Annals of Hematology

, Volume 84, Issue 8, pp 487–497 | Cite as

Chronic myeloid leukemia: a model for oncology

Review Article

Abstract

Leukemias have traditionally served as model systems for research on neoplasia because of the easy availability of cell material from blood and marrow for diagnosis, monitoring and studies on pathophysiology. Beyond these more technical aspects, chronic myeloid leukemia (CML) became the first neoplasia in which the elucidation of the genotype led to a rationally designed therapy of the phenotype. Targeting of the pathogenetically relevant BCR-ABL tyrosine kinase with the selective kinase inhibitor imatinib has induced remissions with almost complete disappearance of any signs and symptoms of CML. This therapeutic success has triggered an intensive search for target structures in other cancers and has led to the development of numerous inhibitors of potential targets, which are being studied in preclinical and clinical trials worldwide. This review deals with some of the recent developments that have evolved since our last review in this journal in 2000 (Hehlmann R, Hochhaus A, Berger U, Reiter A (2000) Current trends in the management of chronic myelogenous leukemia. Ann Hematol 79:345–354).

Keywords

Chronic myeloid leukemia Model for oncology Targeted therapy Imatinib in combination Evolution to blast crisis 

References

  1. 1.
    Baccarani M, Martinelli G, Rosti G, Trabacchi E, Testoni N, Bassi S, Amabile M, Soverini S, Castagnetti F, Cilloni D, Izzo B, De Vivo A, Messa E, Bonifazi F, Poerio A, Luatti S, Giugliano E, Alberti D, Fincato G, Russo D, Pane F, Saglio G (2004) Imatinib and pegylated human recombinant interferon-α2b in early chronic phase chronic myeloid leukemia. Blood 104:4245–4251PubMedGoogle Scholar
  2. 2.
    Bartram CR, de Klein A, Hagemeijer A, van Agthoven T, Geurts van Kessel A, Bootsma D, Grosveld G, Ferguson-Smith MA, Davies T, Stone M, Heisterkamp N, Stephenson JR, Groffen J (1983) Translocation of c-abl oncogene correlates with the presence of a Philadelphia chromosome in chronic myelocytic leukaemia. Nature 306:277–280PubMedGoogle Scholar
  3. 3.
    Berger U, Engelich G, Pfirrmann M, Hochhaus A, Reiter A, Metzgeroth G, Hasford J, Heinze B, Heimpel H, Hossfeld DK, Kolb HJ, Löffler H, Pralle H, Queisser W, Hehlmann R (2003) Chronic myeloid leukemia in the elderly: long-term results from randomized trials with interferon alpha. Leukemia 17:1820–1826PubMedGoogle Scholar
  4. 4.
    Berger U, Maywald O, Pfirrmann M, Lahaye T, Hochhaus A, Reiter A, Hasford J, Heimpel H, Hossfeld DK, Kolb HJ, Löffler H, Pralle H, Queisser W, Hehlmann R, and the German CML Study Group (2005) Gender aspects in chronic myeloid leukemia: long term results from randomized studies. Leukemia (in press)Google Scholar
  5. 5.
    Biernaux C, Loos M, Sels A, Huez G, Stryckmans P (1995) Detection of major BCR-ABL gene expression at a very low level in blood cells of some healthy individuals. Blood 88:3118–3122Google Scholar
  6. 6.
    Bonifazi F, De Vivo A, Rosti G, Guilhot F, Guilhot J, Trabacchi E, Hehlmann R, Hochhaus A, Shepherd PC, Steegmann JL, Kluin-Nelemans HC, Thaler J, Simonsson B, Louwagie A, Reiffers J, Mahon FX, Montefusco E, Alimena G, Hasford J, Richards S, Saglio G, Testoni N, Martinelli G, Tura S, Baccarani M (2001) Chronic myeloid leukemia and interferon-alpha: a study of complete cytogenetic responders. Blood 98:3074–3081PubMedGoogle Scholar
  7. 7.
    Bose S, Deininger M, Gora-Tybor J, Goldman JM, Melo JV (1998) The presence of typical and atypical BCR-ABL fusion genes in leukocytes of normal individuals: biologic significance and implications for the assessment of minimal residual disease. Blood 92:3362–3367PubMedGoogle Scholar
  8. 8.
    Branford S, Rudzki Z, Walsh S, Parkinson I, Grigg A, Szer J, Taylor K, Herrmann R, Seymour JF, Arthur C, Joske D, Lynch K, Hughes T (2003) 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 102:276–283PubMedGoogle Scholar
  9. 9.
    Burchert A, Wolfl S, Schmidt M, Brendel C, Denecke B, Cai D, Odyvanova L, Lahaye T, Müller MC, Berg T, Gschaidmeier H, Wittig B, Hehlmann R, Hochhaus A, Neubauer A (2003) Interferon-alpha, but not the ABL-kinase inhibitor imatinib (STI571), induces expression of myeloblastin and a specific T-cell response in chronic myeloid leukemia. Blood 101:259–264PubMedGoogle Scholar
  10. 10.
    Büsche G, Hehlmann R, Hecker H, Heimpel H, Heinze B, Schmeil A, Pfirrmann M, Gomez G, Tobler A, Herrmann H, Kappler M, Hasford J, Buhr T, Kreipe HH, Georgii A, German CML Study Group (2003) Marrow fibrosis, indicator of therapy failure in chronic myeloid leukemia—prospective long-term results from a randomized-controlled trial. Leukemia 17:2444–2453PubMedGoogle Scholar
  11. 11.
    Cohen MH, Williams GA, Sridhara R, Chen G, McGuinn WD Jr, Morse D, Abraham S, Rahman A, Liang C, Lostritto R, Baird A, Pazdur R (2004) United States food and drug administration drug approval summary: gefitinib (ZD1839; Iressa) tablets. Clin Cancer Res 10:1212–1218PubMedGoogle Scholar
  12. 12.
    Cwynarski K, Laylor R, Macchiarulo E, Goldman J, Lombardi G, Melo JV, Dazzi F (2004) Imatinib inhibits the activation and proliferation of normal T lymphocytes in vitro. Leukemia 18:1332–1339PubMedGoogle Scholar
  13. 13.
    Daley GQ, van Etten RA, Baltimore D (1990) Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 247:824–830PubMedGoogle Scholar
  14. 14.
    Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Fernandez Reese S, Ford JM, Capdeville R, Talpaz M (2001) Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344:1038–1042PubMedGoogle Scholar
  15. 15.
    Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL (2001) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344:1031–1037PubMedGoogle Scholar
  16. 16.
    Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J, Lydon NB (1996) Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of BCR-ABL positive cells. Nat Med 2:561–566CrossRefPubMedGoogle Scholar
  17. 17.
    Duesberg P, Rausch C, Rasnick D, Hehlmann R (1998) Genetic instability of cancer cells is proportional to their degree of aneuploidy. Proc Natl Acad Sci U S A 95:13692–13697PubMedGoogle Scholar
  18. 18.
    Duesberg P, Stindl R, Hehlmann R (2000) Explaining the high mutation rates of cancer cells to drug and multidrug resistance by chromosome reassortments that are catalyzed by aneuploidy. Proc Natl Acad Sci U S A 97:14295–14300PubMedGoogle Scholar
  19. 19.
    Emig M, Saussele S, Wittor H, Weisser A, Reiter A, Willer A, Berger U, Hehlmann R, Cross NCP, Hochhaus A (1999) Accurate and rapid analysis of residual disease in patients with CML using specific fluorescent hybridization probes for real time quantitative RT-PCR. Leukemia 13:1825–1832PubMedGoogle Scholar
  20. 20.
    Fabarius A, Hehlmann R, Duesberg PH (2003) Instability of chromosome structure in cancer cells increases exponentially with degrees of aneuploidy. Cancer Genet Cytogenet 143:59–72PubMedGoogle Scholar
  21. 21.
    Forkner CE, Scott TFM (1931) Arsenic as a therapeutic agent in chronic myelogenous leukemia. Preliminary report. JAMA 97:3–5Google Scholar
  22. 22.
    Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, Nishiwaki Y, Vansteenkiste J, Kudoh S, Rischin D, Eek R, Horai T, Noda K, Takata I, Smit E, Averbuch S, Macleod A, Feyereislova A, Dong RP, Baselga J (2003) Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 21:2237–2246PubMedGoogle Scholar
  23. 23.
    Gale RP, Hehlmann R, Zhang M-J, Hasford J, Goldman JM, Heimpel H, Hochhaus A, Klein JP, Kolb HJ, McGlave PB, Passweg JR, Rowlings PA, Sobocinski KA, Horowitz MM, German CML Study Group (1998) Survival with bone marrow transplantation versus hydroxyurea or interferon for chronic myelogenous leukemia. Blood 91:1810–1819PubMedGoogle Scholar
  24. 24.
    Gardembas M, Rousselot P, Tulliez M, Vigier M, Buzyn A, Rigal-Huguet F, Legros L, Michallet M, Berthou C, Cheron N, Maloisel F, Mahon FX, Facon T, Berthaud P, Guilhot J, Guilhot F (2003) Results of a prospective phase 2 study combining imatinib mesylate and cytarabine for the treatment of Philadelphia-positive patients with chronic myelogenous leukemia in chronic phase. Blood 102:4298–4305CrossRefPubMedGoogle Scholar
  25. 25.
    George DJ, Kaelin WG Jr (2003) The von Hippel–Lindau protein, vascular endothelial growth factor, and kidney cancer. N Engl J Med 349:419–421CrossRefPubMedGoogle Scholar
  26. 26.
    Gilliland DG, Tallman MS (2002) Focus on acute leukemias. Cancer Cell 1:417–420CrossRefPubMedGoogle Scholar
  27. 27.
    Giralt S, Estey E, Albitar M, Van Besien K, Rondon G, Anderlini P, O’Brien S, Khouri I, Gajewski J, Mehra R, Claxton D, Andersson B, Beran M, Prezpiorka D, Koller C, Kornblau S, Körbling M, Keating M, Kantarjian H, Champlin R (1997) Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood 89:4531–4536PubMedGoogle Scholar
  28. 28.
    Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL (2001) Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293:876–880CrossRefPubMedGoogle Scholar
  29. 29.
    Gratwohl A, Baldomero H, Horisberger B, Schmid C, Passweg J, Urbano-Ispizua A (2002) Current trends in hematopoietic stem cell transplantation in Europe. Blood 100:2374–2386CrossRefPubMedGoogle Scholar
  30. 30.
    Gratwohl A, Hermans J, Goldman JM, Frassoni F, Devergie A, Carreras E, Kolb HJ, Gahrton G, Arcese W, Vernant JP, Ruutu T, de Witte T, van Rhee F, Apperley J, Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT) (1998) Risk assessment for patients with chronic myeloid leukemia before allogeneic blood or marrow transplantation. Lancet 352:1087–1092CrossRefPubMedGoogle Scholar
  31. 31.
    Hasford J, Pfirrmann M, Hehlmann R, Allan NC, Baccarani M, Kluin-Nelemans J, Alimena G, Steegmann JL, Ansari H (1998) A new prognostic score for the survival of patients with chronic myeloid leukemia treated with interferon alfa. J Natl Cancer Inst 90:850–858CrossRefPubMedGoogle Scholar
  32. 32.
    Hasford J, Pfirrmann M, Hochhaus A (2005) How long will chronic myeloid leukemia patients treated with imatinib live? Leukemia 19:497–499CrossRefPubMedGoogle Scholar
  33. 33.
    Hehlmann R, Berger U, Pfirrmann M, Hochhaus A, Metzgeroth G, Maywald J, Hasford J, Reiter A, Hossfeld DK, Kolb HJ, Löffler H, Pralle H, Queisser W, Griesshammer M, Nerl C, Kuse R, Tobler A, Eimermacher H, Tichelli A, Aul C, Wilhelm M, Fischer JT, Perker M, Scheid C, Schenk M, Weiß J, Meier CR, Kremers S, Labedzki L, Schmeiser T, Lohrmann HP, Heimpel H, German CML Study Group (2003) Randomized comparison of interferon α and hydroxyurea with hydroxyurea monotherapy in chronic myeloid leukemia (CML-Study II): prolongation of survival by the combination of interferon α and hydroxyurea. Leukemia 17:1529–1537CrossRefPubMedGoogle Scholar
  34. 34.
    Hehlmann R, Heimpel H, Hasford J, Kolb HJ, Pralle H, Hossfeld DK, Queisser W, Löffler H, Hochhaus A, Heinze B, Georgii A, Bartram CR, Griesshammer M, Bergmann L, Essers U, Falge C, Queisser U, Meyer P, Schmitz N, Eimermacher H, Walther F, Fett W, Kleeberg UR, Käbisch A, Nerl C, Zimmermann R, Meuret G, Tichelli A, Kanz L, Tigges FJ, Schmid L, Brockhaus W, Tobler A, Reiter A, Perker M, Emmerich B, Verpoort K, Zankovich R, von Wussow P, Prümmer O, Thiele J, Buhr T, Carbonell F, Ansari H, German CML Study Group (1994) Randomized comparison of interferon-alpha with busulfan and hydroxyurea in chronic myelogenous leukemia. Blood 84:4064–4077PubMedGoogle Scholar
  35. 35.
    Hehlmann R, Hochhaus A, Berger U, Reiter A (2000) Current trends in the management of chronic myelogenous leukemia. Ann Hematol 79:345–354CrossRefPubMedGoogle Scholar
  36. 36.
    Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, McGreevey LS, Chen CJ, Van den Abbeele AD, Druker BJ, Kiese B, Eisenberg B, Roberts PJ, Singer S, Fletcher CD, Silberman S, Dimitrijevic S, Fletcher JA (2003) Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21:4342–4349PubMedGoogle Scholar
  37. 37.
    Heisterkamp N, Stephenson JR, Groffen J, Hansen PF, de Klein A, Bartram CR, Grosveld G (1983) Localization of the c-abl oncogene adjacent to a translocation break point in chronic myelocytic leukaemia. Nature 306:239–242CrossRefPubMedGoogle Scholar
  38. 38.
    Hochhaus A, Fischer T, Brümmendorf T, Bostel T, Burchert A, Neubauer A, Rose MT, Gschaidmeier H, Hehlmann R (2003) Combination therapy of chronic myelogenous leukemia (CML) with imatinib and pegylated interferon α2a. Proc Am Soc Clin Oncol 22:569Google Scholar
  39. 39.
    Hochhaus A, Kreil S, Corbin AS, La Rosée P, Müller MC, Lahaye T, Hanfstein B, Schoch C, Cross NC, Berger U, Gschaidmeier H, Druker BJ, Hehlmann R (2002) Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 16:2190–2196CrossRefPubMedGoogle Scholar
  40. 40.
    Hochhaus A, La Rosée P (2004) Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance. Leukemia 18:1321–1331CrossRefPubMedGoogle Scholar
  41. 41.
    Hochhaus A, Reiter A, Saussele S, Reichert A, Emig M, Kaeda J, Schultheis B, Berger U, Shepherd PCA, Allan NC, Hehlmann R, Goldman JM, Cross NCP, German CML Study Group and the UK MRC CML Study Group (2000) Molecular heterogeneity in complete cytogenetic responders after interferon alpha therapy for chronic myelogenous leukemia: low levels of minimal residual disease are associated with continuing remission. Blood 95:62–66PubMedGoogle Scholar
  42. 42.
    Hughes TP, Kaeda J, Branford S, Rudzki Z, Hochhaus A, Hensley ML, Gathmann I, Bolton AE, Hoomissen IC, Goldman JM, Radich JP, International Randomised Study of Interferon versus STI571 (IRIS) Study Group (2003) Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 349:1423–1432CrossRefPubMedGoogle Scholar
  43. 43.
    Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342CrossRefPubMedGoogle Scholar
  44. 44.
    Jamieson CH, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL, Gotlib J, Li K, Manz MG, Keating A, Sawyers CL, Weissman IL (2004) Granulocyte–macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 351:657–667CrossRefPubMedGoogle Scholar
  45. 45.
    Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, Langer CJ, DeVore RF III, Gaudreault J, Damico LA, Holmgren E, Kabbinavar F (2004) Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 22:2184–2191CrossRefPubMedGoogle Scholar
  46. 46.
    Kano Y, Akutsu M, Tsunoda S, Mano H, Sato Y, Honma Y, Furukawa Y (2001) In vitro cytotoxic effects of a tyrosine kinase inhibitor STI571 in combination with commonly used antileukemic agents. Blood 97:1999–2007CrossRefPubMedGoogle Scholar
  47. 47.
    Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C, Niederwieser D, Resta D, Capdeville R, Zoellner U, Talpaz M, Druker B (2002) Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 346:645–652CrossRefPubMedGoogle Scholar
  48. 48.
    Kantarjian H, Talpaz M, O’Brien S, Gracia-Manero G, Verstovsek S, Giles F, Rios MB, Shan J, Letvak L, Thomas D, Faderl S, Ferrajoli A, Cortes J (2004) High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome-positive chronic phase chronic myeloid leukemia. Blood 103:2873–2878CrossRefPubMedGoogle Scholar
  49. 49.
    Kantarjian HM, O’Brien S, Cortes JE, Shan J, Giles FJ, Rios MB, Faderl SH, Wierda WG, Ferrajoli A, Verstovsek S, Keating MJ, Freireich EJ, Talpaz M (2003) Complete cytogenetic and molecular responses to interferon-alpha-based therapy for chronic myelogenous leukemia are associated with excellent long-term prognosis. Cancer 97:1033–1041CrossRefPubMedGoogle Scholar
  50. 50.
    Kluin-Nelemans HC, Buck G, Le Cessie S, Richards S, Beverloo HB, Falkenburg JH, Littlewood T, Muus P, Bareford D, van der Lelie H, Green AR, Roozendaal KJ, Milne AE, Chapman CS, Shepherd P, MRC and HOVON groups (2004) Randomized comparison of low-dose versus high-dose interferon-alfa in chronic myeloid leukemia: prospective collaboration of 3 joint trials by the MRC and HOVON groups. Blood 103:4408–4415CrossRefPubMedGoogle Scholar
  51. 51.
    Kolb HJ, Mittermüller J, Clemm C, Holler E, Ledderose G, Brehm G, Heim M, Wilmanns W (1990) Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 76:2462–2465PubMedGoogle Scholar
  52. 52.
    Kolb HJ, Schmid C, Barrett AJ, Schendel DJ (2004) Graft-versus-leukemia reactions in allogeneic chimeras. Blood 103:767–776CrossRefPubMedGoogle Scholar
  53. 53.
    Kris MG, Natale RB, Herbst RS, Lynch TJ Jr, Prager D, Belani CP, Schiller JH, Kelly K, Spiridonidis H, Sandler A, Albain KS, Cella D, Wolf MK, Averbuch SD, Ochs JJ, Kay AC (2003) Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 290:2149–2158CrossRefPubMedGoogle Scholar
  54. 54.
    La Rosee P, Johnson K, O’Dwyer ME, Druker BJ (2002) In vitro studies of the combination of imatinib mesylate (Gleevec) and arsenic trioxide (Trisenox) in chronic myelogenous leukemia. Exp Hematol 30:729–737CrossRefPubMedGoogle Scholar
  55. 55.
    La Rosee P, O’Dwyer ME, Druker BJ (2002) Insights from pre-clinical studies for new combination treatment regimens with the BCR-ABL kinase inhibitor imatinib mesylate (Gleevec/Glivec) in chronic myelogenous leukemia: a translational perspective. Leukemia 16:1213–1219CrossRefPubMedGoogle Scholar
  56. 56.
    Li R, Yerganian G, Duesberg P, Krämer A, Willer A, Rausch C, Hehlmann R (1997) Aneuploidy correlated 100% with chemical transformation of Chinese hamster cells. Proc Natl Acad Sci U S A 94:14506–14511CrossRefPubMedGoogle Scholar
  57. 57.
    Lin F, Kirkland MA, van Rhee FV, Chase A, Coulthard S, Bungey J, Goldman JM, Cross NC (1996) Molecular analysis of transient cytogenetic relapse after allogeneic bone marrow transplantation for chronic myeloid leukaemia. Bone Marrow Transplant 18:1147–1152PubMedGoogle Scholar
  58. 58.
    Lipton JH, Khoroshko ND, Golenkov AK, Abdulkadyrov KM, Nair MK, Raghunadharao D, Brümmendorf T, Hooftman L, Pegasys CML Study Group (2002) A randomized multicenter comparative study of peginterferon alfa-2a (40 KD) vs interferon-alfa-2a in patients with treatment-naive chronic-phase chronic myelogenous leukemia. Blood 100(Suppl 1):782aGoogle Scholar
  59. 59.
    Lissauer (1865) Zwei Fälle von Leucaemie. Berl Klin Wochenschr 2:403–404Google Scholar
  60. 60.
    Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139CrossRefPubMedGoogle Scholar
  61. 61.
    McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG, Chauncey TR, Gooley TA, Hegenbart U, Nash RA, Radich J, Wagner JL, Minor S, Appelbaum FR, Bensinger WI, Bryant E, Flowers ME, Georges GE, Grumet FC, Kiem HP, Torok-Storb B, Yu C, Blume KG, Storb RF (2001) Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 97:3390–3400CrossRefPubMedGoogle Scholar
  62. 62.
    Merx K, Müller MC, Kreil S, Lahaye T, Paschka P, Schoch C, Weisser A, Kuhn C, Berger U, Gschaidmeier H, Hehlmann R, Hochhaus A (2002) Early reduction of BCR-ABL mRNA transcript levels predicts cytogenetic response in chronic phase CML patients treated with imatinib after failure of interferon alpha. Leukemia 16:1579–1583CrossRefPubMedGoogle Scholar
  63. 63.
    Michallet M, Maloisel F, Delain M, Hellmann A, Rosas A, Silver RT, Tendler C, PEG-Intron CML Study Group (2004) Pegylated recombinant interferon alpha-2b vs recombinant interferon alpha-2b for the initial treatment of chronic-phase chronic myelogenous leukemia: a phase III study. Leukemia 18:309–315CrossRefPubMedGoogle Scholar
  64. 64.
    Müller MC, Gattermann N, Lahaye T, Deininger MWN, Frühauf S, Neubauer A, Fischer T, Hossfeld DK, Schneller F, Krause SW, Nerl C, Sayer HG, Ottmann OG, Aulitzky W, Freund M, Paschka P, König H, Kreil S, Berger U, Gschaidmeier H, Hehlmann R, Hochhaus A (2003) Dynamics of BCR-ABL mRNA expression in first line therapy of chronic myelogenous leukemia patients with imatinib or interferon α/ara-C. Leukemia 17:2392–2400CrossRefPubMedGoogle Scholar
  65. 65.
    Neumann E (1869) Ein Fall von Leukämie mit Erkrankung des Knochenmarks. Archiv Heilkunde 11:1–13Google Scholar
  66. 66.
    Nowell PC, Hungerford DA (1960) A minute chromosome in human chronic granulocytic leukemia. Science 132:1497–1501Google Scholar
  67. 67.
    O’Brien S, Guilhot F, Larson R, Gathmann I, Baccarani M, Cervantes F, Cornelissen J, Fischer T, Hochhaus A, Hughes T, Lechner K, Mahon FX, Nielsen J, Reiffers J, Saglio G, Shepherd J, Simonsson B, Gratwohl A, Goldman J, Talpaz M, Taylor K, Verhoef G, Bolton A, Capdeville R, Druker B, IRIS investigators (2003) The IRIS study: International randomized study of interferon and low-dose ara-C versus STI571 (imatinib) in patients with newly-diagnosed chronic phase chronic myeloid leukemia. N Engl J Med 348:994–1004CrossRefPubMedGoogle Scholar
  68. 68.
    O’Brien SG, Vallance SE, Craddock C, Holyoake T, Goldman JM (2001) PEGIntron and STI571 combination evaluation study (PISCES) in chronic phase chronic myelogenous leukemia. Blood 98(Suppl 1):846aGoogle Scholar
  69. 69.
    O’Hare T, Pollock R, Stoffregen EP, Keats JA, Abdullah OM, Moseson EM, Rivera VM, Tang H, Metcalf CA III, Bohacek RS, Wang Y, Sundaramoorthi R, Shakespeare WC, Dalgarno D, Clackson T, Sawyer TK, Deininger MW, Druker BJ (2004) Inhibition of wild-type and mutant BCR-ABL by AP23464, a potent ATP-based oncogenic protein kinase inhibitor: implications for CML. Blood 104:2532–2539CrossRefPubMedGoogle Scholar
  70. 70.
    Or R, Shapira MY, Resnick I, Amar A, Ackerstein A, Samuel S, Aker M, Naparstek E, Nagler A, Slavin S (2003) Nonmyeloablative allogeneic stem cell transplantation for the treatment of chronic myeloid leukemia in first chronic phase. Blood 101:441–445CrossRefPubMedGoogle Scholar
  71. 71.
    Ottmann OG, Druker BJ, Sawyers CL, Goldman JM, Reiffers J, Silver RT, Tura S, Fischer T, Deininger MW, Schiffer CA, Baccarani M, Gratwohl A, Hochhaus A, Hoelzer D, Fernandes-Reese S, Gathmann I, Capdeville R, O’Brien SG (2002) A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 100:1965–1971CrossRefPubMedGoogle Scholar
  72. 72.
    Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Kaoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500CrossRefPubMedGoogle Scholar
  73. 73.
    Passweg JR, Walker I, Sobocinski KA, Klein JP, Horowitz MM, Giralt SA (2004) Validation and extension of the EBMT Risk Score for patients with chronic myeloid leukaemia (CML) receiving allogeneic haematopoietic stem cell transplants. Br J Haematol 125:613–620CrossRefPubMedGoogle Scholar
  74. 74.
    Rasnick D, Duesberg PH (1999) How aneuploidy affects metabolic control and causes cancer. Biochem J 340(Pt 3):621–630CrossRefPubMedGoogle Scholar
  75. 75.
    Rowley JD (1973) Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 243:290–293PubMedGoogle Scholar
  76. 76.
    Saltz LB, Meropol NJ, Loehrer PJ Sr, Needle MN, Kopit J, Mayer RJ (2004) Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 22:1201–1208CrossRefPubMedGoogle Scholar
  77. 77.
    Sawyers CL, Hochhaus A, Feldman E, Goldman JM, Miller C, Ottmann OG, Schiffer C, Talpaz M, Guilhot F, Deininger MWG, Fischer T, O’Brien SG, Stone R, Gambacorti-Passerini C, Russel N, Reiffers J, Shea T, Chapuis B, Coutre S, Tura S, Mora E, Larson RA, Saven A, Peschel C, Gratwohl A, Mandelli F, Ben-Am M, Gathmann L, Capdeville R, Paquette RL, Druker BJ (2002) Gleevec/GlivecTM (imatinib mesylate) induces hematologic and cytogenetic responses in patients with chronic myeloid leukemia in myeloid blast crisis: results of a phase II study. Blood 99:3530–3539CrossRefPubMedGoogle Scholar
  78. 78.
    Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J (2000) Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase. Science 289:1938–1942PubMedGoogle Scholar
  79. 79.
    Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL (2004) Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305:399–401CrossRefPubMedGoogle Scholar
  80. 80.
    Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G, Varadi G, Kirschbaum M, Ackerstein A, Samuel S, Amar A, Brautbar C, Ben-Tal O, Eldor A, Or R (1998) Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 91:756–763PubMedGoogle Scholar
  81. 81.
    Speck B, Bortin MM, Champlin R, Goldman JM, Herzig RH, McGlave PB, Messner HA, Weiner RS, Rimm AA (1984) Allogeneic bone-marrow transplantation for chronic myelogenous leukaemia. Lancet 1:665–668CrossRefPubMedGoogle Scholar
  82. 82.
    Talpaz M, Silver RT, Druker BJ, Goldman JM, Gambacorti-Passerini C, Guilhot F, Schiffer CA, Fischer T, Deininger MW, Lennard AL, Hochhaus A, Ottmann OG, Gratwohl A, Baccarani M, Stone R, Tura S, Mahon FX, Fernandes-Reese S, Gathmann I, Capdeville R, Kantarjian HM, Sawyers CL (2002) Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood 99:1928–1937CrossRefPubMedGoogle Scholar
  83. 83.
    Tamborini E, Bonadiman L, Greco A, Albertini V, Negri T, Gronchi A, Bertulli R, Colecchia M, Casali PG, Pierotti MA, Pilotti S (2004) A new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumor patient. Gastroenterology 127:294–299CrossRefPubMedGoogle Scholar
  84. 84.
    The Italian Cooperative Study Group on Chronic Myeloid Leukemia (1998) Long-term follow-up of the Italian trial of interferon-a versus conventional chemotherapy in chronic myeloid leukemia. Blood 92:1541–1548Google Scholar
  85. 85.
    Tipping AJ, Baluch S, Barnes DJ, Veach DR, Clarkson BM, Bornmann WG, Mahon FX, Goldman JM, Melo JV (2004) Efficacy of dual-specific BCR-ABL and Src-family kinase inhibitors in cells sensitive and resistant to imatinib mesylate. Leukemia 18:1352–1356CrossRefPubMedGoogle Scholar
  86. 86.
    Topaly J, Zeller WJ, Fruehauf S (2001) Synergistic activity of the new ABL-specific tyrosine kinase inhibitor STI571 and chemotherapeutic drugs on BCR-ABL-positive chronic myelogenous leukemia cells. Leukemia 15:342–347CrossRefPubMedGoogle Scholar
  87. 87.
    Virchow R (1845) Weisses Blut. Frorieps Notizen 36:151–156Google Scholar
  88. 88.
    Virchow R (1847) Weißes Blut (Leukämie). Archiv Pathol Anat 1:563Google Scholar
  89. 89.
    Wang L, Pearson K, Ferguson JE, Clark E (2003) The early molecular response to imatinib predicts cytogenetic and clinical outcome in chronic myeloid leukaemia. Br J Haematol 120:990–999CrossRefPubMedGoogle Scholar
  90. 90.
    Wilkens L, Flemming P, Gebel M, Bleck J, Terkamp C, Wingen L, Kreipe H, Schlegelberger B (2004) Induction of aneuploidy by increasing chromosomal instability during dedifferentiation of hepatocellular carcinoma. Proc Natl Acad Sci U S A 101:1309–1314CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Rüdiger Hehlmann
    • 1
  • Ute Berger
    • 1
  • Andreas Hochhaus
    • 1
  1. 1.III. Medizinische UniversitätsklinikFakultät für Klinische Medizin Mannheim der Universität HeidelbergMannheimGermany

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