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

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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.

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References

  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 113:983–988

    Article  PubMed  CAS  Google Scholar 

  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 21:6–12

    Article  CAS  Google Scholar 

  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 157:53–61

    Article  PubMed  CAS  Google Scholar 

  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 107:3847–3853

    Article  PubMed  CAS  Google Scholar 

  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 106:839–847

    Article  PubMed  Google Scholar 

  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)

  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 100:991–997

    Article  PubMed  CAS  Google Scholar 

  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 95:726–727

    PubMed  CAS  Google Scholar 

  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 9:1783–1786

    PubMed  CAS  Google Scholar 

  10. Bennett JM (2003) Morphologic dysplasia in acute myeloid leukemia: importance of granulocytic dysplasia; author reply. J Clin Oncol 21:3004–3005

    Article  PubMed  Google Scholar 

  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 33:451–458

    PubMed  CAS  Google Scholar 

  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 103:620–625

    PubMed  CAS  Google Scholar 

  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 95:666–672

    Article  PubMed  CAS  Google Scholar 

  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 11:1416–1424

    Article  PubMed  CAS  Google Scholar 

  15. Biondi A, Masera G (1998) Molecular pathogenesis of childhood acute lymphoblastic leukemia. Haematologica 83:651–659

    PubMed  CAS  Google Scholar 

  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 40:171–185

    Article  PubMed  CAS  Google Scholar 

  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):2191–2198

    Article  PubMed  CAS  Google Scholar 

  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 107:1116–1123

    Article  PubMed  CAS  Google Scholar 

  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 18:709–719

    Article  PubMed  CAS  Google Scholar 

  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 108:3556–3559

    Article  PubMed  CAS  Google Scholar 

  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 19:1391–1398

    Article  PubMed  CAS  Google Scholar 

  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 89:818–825

    PubMed  CAS  Google Scholar 

  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 120:60–70

    Article  Google Scholar 

  24. Campana D (2003) Determination of minimal residual disease in leukaemia patients. Br J Haematol 121:823–838

    Article  PubMed  Google Scholar 

  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 87:3135–3142

    Google Scholar 

  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 34:85–90

    Article  PubMed  CAS  Google Scholar 

  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 21:4642–4649

    Article  PubMed  Google Scholar 

  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 123:243–252

    Article  PubMed  Google Scholar 

  29. Dimartino JF, Cleary ML (1999) Mll rearrangements in haematological malignancies: lessons from clinical and biological studies. Br J Haematol 106:614–626

    Article  PubMed  CAS  Google Scholar 

  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 92:784–789

    PubMed  CAS  Google Scholar 

  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 20:3254–3261

    Article  PubMed  CAS  Google Scholar 

  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 100:2357–2366

    Article  PubMed  CAS  Google Scholar 

  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 344:1038–1042

    Article  PubMed  CAS  Google Scholar 

  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 89:3330–3334

    PubMed  CAS  Google Scholar 

  35. Faderl S, Kantarjian HM, Talpaz M, Estrov Z (1998) Clinical significance of cytogenetic abnormalities in adult acute lymphoblastic leukemia. Blood 91:3995–4019

    PubMed  CAS  Google Scholar 

  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 107:4514–4523

    Article  PubMed  CAS  Google Scholar 

  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 352:254–266

    Article  PubMed  CAS  Google Scholar 

  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 105:986–993

    Article  PubMed  CAS  Google Scholar 

  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 6:500–506

    PubMed  CAS  Google Scholar 

  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 100:4372–4380

    Article  PubMed  CAS  Google Scholar 

  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 22:624–633

    Article  PubMed  CAS  Google Scholar 

  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 106:3768–3776

    Article  PubMed  CAS  Google Scholar 

  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 16:409–417

    Article  PubMed  CAS  Google Scholar 

  44. Gilliland DG (2001) Hematologic malignancies. Curr Opin Hematol 8:189–191

    Article  PubMed  CAS  Google Scholar 

  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 106:4054–4056

    Article  PubMed  CAS  Google Scholar 

  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 99:1536–1543

    Article  PubMed  CAS  Google Scholar 

  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 6:520–525

    PubMed  CAS  Google Scholar 

  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 20:1103–1108

    Article  PubMed  CAS  Google Scholar 

  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 105:241–255

    Article  PubMed  CAS  Google Scholar 

  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 16:1959–1973

    Article  PubMed  CAS  Google Scholar 

  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 92:2322–2333

    PubMed  CAS  Google Scholar 

  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 8:139–143

    Article  PubMed  CAS  Google Scholar 

  53. Haferlach T (2005) Labordiagnostik bei Leukämien und Lymphomen. Uni-Med, Bremen

  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 66:165–170

    Article  PubMed  CAS  Google Scholar 

  55. Haferlach T, Kern W, Schnittger S, Schoch C (2005) Modern diagnostics in acute leukemias. Crit Rev Oncol Hematol 56:223–234

    PubMed  Google Scholar 

  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 40:281–295

    Article  PubMed  CAS  Google Scholar 

  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 43:113–127

    Article  PubMed  CAS  Google Scholar 

  58. Haferlach T, Schoch C (2000) Modern techniques in leukemia diagnosis. Internist 43:1190, 1193-1196, 1199–202

    Article  Google Scholar 

  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 21:256–265

    Article  PubMed  Google Scholar 

  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 16:1270–1278

    PubMed  CAS  Google Scholar 

  61. Hoelzer D, Gokbuget N (2000) Recent approaches in acute lymphoblastic leukemia in adults. Crit Rev Oncol Hematol 36:49–58

    PubMed  CAS  Google Scholar 

  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 11:3217–3224

    Article  PubMed  CAS  Google Scholar 

  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. IARC

  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 96:133–138

    Article  PubMed  CAS  Google Scholar 

  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 101:64–70

    Article  PubMed  CAS  Google Scholar 

  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 55:29–36

    Article  PubMed  CAS  Google Scholar 

  67. Kern W, Schoch C, Haferlach T, Schnittger S (2005) Monitoring of minimal residual disease in acute myeloid leukemia. Crit Rev Oncol Hematol 56:283–309

    PubMed  Google Scholar 

  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 89:528–540

    PubMed  Google Scholar 

  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 34:82–86

    Article  PubMed  CAS  Google Scholar 

  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 93:3074–3080

    PubMed  CAS  Google Scholar 

  71. Knudson AG (2001) Two genetic hits (more or less) to cancer. Nat Rev Cancer 1:157–162

    Article  PubMed  CAS  Google Scholar 

  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 37:396–405

    Article  PubMed  CAS  Google Scholar 

  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 18:63–71

    Article  PubMed  CAS  Google Scholar 

  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 88:733–736

    PubMed  Google Scholar 

  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 98:1752–1759

    Article  PubMed  CAS  Google Scholar 

  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 21:4413–4422

    Article  PubMed  CAS  Google Scholar 

  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 134:616–619

    Article  PubMed  CAS  Google Scholar 

  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 130:196–202

    Article  PubMed  CAS  Google Scholar 

  79. Kurzrock R, Gutterman JU, Talpaz M (1988) The molecular genetics of Philadelphia chromosome-positive leukemias. N Engl J Med 319:990–998

    Article  PubMed  CAS  Google Scholar 

  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 24:3686–3692

    Article  PubMed  Google Scholar 

  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 14:1362–1370

    Article  PubMed  CAS  Google Scholar 

  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 19:367–372

    Article  PubMed  CAS  Google Scholar 

  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:131:185–192

    Article  PubMed  CAS  Google Scholar 

  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 103:4602–4609

    Article  PubMed  CAS  Google Scholar 

  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 77:1657–1659

    PubMed  Google Scholar 

  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 94:12–22

    PubMed  Google Scholar 

  87. Löffler H, Rastetter J, Haferlach T (2005) Atlas of clinical hematology. 6th revised edn. Springer, Berlin, Heidelberg, New York

    Google Scholar 

  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 107:4508–4513

    Article  PubMed  CAS  Google Scholar 

  89. Lowenberg B, Downing JR, Burnett A (1999) Acute myeloid leukemia. N Engl J Med 341:1051–1062

    Article  PubMed  CAS  Google Scholar 

  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 15:1072–1080

    Article  PubMed  CAS  Google Scholar 

  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 12:68–75

    Article  PubMed  CAS  Google Scholar 

  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 22:2410–2418

    Article  PubMed  Google Scholar 

  93. Matutes E, Morilla R, Farahat N, Carbonell F, Swansbury J, Dyer M, Catovsky D (1997) Definition of acute biphenotypic leukemia. Haematologica 82:64–66

    PubMed  CAS  Google Scholar 

  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 7:1807–1815

    PubMed  CAS  Google Scholar 

  95. Mitelman F (1995) Guidelines for cancer cytogenetics, supplement to an international system for human cytogenetic nomenclature, first edn. Karger

  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 126:155–161

    Article  PubMed  CAS  Google Scholar 

  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 18:788–794

    PubMed  CAS  Google Scholar 

  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 18:934–938

    Article  PubMed  CAS  Google Scholar 

  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 85:2748–2752

    Article  PubMed  CAS  Google Scholar 

  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 88:778–783

    PubMed  CAS  Google Scholar 

  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 9:5465–5476

    PubMed  CAS  Google Scholar 

  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 100:1965–1971

    Article  PubMed  CAS  Google Scholar 

  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 7:444–451

    Article  PubMed  CAS  Google Scholar 

  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 97:60–65

    Article  PubMed  CAS  Google Scholar 

  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 11:294–298

    Article  PubMed  CAS  Google Scholar 

  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 100:2717–2723

    Article  PubMed  CAS  Google Scholar 

  107. Pui CH, Campana D (2000) New definition of remission in childhood acute lymphoblastic leukemia. Leukemia 14:783–785

    Article  PubMed  CAS  Google Scholar 

  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 17:700–706

    Article  PubMed  CAS  Google Scholar 

  109. Pui CH, Evans WE (1998) Acute lymphoblastic leukemia. N Engl J Med 339:605–615

    Article  PubMed  CAS  Google Scholar 

  110. Raanani P, Ben-Bassat I (2004) Detection of minimal residual disease in acute myelogenous leukemia. Acta Haematol 112:40–54

    Article  PubMed  CAS  Google Scholar 

  111. Raanani P, Hochhaus A (2004) Minimal residual disease in hematological malignancies. Acta Haematol 112:5–7

    Article  PubMed  Google Scholar 

  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)

  113. Raimondi SC, Behm FG, Roberson PK, Pui CH, Rivera GK, Murphy SB, Williams DL (1988) Cytogenetics of childhood T-cell leukemia. Blood 72:1560–1566

    PubMed  CAS  Google Scholar 

  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 95:678–691

    Article  PubMed  CAS  Google Scholar 

  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 102:2951–2959

    Article  PubMed  CAS  Google Scholar 

  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 101:1277–1283

    Article  PubMed  CAS  Google Scholar 

  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 90:2465–2470

    Google Scholar 

  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 98:1746–1751

    Article  Google Scholar 

  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 17:1700–1706

    Article  PubMed  CAS  Google Scholar 

  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 88:1074–1076

    PubMed  CAS  Google Scholar 

  121. Schichman SA, Croce CM (1995) Approaches to the identification and molecular cloning of chromosome breakpoints. Methods Enzymol 254:321–234

    Google Scholar 

  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 14:796–804

    Article  PubMed  CAS  Google Scholar 

  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 107:1791–1799

    Article  PubMed  CAS  Google Scholar 

  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 100:59–66

    Article  PubMed  CAS  Google Scholar 

  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 112:68–78

    Article  PubMed  CAS  Google Scholar 

  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 106:3733–3739

    Article  PubMed  CAS  Google Scholar 

  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 102:2746–2755

    Article  PubMed  CAS  Google Scholar 

  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 35:20–29

    Article  PubMed  Google Scholar 

  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 112:118–126

    Article  PubMed  CAS  Google Scholar 

  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 43:227–238

    Article  PubMed  CAS  Google Scholar 

  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 98:3500

    Article  PubMed  CAS  Google Scholar 

  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 18:120–125

    Article  PubMed  CAS  Google Scholar 

  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 99:10008–10013

    Article  PubMed  CAS  Google Scholar 

  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 3:259–263

    Article  PubMed  CAS  Google Scholar 

  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 102:2395–2402

    Article  PubMed  CAS  Google Scholar 

  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 145:295–304

    Article  PubMed  CAS  Google Scholar 

  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 96:601–610

    Article  PubMed  CAS  Google Scholar 

  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 86:2343–2349

    PubMed  CAS  Google Scholar 

  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 37:237–251

    Article  PubMed  CAS  Google Scholar 

  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 97:3589–3595

    Article  PubMed  CAS  Google Scholar 

  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 73:1–7

    Article  PubMed  CAS  Google Scholar 

  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 15:406–414

    Article  PubMed  CAS  Google Scholar 

  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 84:256–261

    Article  PubMed  CAS  Google Scholar 

  144. Tallman MS, Nabhan C, Feusner JH, Rowe JM (2002) Acute promyelocytic leukemia: evolving therapeutic strategies. Blood 99:759–767

    Article  PubMed  CAS  Google Scholar 

  145. Theml HD, Diem H, Haferlach T (2002) Taschenatlas der Hämatologie. Stuttgart, Thieme

  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 99:4326–4335

    Article  PubMed  CAS  Google Scholar 

  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 89:106

    PubMed  CAS  Google Scholar 

  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 17:1013–1034

    Article  PubMed  CAS  Google Scholar 

  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 16:1372–1380

    Article  PubMed  CAS  Google Scholar 

  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 13:1901–1928

    Article  PubMed  Google Scholar 

  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 352:1731–1738

    Article  PubMed  Google Scholar 

  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 101:4695–4700

    Article  PubMed  CAS  Google Scholar 

  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 107:473–479

    Article  PubMed  CAS  Google Scholar 

  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 16:2358–2365

    Article  PubMed  CAS  Google Scholar 

  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 106:458–463

    Article  PubMed  CAS  Google Scholar 

  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 90:881–889

    PubMed  CAS  Google Scholar 

  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 97:2434–2439

    Article  PubMed  CAS  Google Scholar 

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Haferlach, T., Bacher, U., Kern, W. et al. Diagnostic pathways in acute leukemias: a proposal for a multimodal approach. Ann Hematol 86, 311–327 (2007). https://doi.org/10.1007/s00277-007-0253-2

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