P, Bali P, Cohen P, et al. Cotreatment with 17-allylamino-demethoxygeldanamycin and FLT-3 kinase inhibitor PKC412 is highly effective against human acute myelogenous leukemia cells with mutant FLT-3. Cancer Res. 2004;64:3645–3652
  74. Mayerhofer M, Valent P, Sperr WR, et al. BCR/ABL induces expression of vascular endothelial growth factor and its transcriptional activator, hypoxia inducible factor-1alpha, through a pathway involving phosphoinositide 3-kinase and the mammalian target of rapamycin. Blood. 2002;100:3767–3775
  75. Ly C, Arechiga AF, Melo JV, et al. Bcr-Abl kinase modulates the translation regulators ribosomal protein S6 and 4E-BP1 in chronic myelogenous leukemia cells via the mammalian target of rapamycin. Cancer Res. 2003;63:5716–5722
  76. Mohi MG, Boulton C, Gu TL, et al. Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proc Natl Acad Sci U S A. 2004;101:3130–3135
  77. Burchert A, Wng Y, Cai D, et al. Compensatory PI3-kinase/Akt/mTor activation regulates imatinib resistance development. Leukemia. 2005;19:1774–1782
  78. Kantarjian HM, Talpaz M, Giles F, et al. New insights into the pathophysiology of chronic myeloid leukemia and imatinib resistance. Ann Intern Med. 2006;145:913–923
  79. 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
  80. 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;106:2520–2526
  81. ten Hoeve J, Arlinghaus RB, Guo JQ, et al. Tyrosine phosphorylation of CRKL in Philadelphia+ leukemia. Blood. 1994;84:1731–1736
  82. 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;108:697–704
  83. Thomas J, Wang L, Clark RE, et al. Active transport of imatinib into and out of cells: Implications for drug resistance. Blood. 2004;104:3739–3745
  84. Golemovic M, Verstovsek S, Giles F, et al. AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, has in vitro activity against imatinib-resistant chronic myeloid leukemia. Clin Cancer Res. 2005;11:4941–4947
  85. Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell. 2005;7:129–141
  86. O’Hare T, Walters DK, Stoffregen EP, et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res. 2005;65:4500–4505
  87. Verstovsek S, Golemovic M, Kantarjian H, et al. AMN107, a novel aminopyrimidine inhibitor of p190 Bcr-Abl activation and of in vitro proliferation of Philadelphia-positive acute lymphoblastic leukemia cells. Cancer. 2005;104:1230–1236
  88. Tokarski JS, Newit 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;66:5790–5797
  89. 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;109:2303–2309
  90. Baccarani M, Kantarjian HM, Apperley JF, et al. Efficacy of dasatinib (Sprycel) in patients (pts) with chronic phase chronic myelogenous leukemia (CP-CML) resistant to or intolerant of imatinib: updated results of the CA180013 ‘START-C’ phase II study. Blood. 2006;108:53a;(abstr 164)
  91. Dombret H, Ottmann OG, Rosti G, et al. Dasatinib (SPRYCEL(R)) in patients (pts) with Philadelphia chromosome-positive acute lymphoblastic leukemia who are imatinib-resistant (im-r) or -intolerant (im-i): Updated results from the CA180-015 ‘START-L’ study. Blood. 2006;11:88a;(abstr 286)
  92. Martinelli G, Hochhaus A, Coutre S, et al. Dasatinib (SPRYCEL(R)) efficacy and safety in patients (pts) with chronic myelogenous leukemia in lymphoid (CML-LB) or myeloid blast (CML-MB) phase who are imatinib-resistant (Im-r) or -intolerant (Im-i). Blood. 2006;11:224a;(abstr 745)
  93. Cortes J, Kim DW, Guilhot F, et al. Dasatinib (Sprycel) in patients (pts) with chronic myelogenous leukemia in accelerated phase (AP-CML) that is imatinib-resistant (im-r) or –intolerant (im-i): Updated results of the CA180-005 ‘START-A’ phase II study. Blood. 2006;108:613a;(abstr 2160)
  94. Guilhot F, Apperley J, Kim DW, et al. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood. 2007;109:4143–4150
  95. 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;109:3207–3213
  96. Weisberg E, Manley P, Mestan J, et al. AMN107 (nilotinib): A novel and selective inhibitor of BCR-ABL. Br J Cancer. 2006;94:1765–1769
  97. 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;110:3540–3546
  98. Kantarjian HM, Gattermann N, Hochhaus A, et al. A phase II study of nilotinib a novel tyrosine kinase inhibitor administered to imatinib-resistant or intolerant patients with chronic myelogenous leukemia (CML) in accelerated phase (AP). Blood. 2006;11:615a;(abstr 2169)
  99. Kantarjian H. Nilotinib is highly active and safe in chronic phase chronic myelogenous leukemia (CML-CP) patients with imatinib-resistance or intolerance. Blood. 2006;11:226a;(abstr 735)
  100. Coutre PL. Nilotinib is safe and effective in accelerated phase chronic myelogenous leukemia (CML-AP) patients with imatinib resistance or intolerance. Blood. 2006;11:145a;(abstr 471)
  101. Giles F. Nilotinib in patients (pts) with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia in blast crisis (CML-BC) who are resistant or intolerant to imatinib. Blood. 2006;11:310a;(abstr 1025)
  102. Larson R, Ottman O, Kantarjian H, et al. A phase II study of nilotinib administered to imatinib resistant or intolerant patients with chronic myelogenous leukemia (CML) in blast crisis (BC) or relapsed/refractory PH+ acute lymphoblastic leukemia (ALL). J Clin Oncol. 2007;25:367s;(abstr 7040)
  103. Giles F, le Coutre P, Bhalla K, et al. A phase II study of nilotinib, a novel tyrosine kinase inhibitor administered to patients with imatinib resistant or intolerant chronic myelogenous leukemia (CML) in chronic phase (CP), accelerated phase (AP) or blast crisis (BC) who have also failed dasatinib therapy. Blood. 2006;11:645a;(abstr 2170)
  104. Gambacorti-Passerini C, Brummendorf T, Kantarjian H, et al. Bosutinib (SKI-606) exhibits clinical activity in patients with Philadelphia chromosome positive CML or ALL who failed imatinib. J Clin Oncol. 2007;25:18S;(abstr 7006)
  105. Craig A, Kantarjian H, Cortes J, et al. A phase I study of INNO-406, a dual inhibitor of Abl and Lyn kinases, in adult patients with Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) relapsed, refractory, or intolerant of imatinib. J Clin Oncol. 2007;25:18S;(abstr 7046)
  106. Bonifazi F, de Vivo A, Rosti G, et al. Chronic myeloid leukemia and interferon-alpha: A study of complete cytogenetic responders. Blood. 2001;98:3074–3081
  107. 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;20:214–220
  108. 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;107:587–599
  109. Cortes J, O’Brien S, Kantarjian H. Discontinuation of imatinib therapy after achieving a molecular response. Blood. 2004;104:2204–2205
  110. Merante S, Orlandi E, Bernasconi P, et al. Outcome of four patients with chronic myeloid leukemia after imatinib mesylate discontinuation. Haematologica. 2005;90:979–981
  111. 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
  112. Jorgensen HG, Allan EK, Graham SM, et al. Lonafarnib reduces the resistance of primitive quiescent CML cells to imatinib mesylate in vitro. Leukemia. 2005;19:1184–1191
  113. Nusse R, Varmus HE. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell. 1982;31:99–109
  114. Clevers H. Wnt/beta-catenin signaling in development and disease. Cell. 2006;127:469–480
  115. Bresalier RS. Malignant and premalignant lesions of the colon. In:  Friedman SL,  McQuaid KR,  Grendell JH editor. Current Diagnosis and Treatment in Gastroenterology. 2nd ed. New York, NY: Lange Medical Books/McGraw-Hill; 2003;p. 407–435
  116. Rubinfeld B, Souza B, Albert I, et al. Association of the APC gene product with beta-catenin. Science. 1993;262:1731–1734
  117. Austin TW, Solar GP, Ziegler FC, et al. A role for the Wnt gene family in hematopoiesis: Expansion of multilineage progenitor cells. Blood. 1997;89:3624–3635
  118. Van Den Berg DJ, Sharma AK, Bruno E, et al. Role of members of the Wnt gene family in human hematopoiesis. Blood. 1998;92:3189–3202
  119. Kavalerchik E, Gotlib J, Geron I, et al. Inhibition of chronic myelogenous leukemia stem cells with novel Wnt antagonists. Blood. 2006;11:74a;(abstr 238)
  120. Shaulian E, Karin M. AP-1 as a regulator of cell life and death. Nat Cell Biol. 2002;4:E131–E136
  121. Schorpp-Kistner M, Wang ZQ, Angel P, et al. JunB is essential for mammalian placentation. Embo J. 1999;18:934–948
  122. Passegue E, Jochum W, Schorpp-Kistner M, et al. Chronic myeloid leukemia with increased granulocyte progenitors in mice lacking junB expression in the myeloid lineage. Cell. 2001;104:21–32
  123. Yang MY, Liu TC, Chang JG, et al. JunB gene expression is inactivated by methylation in chronic myeloid leukemia. Blood. 2003;101:3205–3211
  124. Bonifer C, Lefevre P, Tagoh H. The regulation of chromatin and DNA-methylation patterns in blood cell development. Curr Top Microbiol Immunol. 2006;310:1–12
  125. de Vos D, van Overveld W. Decitabine: A historical review of the development of an epigenetic drug. Ann Hematol. 2005;84(suppl):3–8
  126. Issa JP, Gharibyan V, Cortes J, et al. Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate. J Clin Oncol. 2005;23:3948–3956
  127. La Rosee P, Johnson K, Corbin AS, et al. In vitro efficacy of combined treatment depends on the underlying mechanism of resistance in imatinib-resistant Bcr-Abl-positive cell lines. Blood. 2004;103:208–215
  128. Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006;6:857–866
  129. Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435:834–838
  130. He L, Thomson JM, Hemann MT, et al. A microRNA polycistron as a potential human oncogene. Nature. 2005;435:828–833
  131. Venturini L, Battmer K, Castoldi M, et al. The polycistronic miRNA cluster miR-17-92 is over-expressed in early phase chronic myeloid leukemia (CML) CD34+ cells. Blood. 2006;11:223a;(abstr 741)

PII: S0093-7754(07)00271-0

doi: 10.1053/j.seminoncol.2007.12.002

Seminars in Oncology
Volume 35 , Pages S1-S17 , February 2008