Annals of Hematology

, Volume 86, Issue 5, pp 311–327 | Cite as

Diagnostic pathways in acute leukemias: a proposal for a multimodal approach

  • Torsten Haferlach
  • Ulrike Bacher
  • Wolfgang Kern
  • Susanne Schnittger
  • Claudia Haferlach
Review Article

Abstract

Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) each represent a heterogeneous complex of disorders, which result from diverse mechanisms of leukemogenesis. Modern therapeutic concepts are based on individual risk stratification at diagnosis and during follow-up. For some leukemia subtypes such as AML M3/M3v with t(15;17)/PMLRARA or Philadelphia-positive ALL targeted therapy options are available. Thus, optimal therapeutic conditions are based on exact classification of the acute leukemia subtype at diagnosis and are guided by exact and sensitive quantification of minimal residual disease during complete hematologic remission. Today, a multimodal diagnostic approach combining cytomorphology, multiparameter flow cytometry, chromosome banding analysis, accompanied by diverse fluorescence in situ hybridization techniques, and molecular analyses is needed to meet these requirements. As the diagnostic process becomes more demanding with respect to experience of personnel, time, and costs due to the expansion of methods, algorithms, which guide the diagnostic procedure from basic to more specific methods and which lead finally to a synopsis of the respective results, are essential for modern diagnostics and therapeutic concepts.

Keywords

Acute leukemias Diagnosis Cytogenetics PCR Multiparameter flow cytometry 

References

  1. 1.
    Abu-Duhier FM, Goodeve AC, Wilson GA, Care RS, Peake IR, Reilly JT (2001) Identification of novel FLT-3 Asp835 mutations in adult acute myeloid leukaemia. Br J Haematol 113:983–988PubMedCrossRefGoogle Scholar
  2. 2.
    Asselin BL, Kreissman S, Coppola DJ, Bernal SD, Leavitt PR, Gelber RD, Sallan SE, Cohen HJ (1999) Prognostic significance of early response to a single dose of asparaginase in childhood acute lymphoblastic leukemia. J Pediatr Hematol/Oncol 21:6–12CrossRefGoogle Scholar
  3. 3.
    Bacher U, Haferlach T, Hiddemann W, Schnittger S, Kern W, Schoch C (2005) Additional clonal abnormalities in Philadelphia-positive ALL and CML demonstrate a different cytogenetic pattern at diagnosis and follow different pathways at progression. Cancer Genet Cytogenet 157:53–61PubMedCrossRefGoogle Scholar
  4. 4.
    Bacher U, Haferlach T, Schoch C, Kern W, Schnittger S (2006) NRAS mutations in AML: biology, cytogenetics, and prognosis—a study on 2502 patients. Blood 107:3847–3853PubMedCrossRefGoogle Scholar
  5. 5.
    Bacher U, Kern W, Schoch C, Schnittger S, Hiddemann W, Haferlach T (2006) Evaluation of complete disease remission in acute myeloid leukemia: a prospective study based on cytomorphology, interphase fluorescence in situ hybridization, and immunophenotyping during follow-up in patients with acute myeloid leukemia. Cancer 106:839–847PubMedCrossRefGoogle Scholar
  6. 6.
    Bacher U, Schoch C, Kern W, Haferlach T, Schnittger S (2006) Prognostic relevance of FLT3–TKD mutations in AML: the combination matters—an analysis of 3082 patients. Haematologica (in press)Google Scholar
  7. 7.
    Ballerini P, Blaise A, Busson-Le Coniat M, Su XY, Zucman-Rossi J, Adam M, van den Akker J, Perot C, Pellegrino B, Landman-Parker J, Douay L, Berger R, Bernard OA (2002) HOX11L2 expression defines a clinical subtype of pediatric T-ALL associated with poor prognosis. Blood 100:991–997PubMedCrossRefGoogle Scholar
  8. 8.
    Beghini A, Peterlongo P, Ripamonti CB, Larizza L, Cairoli R, Morra E, Mecucci C (2000) C-kit mutations in core binding factor leukemias. Blood 95:726–727PubMedGoogle Scholar
  9. 9.
    Bene MC, Castoldi G, Knapp W, Ludwig WD, Matutes E, Orfao A, van’t Veer MB (1995) Proposals for the immunological classification of acute leukemias European Group for the Immunological Characterization of Leukemias (EGIL). Leukemia 9:1783–1786PubMedGoogle Scholar
  10. 10.
    Bennett JM (2003) Morphologic dysplasia in acute myeloid leukemia: importance of granulocytic dysplasia; author reply. J Clin Oncol 21:3004–3005PubMedCrossRefGoogle Scholar
  11. 11.
    Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C (1976) Proposals for the classification of the acute leukaemias. French–American–British (FAB) Co-operative Group. Br J Haematol 33:451–458PubMedGoogle Scholar
  12. 12.
    Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C (1985) Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French–American–British Cooperative Group. Ann Intern Med 103:620–625PubMedGoogle Scholar
  13. 13.
    Bernell P, Arvidsson I, Jacobsson B, Hast R (1996) Fluorescence in situ hybridization in combination with morphology detects minimal residual disease in remission and heralds relapse in acute leukaemia. Br J Haematol 95:666–672PubMedCrossRefGoogle Scholar
  14. 14.
    Bienz M, Ludwig M, Leibundgut EO, Mueller BU, Ratschiller D, Solenthaler M, Fey MF, Pabst T (2005) Risk assessment in patients with acute myeloid leukemia and a normal karyotype. Clin Cancer Res 11:1416–1424PubMedCrossRefGoogle Scholar
  15. 15.
    Biondi A, Masera G (1998) Molecular pathogenesis of childhood acute lymphoblastic leukemia. Haematologica 83:651–659PubMedGoogle Scholar
  16. 16.
    Bloomfield CD, Secker-Walker LM, Goldman AI, Van Den Berghe H, de la Chapelle A, Ruutu T, Alimena G, Garson OM, Golomb HM, Rowley JD et al (1989) Six-year follow-up of the clinical significance of karyotype in acute lymphoblastic leukemia. Cancer Genet Cytogenet 40:171–185PubMedCrossRefGoogle Scholar
  17. 17.
    Bloomfield CD, Shuma C, Regal L, Philip PP, Hossfeld DK, Hagemeijer AM, Garson OM, Peterson BA, Sakurai M, Alimena G, Berger R, Rowley JD, Ruutu T, Mitelman F, Dewald GW, Swansbury J (1997) Long-term survival of patients with acute myeloid leukemia: a third follow-up of the Fourth International Workshop on Chromosomes in Leukemia. Cancer 80 (11 Suppl):2191–2198PubMedCrossRefGoogle Scholar
  18. 18.
    Bruggemann M, Raff T, Flohr T, Gokbuget N, Nakao M, Droese J, Luschen S, Pott C, Ritgen M, Scheuring U, Horst HA, Thiel E, Hoelzer D, Bartram CR, Kneba M (2006) Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood 107:1116–1123PubMedCrossRefGoogle Scholar
  19. 19.
    Bruggemann M, van der Velden VH, Raff T, Droese J, Ritgen M, Pott C, Wijkhuijs AJ, Gokbuget N, Hoelzer D, van Wering ER, van Dongen JJ, Kneba M (2004) Rearranged T-cell receptor beta genes represent powerful targets for quantification of minimal residual disease in childhood and adult T-cell acute lymphoblastic leukemia. Leukemia 18:709–719PubMedCrossRefGoogle Scholar
  20. 20.
    Burmeister T, Gokbuget N, Reinhardt R, Rieder H, Hoelzer D, Schwartz S (2006) NUP214-ABL1 in adult T-ALL: the GMALL Study Group experience. Blood 108:3556–3559PubMedCrossRefGoogle Scholar
  21. 21.
    Burmeister T, Schwartz S, Horst HA, Rieder H, Gokbuget N, Hoelzer D, Thiel E (2005) Molecular heterogeneity of sporadic adult Burkitt-type leukemia/lymphoma as revealed by PCR and cytogenetics: correlation with morphology, immunology and clinical features. Leukemia 19:1391–1398PubMedCrossRefGoogle Scholar
  22. 22.
    Busch K, Borkhardt A, Wossmann W, Reiter A, Harbott J (2004) Combined polymerase chain reaction methods to detect c-myc/IgH rearrangement in childhood Burkitt’s lymphoma for minimal residual disease analysis. Haematologica 89:818–825PubMedGoogle Scholar
  23. 23.
    Cairo MS, Sposto R, Perkins SL, Meadows AT, Hoover-Regan ML, Anderson JR, Siegel SE, Lones MA, Tedeschi-Blok N, Kadin ME, Kjeldsberg CR, Wilson JF, Sanger W, Morris E, Krailo MD, Finlay JL (2003) Burkitt’s and Burkitt-like lymphoma in children and adolescents: a review of the Children’s Cancer Group experience. Br J Haematol 120:60–70CrossRefGoogle Scholar
  24. 24.
    Campana D (2003) Determination of minimal residual disease in leukaemia patients. Br J Haematol 121:823–838PubMedCrossRefGoogle Scholar
  25. 25.
    Charrin CM et al (Group Francais de Cytogenetique Hematologique) (1996) Cytogenetic abnormalities in adult acute lymphoblastic leukemia: correlations with hematologic findings outcome. A collaborative study of the Group Francais de Cytogenetique Hematologique. Blood 87:3135–3142Google Scholar
  26. 26.
    Cheok MH, Yang W, Pui CH, Downing JR, Cheng C, Naeve CW, Relling MV, Evans WE (2003) Treatment-specific changes in gene expression discriminate in vivo drug response in human leukemia cells. Nat Genet 34:85–90PubMedCrossRefGoogle Scholar
  27. 27.
    Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Lowenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD (2003) Revised recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol 21:4642–4649PubMedCrossRefGoogle Scholar
  28. 28.
    Coustan-Smith E, Ribeiro RC, Rubnitz JE, Razzouk BI, Pui CH, Pounds S, Andreansky M, Behm FG, Raimondi SC, Shurtleff SA, Downing JR, Campana D (2003) Clinical significance of residual disease during treatment in childhood acute myeloid leukaemia. Br J Haematol 123:243–252PubMedCrossRefGoogle Scholar
  29. 29.
    Dimartino JF, Cleary ML (1999) Mll rearrangements in haematological malignancies: lessons from clinical and biological studies. Br J Haematol 106:614–626PubMedCrossRefGoogle Scholar
  30. 30.
    Diverio D, Rossi V, Avvisati G, De Santis S, Pistilli A, Pane F, Saglio G, Martinelli G, Petti MC, Santoro A, Pelicci PG, Mandelli F, Biondi A, Lo Coco F (1998) Early detection of relapse by prospective reverse transcriptase-polymerase chain reaction analysis of the PML/RARalpha fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA–AIEOP multicenter “AIDA” trial. GIMEMA–AIEOP multicenter “AIDA” trial. Blood 92:784–789PubMedGoogle Scholar
  31. 31.
    Dohner K, Tobis K, Ulrich R, Frohling S, Benner A, Schlenk RF, Dohner H (2002) Prognostic significance of partial tandem duplications of the MLL gene in adult patients 16 to 60 years old with acute myeloid leukemia and normal cytogenetics: a study of the Acute Myeloid Leukemia Study Group Ulm. J Clin Oncol 20:3254–3261PubMedCrossRefGoogle Scholar
  32. 32.
    Dombret H, Gabert J, Boiron JM, Rigal-Huguet F, Blaise D, Thomas X, Delannoy A, Buzyn A, Bilhou-Nabera C, Cayuela JM, Fenaux P, Bourhis JH, Fegueux N, Charrin C, Boucheix C, Lheritier V, Esperou H, MacIntyre E, Vernant JP, Fiere D (2002) Outcome of treatment in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia—results of the prospective multicenter LALA-94 trial. Blood 100:2357–2366PubMedCrossRefGoogle Scholar
  33. 33.
    Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, 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 344:1038–1042PubMedCrossRefGoogle Scholar
  34. 34.
    El-Rifai W, Ruutu T, Elonen E, Volin L, Knuutila S (1997) Prognostic value of metaphase-fluorescence in situ hybridization in follow-up of patients with acute myeloid leukemia in remission. Blood 89:3330–3334PubMedGoogle Scholar
  35. 35.
    Faderl S, Kantarjian HM, Talpaz M, Estrov Z (1998) Clinical significance of cytogenetic abnormalities in adult acute lymphoblastic leukemia. Blood 91:3995–4019PubMedGoogle Scholar
  36. 36.
    Falini B, Bolli N, Shan J, Martelli MP, Liso A, Pucciarini A, Bigerna B, Pasqualucci L, Mannucci R, Rosati R, Gorello P, Diverio D, Roti G, Tiacci E, Cazzaniga G, Biondi A, Schnittger S, Haferlach T, Hiddemann W, Martelli MF, Gu W, Mecucci C, Nicoletti I (2006) Both carboxy-terminus NES motif and mutated tryptophan(s) are crucial for aberrant nuclear export of nucleophosmin leukemic mutants in NPMc+ AML. Blood 107:4514–4523PubMedCrossRefGoogle Scholar
  37. 37.
    Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati R, Pasqualucci L, La Starza R, Diverio D, Colombo E, Santucci A, Bigerna B, Pacini R, Pucciarini A, Liso A, Vignetti M, Fazi P, Meani N, Pettirossi V, Saglio G, Mandelli F, Lo-Coco F, Pelicci PG, Martelli MF (2005) Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 352:254–266PubMedCrossRefGoogle Scholar
  38. 38.
    Fiedler W, Serve H, Dohner H, Schwittay M, Ottmann OG, O’Farrell AM, Bello CL, Allred R, Manning WC, Cherrington JM, Louie SG, Hong W, Brega NM, Massimini G, Scigalla P, Berdel WE, Hossfeld DK (2005) A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood 105:986–993PubMedCrossRefGoogle Scholar
  39. 39.
    Freireich EJ, Cork A, Stass SA, McCredie KB, Keating MJ, Estey EH, Kantarjian HM, Trujillo JM (1992) Cytogenetics for detection of minimal residual disease in acute myeloblastic leukemia. Leukemia 6:500–506PubMedGoogle Scholar
  40. 40.
    Frohling S, Schlenk RF, Breitruck J, Benner A, Kreitmeier S, Tobis K, Dohner H, Dohner K (2002) Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood 100:4372–4380PubMedCrossRefGoogle Scholar
  41. 41.
    Frohling S, Schlenk RF, Stolze I, Bihlmayr J, Benner A, Kreitmeier S, Tobis K, Dohner H, Dohner K (2004) CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: prognostic relevance and analysis of cooperating mutations. J Clin Oncol 22:624–633PubMedCrossRefGoogle Scholar
  42. 42.
    Gale RE, Hills R, Pizzey AR, Kottaridis PD, Swirsky D, Gilkes AF, Nugent E, Mills KI, Wheatley K, Solomon E, Burnett AK, Linch DC, Grimwade D (2005) Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia. Blood 106:3768–3776PubMedCrossRefGoogle Scholar
  43. 43.
    Gilliland DG (2003) FLT3-activating mutations in acute promyelocytic leukaemia: a rationale for risk-adapted therapy with FLT3 inhibitors. Best Pract Res Clin Haematol 16:409–417PubMedCrossRefGoogle Scholar
  44. 44.
    Gilliland DG (2001) Hematologic malignancies. Curr Opin Hematol 8:189–191PubMedCrossRefGoogle Scholar
  45. 45.
    Gleissner B, Goekbuget N, Rieder H, Arnold R, Schwartz S, Diedrich H, Schoch C, Heinze B, Fonatsch C, Bartram CR, Hoelzer D, Thiel E (2005) CD10-pre-B acute lymphoblastic leukemia (ALL) is a distinct high-risk subgroup of adult ALL associated with a high frequency of MLL aberrations: results of the German Multicenter Trials for Adult ALL (GMALL). Blood 106:4054–4056PubMedCrossRefGoogle Scholar
  46. 46.
    Gleissner B, Gokbuget N, Bartram CR, Janssen B, Rieder H, Janssen JW, Fonatsch C, Heyll A, Voliotis D, Beck J, Lipp T, Munzert G, Maurer J, Hoelzer D, Thiel E (2002) Leading prognostic relevance of the BCR–ABL translocation in adult acute B-lineage lymphoblastic leukemia: a prospective study of the German Multicenter Trial Group and confirmed polymerase chain reaction analysis. Blood 99:1536–1543PubMedCrossRefGoogle Scholar
  47. 47.
    Goasguen JE, Matsuo T, Cox C, Bennett JM (1992) Evaluation of the dysmyelopoiesis in 336 patients with de novo acute myeloid leukemia: major importance of dysgranulopoiesis for remission and survival. Leukemia 6:520–525PubMedGoogle Scholar
  48. 48.
    Gorello P, Cazzaniga G, Alberti F, Dell’Oro MG, Gottardi E, Specchia G, Roti G, Rosati R, Martelli MF, Diverio D, Lo Coco F, Biondi A, Saglio G, Mecucci C, Falini B (2006) Quantitative assessment of minimal residual disease in acute myeloid leukemia carrying nucleophosmin (NPM1) gene mutations. Leukemia 20:1103–1108PubMedCrossRefGoogle Scholar
  49. 49.
    Griesinger F, Piro-Noack M, Kaib N, Falk M, Renziehausen A, Troff C, Grove D, Schnittger S, Buchner T, Ritter J, Hiddemann W, Wormann B (1999) Leukaemia-associated immunophenotypes (LAIP) are observed in 90% of adult and childhood acute lymphoblastic leukaemia: detection in remission marrow predicts outcome. Br J Haematol 105:241–255PubMedCrossRefGoogle Scholar
  50. 50.
    Grimwade D, Lo Coco F (2002) Acute promyelocytic leukemia: a model for the role of molecular diagnosis and residual disease monitoring in directing treatment approach in acute myeloid leukemia. Leukemia 16:1959–1973PubMedCrossRefGoogle Scholar
  51. 51.
    Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G, Rees J, Hann I, Stevens R, Burnett A, Goldstone A (1998) The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The medical research council adult and children’s leukaemia working parties. Blood 92:2322–2333PubMedGoogle Scholar
  52. 52.
    Gupta V, Kamel-Reid S, Minden MD, Lipton JH, Brandwein J, Messner HA (2003) Imatinib mesylate (Gleevec) is a useful agent in the salvage treatment of adults with relapsed/refractory Philadelphia positive acute leukemias. Hematology 8:139–143PubMedCrossRefGoogle Scholar
  53. 53.
    Haferlach T (2005) Labordiagnostik bei Leukämien und Lymphomen. Uni-Med, BremenGoogle Scholar
  54. 54.
    Haferlach T, Gassmann W, Loffler H, Jurgensen C, Noak J, Ludwig WD, Thiel E, Haase D, Fonatsch C, Becher R et al (1993) Clinical aspects of acute myeloid leukemias of the FAB types M3 and M4Eo. The AML Cooperative Group. Ann Hematol 66:165–170PubMedCrossRefGoogle Scholar
  55. 55.
    Haferlach T, Kern W, Schnittger S, Schoch C (2005) Modern diagnostics in acute leukemias. Crit Rev Oncol Hematol 56:223–234PubMedGoogle Scholar
  56. 56.
    Haferlach T, Kohlmann A, Kern W, Hiddemann W, Schnittger S, Schoch C (2003) Gene expression profiling as a tool for the diagnosis of acute leukemias. Semin Hematol 40:281–295PubMedCrossRefGoogle Scholar
  57. 57.
    Haferlach T, Kohlmann A, Schnittger S, Dugas M, Hiddemann W, Kern W, Schoch C (2005) AML M3 and AML M3 variant each have a distinct gene expression signature but also share patterns different from other genetically defined AML subtypes. Genes Chromosomes Cancer 43:113–127PubMedCrossRefGoogle Scholar
  58. 58.
    Haferlach T, Schoch C (2000) Modern techniques in leukemia diagnosis. Internist 43:1190, 1193-1196, 1199–202CrossRefGoogle Scholar
  59. 59.
    Haferlach T, Schoch C, Loffler H, Gassmann W, Kern W, Schnittger S, Fonatsch C, Ludwig WD, Wuchter C, Schlegelberger B, Staib P, Reichle A, Kubica U, Eimermacher H, Balleisen L, Gruneisen A, Haase D, Aul C, Karow J, Lengfelder E, Wormann B, Heinecke A, Sauerland MC, Buchner T, Hiddemann W (2003) Morphologic dysplasia in de novo acute myeloid leukemia (AML) is related to unfavorable cytogenetics but has no independent prognostic relevance under the conditions of intensive induction therapy: results of a multiparameter analysis from the German AML Cooperative Group studies. J Clin Oncol 21:256–265PubMedCrossRefGoogle Scholar
  60. 60.
    Heerema NA, Sather HN, Sensel MG, Kraft P, Nachman JB, Steinherz PG, Lange BJ, Hutchinson RS, Reaman GH, Trigg ME, Arthur DC, Gaynon PS, Uckun FM (1998) Frequency and clinical significance of cytogenetic abnormalities in pediatric T-lineage acute lymphoblastic leukemia: a report from the Children’s Cancer Group. J Clin Oncol 16:1270–1278PubMedGoogle Scholar
  61. 61.
    Hoelzer D, Gokbuget N (2000) Recent approaches in acute lymphoblastic leukemia in adults. Crit Rev Oncol Hematol 36:49–58PubMedGoogle Scholar
  62. 62.
    Illmer T, Thiede C, Fredersdorf A, Stadler S, Neubauer A, Ehninger G, Schaich M (2005) Activation of the RAS pathway is predictive for a chemosensitive phenotype of acute myelogenous leukemia blasts. Clin Cancer Res 11:3217–3224PubMedCrossRefGoogle Scholar
  63. 63.
    Jaffe ES, Harris NL, Stein H, Vardiman JW (2001) World health organization classification of tumours: pathology and genetics of tumours of haematopoietic and lymphoid tissues lyon. IARCGoogle Scholar
  64. 64.
    Kantarjian H, Talpaz M, Estey E, Ku S, Kurzrock R (1994) What is the contribution of molecular studies to the diagnosis of BCR–ABL-positive disease in adult acute leukemia? Am J Med 96:133–138PubMedCrossRefGoogle Scholar
  65. 65.
    Kern W, Haferlach T, Schoch C, Loffler H, Gassmann W, Heinecke A, Sauerland MC, Berdel W, Buchner T, Hiddemann W (2003) Early blast clearance by remission induction therapy is a major independent prognostic factor for both achievement of complete remission and long-term outcome in acute myeloid leukemia: data from the German AML Cooperative Group (AMLCG) 1992 trial. Blood 101:64–70PubMedCrossRefGoogle Scholar
  66. 66.
    Kern W, Kohlmann A, Wuchter C, Schnittger S, Schoch C, Mergenthaler S, Ratei R, Ludwig WD, Hiddemann W, Haferlach T (2003) Correlation of protein expression and gene expression in acute leukemia. Cytometry B Clin Cytom 55:29–36PubMedCrossRefGoogle Scholar
  67. 67.
    Kern W, Schoch C, Haferlach T, Schnittger S (2005) Monitoring of minimal residual disease in acute myeloid leukemia. Crit Rev Oncol Hematol 56:283–309PubMedGoogle Scholar
  68. 68.
    Kern W, Voskova D, Schoch C, Schnittger S, Hiddemann W, Haferlach T (2004) Prognostic impact of early response to induction therapy as assessed by multiparameter flow cytometry in acute myeloid leukemia. Haematologica 89:528–540PubMedGoogle Scholar
  69. 69.
    Kheiri SA, MacKerrell T, Bonagura VR, Fuchs A, Billett HH (1998) Flow cytometry with or without cytochemistry for the diagnosis of acute leukemias? Cytometry 34:82–86PubMedCrossRefGoogle Scholar
  70. 70.
    Kiyoi H, Naoe T, Nakano Y, Yokota S, Minami S, Miyawaki S, Asou N, Kuriyama K, Jinnai I, Shimazaki C, Akiyama H, Saito K, Oh H, Motoji T, Omoto E, Saito H, Ohno R, Ueda R (1999) Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood 93:3074–3080PubMedGoogle Scholar
  71. 71.
    Knudson AG (2001) Two genetic hits (more or less) to cancer. Nat Rev Cancer 1:157–162PubMedCrossRefGoogle Scholar
  72. 72.
    Kohlmann A, Schoch C, Schnittger S, Dugas M, Hiddemann W, Kern W, Haferlach T (2003) Molecular characterization of acute leukemias by use of microarray technology. Genes Chromosomes Cancer 37:396–405PubMedCrossRefGoogle Scholar
  73. 73.
    Kohlmann A, Schoch C, Schnittger S, Dugas M, Hiddemann W, Kern W, Haferlach T (2004) Pediatric acute lymphoblastic leukemia (ALL) gene expression signatures classify an independent cohort of adult ALL patients. Leukemia 18:63–71PubMedCrossRefGoogle Scholar
  74. 74.
    Konopleva M, Cheng SC, Cortes JE, Hayes KJ, Pierce SA, Andreeff M, Giles FJ, O’Brien S, Kantarjian HM, Estey EH (2003) Independent prognostic significance of day 21 cytogenetic findings in newly-diagnosed acute myeloid leukemia or refractory anemia with excess blasts. Haematologica 88:733–736PubMedGoogle Scholar
  75. 75.
    Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA, Walker H, Wheatley K, Bowen DT, Burnett AK, Goldstone AH, Linch DC (2001) The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 98:1752–1759PubMedCrossRefGoogle Scholar
  76. 76.
    Krauter J, Gorlich K, Ottmann O, Lubbert M, Dohner H, Heit W, Kanz L, Ganser A, Heil G (2003) Prognostic value of minimal residual disease quantification by real-time reverse transcriptase polymerase chain reaction in patients with core binding factor leukemias. J Clin Oncol 21:4413–4422PubMedCrossRefGoogle Scholar
  77. 77.
    Kuchenbauer F, Schnittger S, Look T, Gilliland G, Tenen D, Haferlach T, Hiddemann W, Buske C, Schoch C (2006) Identification of additional cytogenetic and molecular genetic abnormalities in acute myeloid leukaemia with t(8;21)/AML1-ETO. Br J Haematol 134:616–619PubMedCrossRefGoogle Scholar
  78. 78.
    Kuchenbauer F, Schoch C, Kern W, Hiddemann W, Haferlach T, Schnittger S (2005) Impact of FLT3 mutations and promyelocytic leukaemia-breakpoint on clinical characteristics and prognosis in acute promyelocytic leukaemia. Br J Haematol 130:196–202PubMedCrossRefGoogle Scholar
  79. 79.
    Kurzrock R, Gutterman JU, Talpaz M (1988) The molecular genetics of Philadelphia chromosome-positive leukemias. N Engl J Med 319:990–998PubMedCrossRefGoogle Scholar
  80. 80.
    Langebrake C, Creutzig U, Dworzak M, Hrusak O, Mejstrikova E, Griesinger F, Zimmermann M, Reinhardt D (2006) Residual disease monitoring in childhood acute myeloid leukemia by multiparameter flow cytometry: the MRD–AML–BFM Study Group. J Clin Oncol 24:3686–3692PubMedCrossRefGoogle Scholar
  81. 81.
    Lengfelder E, Reichert A, Schoch C, Haase D, Haferlach T, Loffler H, Staib P, Heyll A, Seifarth W, Saussele S, Fonatsch C, Gassmann W, Ludwig WD, Hochhaus A, Beelen D, Aul C, Sauerland MC, Heinecke A, Hehlmann R, Wormann B, Hiddemann W, Buchner T (2000) Double induction strategy including high dose cytarabine in combination with all-trans retinoic acid: effects in patients with newly diagnosed acute promyelocytic leukemia. German AML Cooperative Group. Leukemia 14:1362–1370PubMedCrossRefGoogle Scholar
  82. 82.
    Leroy H, de Botton S, Grardel-Duflos N, Darre S, Leleu X, Roumier C, Morschhauser F, Lai JL, Bauters F, Fenaux P, Preudhomme C (2005) Prognostic value of real-time quantitative PCR (RQ-PCR) in AML with t(8;21). Leukemia 19:367–372PubMedCrossRefGoogle Scholar
  83. 83.
    Li A, Goldwasser MA, Zhou J, Armstrong SA, Wang H, Dalton V, Fletcher JA, Sallan SE, Silverman LB, Gribben JG (2005) Distinctive IGH gene segment usage and minimal residual disease detection in infant acute lymphoblastic leukaemias. Br J Haematol:131:185–192PubMedCrossRefGoogle Scholar
  84. 84.
    Li A, Rue M, Zhou J, Wang H, Goldwasser MA, Neuberg D, Dalton V, Zuckerman D, Lyons C, Silverman LB, Sallan SE, Gribben JG (2004) Utilization of Ig heavy chain variable, diversity, and joining gene segments in children with B-lineage acute lymphoblastic leukemia: implications for the mechanisms of VDJ recombination and for pathogenesis. Blood 103:4602–4609PubMedCrossRefGoogle Scholar
  85. 85.
    Lo Coco F, Avvisati G, Diverio D, Petti MC, Alcalay M, Pandolfi PP, Zangrilli D, Biondi A, Rambaldi A, Moleti ML et al (1991) Molecular evaluation of response to all-trans-retinoic acid therapy in patients with acute promyelocytic leukemia. Blood 77:1657–1659PubMedGoogle Scholar
  86. 86.
    Lo Coco F, Diverio D, Falini B, Biondi A, Nervi C, Pelicci PG (1999) Genetic diagnosis and molecular monitoring in the management of acute promyelocytic leukemia. Blood 94:12–22PubMedGoogle Scholar
  87. 87.
    Löffler H, Rastetter J, Haferlach T (2005) Atlas of clinical hematology. 6th revised edn. Springer, Berlin, Heidelberg, New YorkGoogle Scholar
  88. 88.
    Loh ML, Goldwasser MA, Silverman LB, Poon WM, Vattikuti S, Cardoso A, Neuberg DS, Shannon KM, Sallan SE, Gilliland DG (2006) Prospective analysis of TEL/AML1-positive patients treated on Dana-Farber Cancer Institute Consortium Protocol 95-01. Blood 107:4508–4513PubMedCrossRefGoogle Scholar
  89. 89.
    Lowenberg B, Downing JR, Burnett A (1999) Acute myeloid leukemia. N Engl J Med 341:1051–1062PubMedCrossRefGoogle Scholar
  90. 90.
    Marcucci G, Caligiuri MA, Dohner H, Archer KJ, Schlenk RF, Dohner K, Maghraby EA, Bloomfield CD (2001) Quantification of CBFbeta/MYH11 fusion transcript by real time RT-PCR in patients with INV(16) acute myeloid leukemia. Leukemia 15:1072–1080PubMedCrossRefGoogle Scholar
  91. 91.
    Marcucci G, Mrozek K, Bloomfield CD (2005) Molecular heterogeneity and prognostic biomarkers in adults with acute myeloid leukemia and normal cytogenetics. Curr Opin Hematol 12:68–75PubMedCrossRefGoogle Scholar
  92. 92.
    Marcucci G, Mrozek K, Ruppert AS, Archer KJ, Pettenati MJ, Heerema NA, Carroll AJ, Koduru PR, Kolitz JE, Sterling LJ, Edwards CG, Anastasi J, Larson RA, Bloomfield CD (2004) Abnormal cytogenetics at date of morphologic complete remission predicts short overall and disease-free survival, and higher relapse rate in adult acute myeloid leukemia: results from Cancer and Leukemia Group B Study 8461. J Clin Oncol 22:2410–2418PubMedCrossRefGoogle Scholar
  93. 93.
    Matutes E, Morilla R, Farahat N, Carbonell F, Swansbury J, Dyer M, Catovsky D (1997) Definition of acute biphenotypic leukemia. Haematologica 82:64–66PubMedGoogle Scholar
  94. 94.
    Miller DR, Coccia PF, Bleyer WA, Lukens JN, Siegel SE, Sather HN, Hammond GD (1989) Early response to induction therapy as a predictor of disease-free survival and late recurrence of childhood acute lymphoblastic leukemia: a report from the Childrens Cancer Study Group. J Clin Oncol 7:1807–1815PubMedGoogle Scholar
  95. 95.
    Mitelman F (1995) Guidelines for cancer cytogenetics, supplement to an international system for human cytogenetic nomenclature, first edn. KargerGoogle Scholar
  96. 96.
    Moorman AV, Roman E, Willett EV, Dovey GJ, Cartwright RA, Morgan GJ (2001) Karyotype and age in acute myeloid leukemia. Are they linked? Cancer Genet Cytogenet 126:155–161PubMedCrossRefGoogle Scholar
  97. 97.
    Morschhauser F, Cayuela JM, Martini S, Baruchel A, Rousselot P, Socie G, Berthou P, Jouet JP, Straetmans N, Sigaux F, Fenaux P, Preudhomme C (2000) Evaluation of minimal residual disease using reverse-transcription polymerase chain reaction in t(8;21) acute myeloid leukemia: a multicenter study of 51 patients. J Clin Oncol 18:788–794PubMedGoogle Scholar
  98. 98.
    Neale GA, Coustan-Smith E, Stow P, Pan Q, Chen X, Pui CH, Campana D (2004) Comparative analysis of flow cytometry and polymerase chain reaction for the detection of minimal residual disease in childhood acute lymphoblastic leukemia. Leukemia 18:934–938PubMedCrossRefGoogle Scholar
  99. 99.
    Neri A, Barriga F, Knowles DM, Magrath IT, Dalla-Favera R (1988) Different regions of the immunoglobulin heavy-chain locus are involved in chromosomal translocations in distinct pathogenetic forms of Burkitt lymphoma. Proc Natl Acad Sci USA 85:2748–2752PubMedCrossRefGoogle Scholar
  100. 100.
    Nylund SJ, Ruutu T, Saarinen U, Knuutila S (1994) Metaphase fluorescence in situ hybridization (FISH) in the follow-up of 60 patients with haemopoietic malignancies. Br J Haematol 88:778–783PubMedGoogle Scholar
  101. 101.
    O’Farrell AM, Foran JM, Fiedler W, Serve H, Paquette RL, Cooper MA, Yuen HA, Louie SG, Kim H, Nicholas S, Heinrich MC, Berdel WE, Bello C, Jacobs M, Scigalla P, Manning WC, Kelsey S, Cherrington JM (2003) An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients. Clin Cancer Res 9:5465–5476PubMedGoogle Scholar
  102. 102.
    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 100:1965–1971PubMedCrossRefGoogle Scholar
  103. 103.
    Pabst T, Mueller BU, Harakawa N, Schoch C, Haferlach T, Behre G, Hiddemann W, Zhang DE, Tenen DG (2001) AML1-ETO downregulates the granulocytic differentiation factor C/EBPalpha in t(8;21) myeloid leukemia. Nat Med 7:444–451PubMedCrossRefGoogle Scholar
  104. 104.
    Preti HA, O’Brien S, Giralt S, Beran M, Pierce S, Kantarjian HM (1994) Philadelphia-chromosome-positive adult acute lymphocytic leukemia: characteristics, treatment results, and prognosis in 41 patients. Am J Med 97:60–65PubMedCrossRefGoogle Scholar
  105. 105.
    Preudhomme C, Henic N, Cazin B, Lai JL, Bertheas MF, Vanrumbeke M, Lemoine F, Jouet JP, Deconninck E, Nelken B, Cosson A, Fenaux P (1997) Good correlation between RT-PCR analysis and relapse in Philadelphia (Ph1)-positive acute lymphoblastic leukemia (ALL). Leukemia 11:294–298PubMedCrossRefGoogle Scholar
  106. 106.
    Preudhomme C, Sagot C, Boissel N, Cayuela JM, Tigaud I, de Botton S, Thomas X, Raffoux E, Lamandin C, Castaigne S, Fenaux P, Dombret H (2002) Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA). Blood 100:2717–2723PubMedCrossRefGoogle Scholar
  107. 107.
    Pui CH, Campana D (2000) New definition of remission in childhood acute lymphoblastic leukemia. Leukemia 14:783–785PubMedCrossRefGoogle Scholar
  108. 108.
    Pui CH, Chessells JM, Camitta B, Baruchel A, Biondi A, Boyett JM, Carroll A, Eden OB, Evans WE, Gadner H, Harbott J, Harms DO, Harrison CJ, Harrison PL, Heerema N, Janka-Schaub G, Kamps W, Masera G, Pullen J, Raimondi SC, Richards S, Riehm H, Sallan S, Sather H, Shuster J, Silverman LB, Valsecchi MG, Vilmer E, Zhou Y, Gaynon PS, Schrappe M (2003) Clinical heterogeneity in childhood acute lymphoblastic leukemia with 11q23 rearrangements. Leukemia 17:700–706PubMedCrossRefGoogle Scholar
  109. 109.
    Pui CH, Evans WE (1998) Acute lymphoblastic leukemia. N Engl J Med 339:605–615PubMedCrossRefGoogle Scholar
  110. 110.
    Raanani P, Ben-Bassat I (2004) Detection of minimal residual disease in acute myelogenous leukemia. Acta Haematol 112:40–54PubMedCrossRefGoogle Scholar
  111. 111.
    Raanani P, Hochhaus A (2004) Minimal residual disease in hematological malignancies. Acta Haematol 112:5–7PubMedCrossRefGoogle Scholar
  112. 112.
    Raff T, Gokbuget N, Luschen S, Reutzel R, Ritgen M, Irmer S, Bottcher S, Horst HA, Kneba M, Hoelzer D, Bruggemann M (2006) Molecular relapse in adult standard risk ALL patients detected by prospective MRD-monitoring during and after maintenance treatment-data from the GMALL 06/99 and 07/03 trials. Blood (in press)Google Scholar
  113. 113.
    Raimondi SC, Behm FG, Roberson PK, Pui CH, Rivera GK, Murphy SB, Williams DL (1988) Cytogenetics of childhood T-cell leukemia. Blood 72:1560–1566PubMedGoogle Scholar
  114. 114.
    Rieder H, Ludwig WD, Gassmann W, Maurer J, Janssen JW, Gokbuget N, Schwartz S, Thiel E, Loffler H, Bartram CR, Hoelzer D, Fonatsch C (1996) Prognostic significance of additional chromosome abnormalities in adult patients with Philadelphia chromosome positive acute lymphoblastic leukaemia. Br J Haematol 95:678–691PubMedCrossRefGoogle Scholar
  115. 115.
    Ross ME, Zhou X, Song G, Shurtleff SA, Girtman K, Williams WK, Liu HC, Mahfouz R, Raimondi SC, Lenny N, Patel A, Downing JR (2003) Classification of pediatric acute lymphoblastic leukemia by gene expression profiling. Blood 102:2951–2959PubMedCrossRefGoogle Scholar
  116. 116.
    Roumier C, Eclache V, Imbert M, Davi F, MacIntyre E, Garand R, Talmant P, Lepelley P, Lai JL, Casasnovas O, Maynadie M, Mugneret F, Bilhou-Naberra C, Valensi F, Radford I, Mozziconacci MJ, Arnoulet C, Duchayne E, Dastugue N, Cornillet P, Daliphard S, Garnache F, Boudjerra N, Jouault H, Fenneteau O, Pedron B, Berger R, Flandrin G, Fenaux P, Preudhomme C (2003) M0 AML, clinical and biologic features of the disease, including AML1 gene mutations: a report of 59 cases by the Groupe Francais d’Hematologie Cellulaire (GFHC) and the Groupe Francais de Cytogenetique Hematologique (GFCH). Blood 101:1277–1283PubMedCrossRefGoogle Scholar
  117. 117.
    San Miguel JF, Martinez A, Macedo A, Vidriales MB, Lopez-Berges C, Gonzalez M, Caballero D, Garcia-Marcos MA, Ramos F, Fernandez-Calvo J, Calmuntia MJ, Diaz-Mediavilla J, Orfao A (1997) Immunophenotyping investigation of minimal residual disease is a useful approach for predicting relapse in acute myeloid leukemia patients. Blood 90:2465–2470Google Scholar
  118. 118.
    San Miguel JF, Vidriales MB, Lopez-Berges C, Diaz-Mediavilla J, Gutierrez N, Canizo C, Ramos F, Calmuntia MJ, Perez JJ, Gonzalez M, Orfao A (2001) Early immunophenotypical evaluation of minimal residual disease in acute myeloid leukemia identifies different patient risk groups and may contribute to postinduction treatment stratification. Blood 98:1746–1751CrossRefGoogle Scholar
  119. 119.
    Scheuring UJ, Pfeifer H, Wassmann B, Bruck P, Gehrke B, Petershofen EK, Gschaidmeier H, Hoelzer D, Ottmann OG (2003) Serial minimal residual disease (MRD) analysis as a predictor of response duration in Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL) during imatinib treatment. Leukemia 17:1700–1706PubMedCrossRefGoogle Scholar
  120. 120.
    Scheuring UJ, Pfeifer H, Wassmann B, Bruck P, Hoelzer D, Ottmann OG (2003) Methodologic and biological variability of quantitative real-time polymerase chain reaction analysis of Bcr–Abl expression in Philadelphia chromosome-positive acute lymphoblastic leukemia. Haematologica 88:1074–1076PubMedGoogle Scholar
  121. 121.
    Schichman SA, Croce CM (1995) Approaches to the identification and molecular cloning of chromosome breakpoints. Methods Enzymol 254:321–234Google Scholar
  122. 122.
    Schnittger S, Kinkelin U, Schoch C, Heinecke A, Haase D, Haferlach T, Buchner T, Wormann B, Hiddemann W, Griesinger F (2000) Screening for MLL tandem duplication in 387 unselected patients with AML identify a prognostically unfavorable subset of AML. Leukemia 14:796–804PubMedCrossRefGoogle Scholar
  123. 123.
    Schnittger S, Kohl TM, Haferlach T, Kern W, Hiddemann W, Spiekermann K, Schoch C (2006) KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival. Blood 107:1791–1799PubMedCrossRefGoogle Scholar
  124. 124.
    Schnittger S, Schoch C, Dugas M, Kern W, Staib P, Wuchter C, Loffler H, Sauerland CM, Serve H, Buchner T, Haferlach T, Hiddemann W (2002) Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood 100:59–66PubMedCrossRefGoogle Scholar
  125. 125.
    Schnittger S, Schoch C, Kern W, Hiddemann W, Haferlach T (2004) FLT3 length mutations as marker for follow-up studies in acute myeloid leukaemia. Acta Haematol 112:68–78PubMedCrossRefGoogle Scholar
  126. 126.
    Schnittger S, Schoch C, Kern W, Mecucci C, Tschulik C, Martelli MF, Haferlach T, Hiddemann W, Falini B (2005) Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood 106:3733–3739PubMedCrossRefGoogle Scholar
  127. 127.
    Schnittger S, Weisser M, Schoch C, Hiddemann W, Haferlach T, Kern W (2003) New score predicting for prognosis in PML–RARA+, AML1–ETO+, or CBFBMYH11+ acute myeloid leukemia based on quantification of fusion transcripts. Blood 102:2746–2755PubMedCrossRefGoogle Scholar
  128. 128.
    Schoch C, Haferlach T, Bursch S, Gerstner D, Schnittger S, Dugas M, Kern W, Loffler H, Hiddemann W (2002) Loss of genetic material is more common than gain in acute myeloid leukemia with complex aberrant karyotype: a detailed analysis of 125 cases using conventional chromosome analysis and fluorescence in situ hybridization including 24-color FISH. Genes Chromosomes Cancer 35:20–29PubMedCrossRefGoogle Scholar
  129. 129.
    Schoch C, Haferlach T, Haase D, Fonatsch C, Loffler H, Schlegelberger B, Staib P, Sauerland MC, Heinecke A, Buchner T, Hiddemann W (2001) Patients with de novo acute myeloid leukaemia and complex karyotype aberrations show a poor prognosis despite intensive treatment: a study of 90 patients. Br J Haematol 112:118–126PubMedCrossRefGoogle Scholar
  130. 130.
    Schoch C, Kern W, Kohlmann A, Hiddemann W, Schnittger S, Haferlach T (2005) Acute myeloid leukemia with a complex aberrant karyotype is a distinct biological entity characterized by genomic imbalances and a specific gene expression profile. Genes Chromosomes Cancer 43:227–238PubMedCrossRefGoogle Scholar
  131. 131.
    Schoch C, Kern W, Krawitz P, Dugas M, Schnittger S, Haferlach T, Hiddemann W (2001) Dependence of age-specific incidence of acute myeloid leukemia on karyotype. Blood 98:3500PubMedCrossRefGoogle Scholar
  132. 132.
    Schoch C, Kern W, Schnittger S, Hiddemann W, Haferlach T (2004) Karyotype is an independent prognostic parameter in therapy-related acute myeloid leukemia (t-AML): an analysis of 93 patients with t-AML in comparison to 1091 patients with de novo AML. Leukemia 18:120–125PubMedCrossRefGoogle Scholar
  133. 133.
    Schoch C, Kohlmann A, Schnittger S, Brors B, Dugas M, Mergenthaler S, Kern W, Hiddemann W, Eils R, Haferlach T (2002) Acute myeloid leukemias with reciprocal rearrangements can be distinguished by specific gene expression profiles. Proc Natl Acad Sci USA 99:10008–10013PubMedCrossRefGoogle Scholar
  134. 134.
    Schoch C, Schnittger S, Kern W, Lengfelder E, Loffler H, Hiddemann W, Haferlach T (2002) Rapid diagnostic approach to PML–RARalpha-positive acute promyelocytic leukemia. Hematol J 3:259–263PubMedCrossRefGoogle Scholar
  135. 135.
    Schoch C, Schnittger S, Klaus M, Kern W, Hiddemann W, Haferlach T (2003) AML with 11q23/MLL abnormalities as defined by the WHO classification: incidence, partner chromosomes, FAB subtype, age distribution, and prognostic impact in an unselected series of 1897 cytogenetically analyzed AML cases. Blood 102:2395–2402PubMedCrossRefGoogle Scholar
  136. 136.
    Scholl S, Krause C, Loncarevic IF, Muller R, Kunert C, Wedding U, Sayer HG, Clement JH, Hoffken K (2005) Specific detection of Flt3 point mutations by highly sensitive real-time polymerase chain reaction in acute myeloid leukemia. J Lab Clin Med 145:295–304PubMedCrossRefGoogle Scholar
  137. 137.
    Secker-Walker LM, Prentice HG, Durrant J, Richards S, Hall E, Harrison G (1997) Cytogenetics adds independent prognostic information in adults with acute lymphoblastic leukaemia on MRC trial UKALL XA. MRC Adult Leukaemia Working Party. Br J Haematol 96:601–610PubMedCrossRefGoogle Scholar
  138. 138.
    Seong DC, Kantarjian HM, Ro JY, Talpaz M, Xu J, Robinson JR, Deisseroth AB, Champlin RE, Siciliano MJ (1995) Hypermetaphase fluorescence in situ hybridization for quantitative monitoring of Philadelphia chromosome-positive cells in patients with chronic myelogenous leukemia during treatment. Blood 86:2343–2349PubMedGoogle Scholar
  139. 139.
    Steudel C, Wermke M, Schaich M, Schakel U, Illmer T, Ehninger G, Thiede C (2003) Comparative analysis of MLL partial tandem duplication and FLT3 internal tandem duplication mutations in 956 adult patients with acute myeloid leukemia. Genes Chromosomes Cancer 37:237–251PubMedCrossRefGoogle Scholar
  140. 140.
    Stirewalt DL, Kopecky KJ, Meshinchi S, Appelbaum FR, Slovak ML, Willman CL, Radich JP (2001) FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia. Blood 97:3589–3595PubMedCrossRefGoogle Scholar
  141. 141.
    Swansbury GJ, Lawler SD, Alimena G, Arthur D, Berger R, Van den Berghe H, Bloomfield CD, de la Chappelle A, Dewald G, Garson OM, et al (1994) Long-term survival in acute myelogenous leukemia: a second follow-up of the fourth international workshop on chromosomes in leukemia. Cancer Genet Cytogenet 73:1–7PubMedCrossRefGoogle Scholar
  142. 142.
    Tabernero MD, Bortoluci AM, Alaejos I, Lopez-Berges MC, Rasillo A, Garcia-Sanz R, Garcia M, Sayagues JM, Gonzalez M, Mateo G, San Miguel JF, Orfao A (2001) Adult precursor B-ALL with BCR/ABL gene rearrangements displays a unique immunophenotype based on the pattern of CD10, CD34, CD13 and CD38 expresssion. Leukemia 15:406–414PubMedCrossRefGoogle Scholar
  143. 143.
    Takahashi S, Harigae H, Yokoyama H, Ishikawa I, Abe S, Imaizumi M, Sasaki T, Kaku M (2006) Synergistic effect of arsenic trioxide and flt3 inhibition on cells with flt3 internal tandem duplication. Int J Hematol 84:256–261PubMedCrossRefGoogle Scholar
  144. 144.
    Tallman MS, Nabhan C, Feusner JH, Rowe JM (2002) Acute promyelocytic leukemia: evolving therapeutic strategies. Blood 99:759–767PubMedCrossRefGoogle Scholar
  145. 145.
    Theml HD, Diem H, Haferlach T (2002) Taschenatlas der Hämatologie. Stuttgart, ThiemeGoogle Scholar
  146. 146.
    Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U, Wermke M, Bornhauser M, Ritter M, Neubauer A, Ehninger G, Illmer T (2002) Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 99:4326–4335PubMedCrossRefGoogle Scholar
  147. 147.
    Valk PJ, Bowen DT, Frew ME, Goodeve AC, Lowenberg B, Reilly JT (2004) Second hit mutations in the RTK/RAS signaling pathway in acute myeloid leukemia with inv(16). Haematologica 89:106PubMedGoogle Scholar
  148. 148.
    van der Velden VH, Hochhaus A, Cazzaniga G, Szczepanski T, Gabert J, van Dongen JJ (2003) Detection of minimal residual disease in hematologic malignancies by real-time quantitative PCR: principles, approaches, and laboratory aspects. Leukemia 17:1013–1034PubMedCrossRefGoogle Scholar
  149. 149.
    van der Velden VH, Wijkhuijs JM, Jacobs DC, van Wering ER, van Dongen JJ (2002) T cell receptor gamma gene rearrangements as targets for detection of minimal residual disease in acute lymphoblastic leukemia by real-time quantitative PCR analysis. Leukemia 16:1372–1380PubMedCrossRefGoogle Scholar
  150. 150.
    van Dongen JJ, Macintyre EA, Gabert JA, Delabesse E, Rossi V, Saglio G, Gottardi E, Rambaldi A, Dotti G, Griesinger F, Parreira A, Gameiro P, Diaz MG, Malec M, Langerak AW, San Miguel JF, Biondi A (1999) Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Report of the BIOMED-1 concerted action: investigation of minimal residual disease in acute leukemia. Leukemia 13:1901–1928PubMedCrossRefGoogle Scholar
  151. 151.
    van Dongen JJ, Seriu T, Panzer-Grumayer ER, Biondi A, Pongers-Willemse MJ, Corral L, Stolz F, Schrappe M, Masera G, Kamps WA, Gadner H, van Wering ER, Ludwig WD, Basso G, de Bruijn MA, Cazzaniga G, Hettinger K, van der Does-van den Berg A, Hop WC, Riehm H, Bartram CR (1998) Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet 352:1731–1738PubMedCrossRefGoogle Scholar
  152. 152.
    Vidriales MB, Perez JJ, Lopez-Berges MC, Gutierrez N, Ciudad J, Lucio P, Vazquez L, Garcia-Sanz R, del Canizo MC, Fernandez-Calvo J, Ramos F, Rodriguez MJ, Calmuntia MJ, Porwith A, Orfao A, San-Miguel JF (2003) Minimal residual disease in adolescent (older than 14 years) and adult acute lymphoblastic leukemias: early immunophenotypic evaluation has high clinical value. Blood 101:4695–4700PubMedCrossRefGoogle Scholar
  153. 153.
    Vitale A, Guarini A, Ariola C, Mancini M, Mecucci C, Cuneo A, Pane F, Saglio G, Cimino G, Tafuri A, Meloni G, Fabbiano F, Recchia A, Kropp MG, Krampera M, Cascavilla N, Ferrara F, Romano A, Mazza P, Fozza C, Paoloni F, Vignetti M, Foa R (2006) Adult T-cell acute lymphoblastic leukemia: biologic profile at presentation and correlation with response to induction treatment in patients enrolled in the GIMEMA LAL 0496 protocol. Blood 107:473–479PubMedCrossRefGoogle Scholar
  154. 154.
    Wassmann B, Pfeifer H, Scheuring U, Klein SA, Gokbuget N, Binckebanck A, Martin H, Gschaidmeier H, Hoelzer D, Ottmann OG (2002) Therapy with imatinib mesylate (Glivec) preceding allogeneic stem cell transplantation (SCT) in relapsed or refractory Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL). Leukemia 16:2358–2365PubMedCrossRefGoogle Scholar
  155. 155.
    Wassmann B, Pfeifer H, Stadler M, Bornhauser M, Bug G, Scheuring UJ, Bruck P, Stelljes M, Schwerdtfeger R, Basara N, Perz J, Bunjes D, Ledderose G, Mahlberg R, Binckebanck A, Gschaidmeier H, Hoelzer D, Ottmann OG (2005) Early molecular response to posttransplantation imatinib determines outcome in MRD + Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood 106:458–463PubMedCrossRefGoogle Scholar
  156. 156.
    Weisser M, Kern W, Schoch C, Hiddemann W, Haferlach T, Schnittger S (2005) Risk assessment by monitoring expression levels of partial tandem duplications in the MLL gene in acute myeloid leukemia during therapy. Haematologica 90:881–889PubMedGoogle Scholar
  157. 157.
    Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, Asou N, Kuriyama K, Yagasaki F, Shimazaki C, Akiyama H, Saito K, Nishimura M, Motoji T, Shinagawa K, Takeshita A, Saito H, Ueda R, Ohno R, Naoe T (2001) Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 97:2434–2439PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Torsten Haferlach
    • 1
  • Ulrike Bacher
    • 2
  • Wolfgang Kern
    • 1
  • Susanne Schnittger
    • 1
  • Claudia Haferlach
    • 1
  1. 1.MLL Munich Leukemia LaboratoryMunichGermany
  2. 2.Bone Marrow TransplantationUniversity Hospital Hamburg EppendorfHamburgGermany

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