Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Interactive diagnostics in the indication to allogeneic SCT in AML

Abstract

Owing to the heterogeneity of AML, the indication for allogeneic SCT (allo-SCT) requires an exact definition of the individual subentity and risk category. A comprehensive diagnostic approach is needed, which combines cytomorphology, cytogenetics, FISH, molecular genetics and immunophenotyping. Whereas the categorization in three prognostic karyotype groups is well established, rare recurrent aberrations as the unfavorable t(8;16)(p11;p13), inv(3)(q21q26) and t(6;9)(p23;q34) must also be considered. In normal karyotype, PCR analyses reveal prognostically relevant mutations in >85% of cases, and a molecular data set composed of the FLT3-ITD, MLL-PTD, NPM1 and CEBPA mutations was found able to guide the selection of patients for allo-SCT. Some novel markers as the WT1 mutations might further contribute to risk stratification in normal karyotype. The panel of minimal residual disease parameters is being expanded at this time, for example, by quantitative PCR for the NPM1 mutations. Immunophenotyping allows the definition of leukemia-associated phenotypes in nearly all cases, but its position in the indication to allo-SCT has to be validated. Thus, the optimization of the indication to allo-SCT is an ongoing process that should remain in continuous interaction with the increasing panel of known genetic markers and diagnostic methods.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Haferlach T, Bacher U, Kern W, Schnittger S, Haferlach C . Diagnostic pathways in acute leukemias: a proposal for a multimodal approach. Ann Hematol 2007; 86: 311–327.

    PubMed  Google Scholar 

  2. Falini B, Nicoletti I, Martelli MF, Mecucci C . Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features. Blood 2007; 109: 874–885.

    CAS  PubMed  Google Scholar 

  3. Lo Coco F, Diverio D, Falini B, Biondi A, Nervi C, Pelicci PG . Genetic diagnosis and molecular monitoring in the management of acute promyelocytic leukemia. Blood 1999; 94: 12–22.

    PubMed  Google Scholar 

  4. Grimwade D, Howe K, Langabeer S, Burnett A, Goldstone A, Solomon E . Minimal residual disease detection in acute promyelocytic leukemia by reverse-transcriptase PCR: evaluation of PML-RAR alpha and RAR alpha-PML assessment in patients who ultimately relapse. Leukemia 1996; 10: 61–66.

    CAS  PubMed  Google Scholar 

  5. Schnittger S, Weisser M, Schoch C, Hiddemann W, Haferlach T, Kern W . New score predicting for prognosis in PML-RARA+, AML1-ETO+, or CBFBMYH11+ acute myeloid leukemia based on quantification of fusion transcripts. Blood 2003; 102: 2746–2755.

    CAS  PubMed  Google Scholar 

  6. Laane E, Derolf AR, Bjorklund E, Mazur J, Everaus H, Soderhall S et al. The effect of allogeneic stem cell transplantation on outcome in younger acute myeloid leukemia patients with minimal residual disease detected by flow cytometry at the end of post-remission chemotherapy. Haematologica 2006; 91: 833–836.

    PubMed  Google Scholar 

  7. Messerer D, Engel J, Hasford J, Schaich M, Ehninger G, Sauerland C et al. Impact of different post-remission strategies on quality of life in patients with acute myeloid leukemia. Haematologica 2008; 93: 826–833.

    PubMed  Google Scholar 

  8. Bloomfield CD, Shuma C, Regal L, Philip PP, Hossfeld DK, Hagemeijer AM et al. Long-term survival of patients with acute myeloid leukemia: a third follow-up of the Fourth International Workshop on Chromosomes in Leukemia. Cancer 1997; 80 (11 Suppl): 2191–2198.

    CAS  PubMed  Google Scholar 

  9. Swansbury GJ, Lawler SD, Alimena G, Arthur D, Berger R, Van den BH et al. Long-term survival in acute myelogenous leukemia: a second follow-up of the Fourth International Workshop on Chromosomes in Leukemia. Cancer Genet Cytogenet 1994; 73: 1–7.

    CAS  PubMed  Google Scholar 

  10. Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G et al. 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 1998; 92: 2322–2333.

    CAS  PubMed  Google Scholar 

  11. Schlenk RF, Benner A, Krauter J, Buchner T, Sauerland C, Ehninger G et al. Individual patient data-based meta-analysis of patients aged 16 to 60 years with core binding factor acute myeloid leukemia: a survey of the German Acute Myeloid Leukemia Intergroup. J Clin Oncol 2004; 22: 3741–3750.

    CAS  PubMed  Google Scholar 

  12. Cairoli R, Grillo G, Beghini A, Tedeschi A, Ripamonti CB, Larizza L et al. C-Kit point mutations in core binding factor leukemias: correlation with white blood cell count and the white blood cell index. Leukemia 2003; 17: 471–472.

    CAS  PubMed  Google Scholar 

  13. Cairoli R, Beghini A, Grillo G, Nadali G, Elice F, Ripamonti CB et al. Prognostic impact of c-KIT mutations in core binding factor leukemias: an Italian retrospective study. Blood 2006; 107: 3463–3468.

    CAS  PubMed  Google Scholar 

  14. Kuchenbauer F, Schoch C, Kern W, Hiddemann W, Haferlach T, Schnittger S . Impact of FLT3 mutations and promyelocytic leukaemia-breakpoint on clinical characteristics and prognosis in acute promyelocytic leukaemia. Br J Haematol 2005; 130: 196–202.

    CAS  PubMed  Google Scholar 

  15. Marcucci G, Mrozek K, Bloomfield CD . Molecular heterogeneity and prognostic biomarkers in adults with acute myeloid leukemia and normal cytogenetics. Curr Opin Hematol 2005; 12: 68–75.

    CAS  PubMed  Google Scholar 

  16. Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 2002; 99: 4326–4335.

    CAS  PubMed  Google Scholar 

  17. Schnittger S, Schoch C, Dugas M, Kern W, Staib P, Wuchter C et al. 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 2002; 100: 59–66.

    CAS  PubMed  Google Scholar 

  18. Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati R, Pasqualucci L et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 2005; 352: 254–266.

    CAS  PubMed  Google Scholar 

  19. Bacher U, Haferlach C, Kern W, Haferlach T, Schnittger S . Prognostic relevance of FLT3-TKD mutations in AML: the combination matters—an analysis of 3082 patients. Blood 2008; 111: 2527–2537.

    CAS  PubMed  Google Scholar 

  20. Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 2001; 97: 2434–2439.

    CAS  PubMed  Google Scholar 

  21. Bacher U, Haferlach T, Schoch C, Kern W, Schnittger S . Implications of NRAS mutations in AML: a study of 2502 patients. Blood 2006; 107: 3847–3853.

    CAS  PubMed  Google Scholar 

  22. Bowen DT, Frew ME, Hills R, Gale RE, Wheatley K, Groves MJ et al. RAS mutation in acute myeloid leukemia is associated with distinct cytogenetic subgroups but does not influence outcome in patients younger than 60 years. Blood 2005; 106: 2113–2119.

    CAS  PubMed  Google Scholar 

  23. Virappane P, Gale R, Hills R, Kakkas I, Summers K, Stevens J et al. Mutation of the Wilms’ tumor 1 gene is a poor prognostic factor associated with chemotherapy resistance in normal karyotype acute myeloid leukemia: The United Kingdom Medical Research Council Adult Leukaemia Working Party. J Clin Oncol 2008; 26: 5429–5435.

    CAS  PubMed  Google Scholar 

  24. Paschka P, Marcucci G, Ruppert AS, Whitman SP, Mrozek K, Maharry K et al. Wilms tumor 1 gene mutations independently predict poor outcome in adults with cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol 2008; 26: 4595–4602.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Barragan E, Cervera J, Bolufer P, Ballester S, Martin G, Fernandez P et al. Prognostic implications of Wilms’ tumor gene (WT1) expression in patients with de novo acute myeloid leukemia. Haematologica 2004; 89: 926–933.

    CAS  PubMed  Google Scholar 

  26. Ommen HB, Nyvold CG, Braendstrup K, Andersen BL, Ommen IB, Hasle H et al. Relapse prediction in acute myeloid leukaemia patients in complete remission using WT1 as a molecular marker: development of a mathematical model to predict time from molecular to clinical relapse and define optimal sampling intervals. Br J Haematol 2008; 141: 782–791.

    CAS  PubMed  Google Scholar 

  27. Langer C, Radmacher MD, Ruppert AS, Whitman SP, Paschka P, Mrozek K et al. High BAALC expression associates with other molecular prognostic markers, poor outcome, and a distinct gene-expression signature in cytogenetically normal patients younger than 60 years with acute myeloid leukemia: a Cancer and Leukemia Group B (CALGB) study. Blood 2008; 111: 5371–5379.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Kern W, Haferlach T, Schoch C, Loffler H, Gassmann W, Heinecke A et al. 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 2003; 101: 64–70.

    CAS  PubMed  Google Scholar 

  29. Kern W, Dannhauser-Riedl S, Ratei R, Schnittger S, Schoch C, Kolb HJ et al. Detection of minimal residual disease in unselected patients with acute myeloid leukemia using multiparameter flow cytometry for definition of leukemia-associated immunophenotypes and determination of their frequencies in normal bone marrow. Haematologica 2003; 88: 646–653.

    PubMed  Google Scholar 

  30. Chou WC, Tang JL, Wu SJ, Tsay W, Yao M, Huang SY et al. Clinical implications of minimal residual disease monitoring by quantitative polymerase chain reaction in acute myeloid leukemia patients bearing nucleophosmin (NPM1) mutations. Leukemia 2007; 21: 998–1004.

    CAS  PubMed  Google Scholar 

  31. Gorello P, Cazzaniga G, Alberti F, Dell’Oro MG, Gottardi E, Specchia G et al. Quantitative assessment of minimal residual disease in acute myeloid leukemia carrying nucleophosmin (NPM1) gene mutations. Leukemia 2006; 20: 1103–1108.

    CAS  PubMed  Google Scholar 

  32. Scholl S, Mugge LO, Landt O, Loncarevic IF, Kunert C, Clement JH et al. Rapid screening and sensitive detection of NPM1 (nucleophosmin) exon 12 mutations in acute myeloid leukaemia. Leuk Res 2007; 31: 1205–1211.

    CAS  PubMed  Google Scholar 

  33. Schnittger S, Schoch C, Kern W, Hiddemann W, Haferlach T . FLT3 length mutations as marker for follow-up studies in acute myeloid leukaemia. Acta Haematol 2004; 112: 68–78.

    CAS  PubMed  Google Scholar 

  34. Scholl S, Loncarevic IF, Krause C, Kunert C, Clement JH, Hoffken K . Minimal residual disease based on patient specific Flt3-ITD and -ITT mutations in acute myeloid leukemia. Leuk Res 2005; 29: 849–853.

    CAS  PubMed  Google Scholar 

  35. Scholl S, Krause C, Loncarevic IF, Muller R, Kunert C, Wedding U et al. Specific detection of Flt3 point mutations by highly sensitive real-time polymerase chain reaction in acute myeloid leukemia. J Lab Clin Med 2005; 145: 295–304.

    CAS  PubMed  Google Scholar 

  36. Weisser M, Kern W, Schoch C, Hiddemann W, Haferlach T, Schnittger S . Risk assessment by monitoring expression levels of partial tandem duplications in the MLL gene in acute myeloid leukemia during therapy. Haematologica 2005; 90: 881–889.

    CAS  PubMed  Google Scholar 

  37. Preisler HD, Priore R, Azarnia N, Barcos M, Raza A, Rakowski I et al. Prediction of response of patients with acute nonlymphocytic leukaemia to remission induction therapy: use of clinical measurements. Br J Haematol 1986; 63: 625–636.

    CAS  PubMed  Google Scholar 

  38. Hussein K, Jahagirdar B, Gupta P, Burns L, Larsen K, Weisdorf D . Day 14 bone marrow biopsy in predicting complete remission and survival in acute myeloid leukemia. Am J Hematol 2008; 83: 446–450.

    PubMed  Google Scholar 

  39. Haferlach T, Kern W, Schoch C, Schnittger S, Sauerland MC, Heinecke A et al. A new prognostic score for patients with acute myeloid leukemia based on cytogenetics and early blast clearance in trials of the German AML Cooperative Group. Haematologica 2004; 89: 408–418.

    PubMed  Google Scholar 

  40. Wells RJ, Arthur DC, Srivastava A, Heerema NA, Le BM, Alonzo TA et al. Prognostic variables in newly diagnosed children and adolescents with acute myeloid leukemia: Children's Cancer Group Study 213. Leukemia 2002; 16: 601–607.

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  42. Griesinger F, Piro-Noack M, Kaib N, Falk M, Renziehausen A, Troff C et al. Leukaemia-associated immunophenotypes (LAIP) are observed in 90% of adult and childhood acute lymphoblastic leukaemia: detection in remission marrow predicts outcome. Br J Haematol 1999; 105: 241–255.

    CAS  PubMed  Google Scholar 

  43. Kern W, Haferlach C, Haferlach T, Schnittger S . Monitoring of minimal residual disease in acute myeloid leukemia. Cancer 2008; 112: 4–16.

    CAS  PubMed  Google Scholar 

  44. Feller N, van der Pol MA, van SA, Weijers GW, Westra AH, Evertse BW et al. MRD parameters using immunophenotypic detection methods are highly reliable in predicting survival in acute myeloid leukaemia. Leukemia 2004; 18: 1380–1390.

    CAS  PubMed  Google Scholar 

  45. Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH et al. 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 2003; 21: 4642–4649.

    PubMed  Google Scholar 

  46. Kern W, Voskova D, Schoch C, Schnittger S, Hiddemann W, Haferlach T . Prognostic impact of early response to induction therapy as assessed by multiparameter flow cytometry in acute myeloid leukemia. Haematologica 2004; 89: 528–540.

    PubMed  Google Scholar 

  47. Coustan-Smith E, Ribeiro RC, Rubnitz JE, Razzouk BI, Pui CH, Pounds S et al. Clinical significance of residual disease during treatment in childhood acute myeloid leukaemia. Br J Haematol 2003; 123: 243–252.

    PubMed  Google Scholar 

  48. Kern W, Voskova D, Schoch C, Hiddemann W, Schnittger S, Haferlach T . Determination of relapse risk based on assessment of minimal residual disease during complete remission by multiparameter flow cytometry in unselected patients with acute myeloid leukemia. Blood 2004; 104: 3078–3085.

    CAS  PubMed  Google Scholar 

  49. Sievers EL, Lange BJ, Alonzo TA, Gerbing RB, Bernstein ID, Smith FO et al. Immunophenotypic evidence of leukemia after induction therapy predicts relapse: results from a prospective Children's Cancer Group study of 252 patients with acute myeloid leukemia. Blood 2003; 101: 3398–3406.

    CAS  PubMed  Google Scholar 

  50. Venditti A, Buccisano F, Del PG, Maurillo L, Tamburini A, Cox C et al. Level of minimal residual disease after consolidation therapy predicts outcome in acute myeloid leukemia. Blood 2000; 96: 3948–3952.

    CAS  PubMed  Google Scholar 

  51. de Labarthe A, Pautas C, Thomas X, de Botton S, Bordessoule D, Tilly H et al. Allogeneic stem cell transplantation in second rather than first complete remission in selected patients with good-risk acute myeloid leukemia. Bone Marrow Transplant 2005; 35: 767–773.

    CAS  PubMed  Google Scholar 

  52. Grimwade D, Jamal R, Goulden N, Kempski H, Mastrangelo S, Veys P . Salvage of patients with acute promyelocytic leukaemia with residual disease following ABMT performed in second CR using all-trans retinoic acid. Br J Haematol 1998; 103: 559–562.

    CAS  PubMed  Google Scholar 

  53. Yanada M, Matsuo K, Emi N, Naoe T . Efficacy of allogeneic hematopoietic stem cell transplantation depends on cytogenetic risk for acute myeloid leukemia in first disease remission: a metaanalysis. Cancer 2005; 103: 1652–1658.

    PubMed  Google Scholar 

  54. Byrd JC, Mrozek K, Dodge RK, Carroll AJ, Edwards CG, Arthur DC et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002; 100: 4325–4336.

    CAS  PubMed  Google Scholar 

  55. Farag SS, Archer KJ, Mrozek K, Vardiman JW, Carroll AJ, Pettenati MJ et al. Isolated trisomy of chromosomes 8, 11, 13 and 21 is an adverse prognostic factor in adults with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B 8461. Int J Oncol 2002; 21: 1041–1051.

    CAS  PubMed  Google Scholar 

  56. Schaich M, Schlenk RF, Al-Ali HK, Dohner H, Ganser A, Heil G et al. Prognosis of acute myeloid leukemia patients up to 60 years of age exhibiting trisomy 8 within a non-complex karyotype: individual patient data-based meta-analysis of the German Acute Myeloid Leukemia Intergroup. Haematologica 2007; 92: 763–770.

    PubMed  Google Scholar 

  57. Farag SS, Ruppert AS, Mrozek K, Mayer RJ, Stone RM, Carroll AJ et al. Outcome of induction and postremission therapy in younger adults with acute myeloid leukemia with normal karyotype: a Cancer and Leukemia Group B study. J Clin Oncol 2005; 23: 482–493.

    CAS  PubMed  Google Scholar 

  58. Schlenk RF, Dohner K, Krauter J, Frohling S, Corbacioglu A, Bullinger L et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008; 358: 1909–1918.

    CAS  PubMed  Google Scholar 

  59. Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 2000; 96: 4075–4083.

    CAS  PubMed  Google Scholar 

  60. Haferlach T, Schoch C, Loffler H, Gassmann W, Kern W, Schnittger S et al. 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 2003; 21: 256–265.

    PubMed  Google Scholar 

  61. Yanada M, Matsuo K, Suzuki T, Kiyoi H, Naoe T . Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia 2005; 19: 1345–1349.

    CAS  PubMed  Google Scholar 

  62. Preudhomme C, Sagot C, Boissel N, Cayuela JM, Tigaud I, de BS et al. Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA). Blood 2002; 100: 2717–2723.

    CAS  PubMed  Google Scholar 

  63. Dohner K, Tobis K, Ulrich R, Frohling S, Benner A, Schlenk RF et al. 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 2002; 20: 3254–3261.

    PubMed  Google Scholar 

  64. Baldus CD, Tanner SM, Ruppert AS, Whitman SP, Archer KJ, Marcucci G et al. BAALC expression predicts clinical outcome of de novo acute myeloid leukemia patients with normal cytogenetics: a Cancer and Leukemia Group B Study. Blood 2003; 102: 1613–1618.

    CAS  PubMed  Google Scholar 

  65. Mrozek K, Heinonen K, Lawrence D, Carroll AJ, Koduru PR, Rao KW et al. Adult patients with de novo acute myeloid leukemia and t(9; 11)(p22; q23) have a superior outcome to patients with other translocations involving band 11q23: a Cancer and Leukemia Group B study. Blood 1997; 90: 4532–4538.

    CAS  PubMed  Google Scholar 

  66. Schoch C, Schnittger S, Klaus M, Kern W, Hiddemann W, Haferlach T . 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 2003; 102: 2395–2402.

    CAS  PubMed  Google Scholar 

  67. Rubnitz JE, Raimondi SC, Tong X, Srivastava DK, Razzouk BI, Shurtleff SA et al. Favorable impact of the t(9;11) in childhood acute myeloid leukemia. J Clin Oncol 2002; 20: 2302–2309.

    CAS  PubMed  Google Scholar 

  68. Lo Nigro L, Bottino D, Panarello C, Morerio C, Mirabile E, Rapella AM et al. Prognostic impact of t(9;11) in childhood acute myeloid leukemia (AML). Leukemia 2003; 17: 636.

    PubMed  Google Scholar 

  69. Jaffe ES, Harris NL, Stein H, Vardiman JW . World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press: Lyon, 2008.

    Google Scholar 

  70. Buchner T, Hiddemann W, Berdel WE, Wormann B, Schoch C, Fonatsch C et al. Subgroup specific therapy effects in AML: AMLCG data. Ann Hematol 2004; 83 (Suppl 1): S100–S101.

    PubMed  Google Scholar 

  71. Schoch C, Kern W, Kohlmann A, Hiddemann W, Schnittger S, Haferlach T . 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 2005; 43: 227–238.

    CAS  PubMed  Google Scholar 

  72. Breems DA, Van Putten WL, De Greef GE, Van Zelderen-Bhola SL, Gerssen-Schoorl KB, Mellink CH et al. Monosomal karyotype in acute myeloid leukemia: a better indicator of poor prognosis than a complex karyotype. J Clin Oncol 2008; 26: 4791–4797.

    PubMed  Google Scholar 

  73. Suciu S, Mandelli F, de Witte T, Zittoun R, Gallo E, Labar B et al. Allogeneic compared with autologous stem cell transplantation in the treatment of patients younger than 46 years with acute myeloid leukemia (AML) in first complete remission (CR1): an intention-to-treat analysis of the EORTC/GIMEMAAML-10 trial. Blood 2003; 102: 1232–1240.

    CAS  PubMed  Google Scholar 

  74. van der Straaten HM, van BA, Brand R, Schattenberg AV, Egeler RM, Barge RM et al. Allogeneic stem cell transplantation for patients with acute myeloid leukemia or myelodysplastic syndrome who have chromosome 5 and/or 7 abnormalities. Haematologica 2005; 90: 1339–1345.

    PubMed  Google Scholar 

  75. Armand P, Kim HT, DeAngelo DJ, Ho VT, Cutler CS, Stone RM et al. Impact of cytogenetics on outcome of de novo and therapy-related AML and MDS after allogeneic transplantation. Biol Blood Marrow Transplant 2007; 13: 655–664.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Schoch C, Kern W, Schnittger S, Hiddemann W, Haferlach T . 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 2004; 18: 120–125.

    CAS  PubMed  Google Scholar 

  77. Messner HA . How good is allogeneic transplantation for high-risk patients with AML? Best Pract Res Clin Haematol 2006; 19: 329–332.

    PubMed  Google Scholar 

  78. Larson RA . Is secondary leukemia an independent poor prognostic factor in acute myeloid leukemia? Best Pract Res Clin Haematol 2007; 20: 29–37.

    PubMed  Google Scholar 

  79. de Witte T, Hermans J, Vossen J, Bacigalupo A, Meloni G, Jacobsen N et al. Haematopoietic stem cell transplantation for patients with myelo-dysplastic syndromes and secondary acute myeloid leukaemias: a report on behalf of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Br J Haematol 2000; 110: 620–630.

    CAS  PubMed  Google Scholar 

  80. Breems DA, Van Putten WL, Huijgens PC, Ossenkoppele GJ, Verhoef GE, Verdonck LF et al. Prognostic index for adult patients with acute myeloid leukemia in first relapse. J Clin Oncol 2005; 23: 1969–1978.

    PubMed  Google Scholar 

  81. Lugthart S, van Drunen E, van NY, van HA, Erpelinck CA, Valk PJ et al. High EVI1 levels predict adverse outcome in acute myeloid leukemia: prevalence of EVI1 overexpression and chromosome 3q26 abnormalities underestimated. Blood 2008; 111: 4329–4337.

    CAS  PubMed  Google Scholar 

  82. Weisser M, Haferlach C, Haferlach T, Schnittger S . Advanced age and high initial WBC influence the outcome of inv(3) (q21q26)/t(3;3) (q21;q26) positive AML. Leuk Lymphoma 2007; 48: 2145–2151.

    CAS  PubMed  Google Scholar 

  83. Visani G, Bernasconi P, Boni M, Castoldi GL, Ciolli S, Clavio M et al. The prognostic value of cytogenetics is reinforced by the kind of induction/consolidation therapy in influencing the outcome of acute myeloid leukemia—analysis of 848 patients. Leukemia 2001; 15: 903–909.

    CAS  PubMed  Google Scholar 

  84. Dohner K, Dohner H . Molecular characterization of acute myeloid leukemia. Haematologica 2008; 93: 976–982.

    PubMed  Google Scholar 

  85. Garcon L, Libura M, Delabesse E, Valensi F, Asnafi V, Berger C et al. DEK-CAN molecular monitoring of myeloid malignancies could aid therapeutic stratification. Leukemia 2005; 19: 1338–1344.

    CAS  PubMed  Google Scholar 

  86. Jacobson S, Pillus L . Modifying chromatin and concepts of cancer. Curr Opin Genet Dev 1999; 9: 175–184.

    CAS  PubMed  Google Scholar 

  87. Velloso ER, Mecucci C, Michaux L, Van OA, Stul M, Boogaerts M et al. Translocation t(8;16)(p11;p13) in acute non-lymphocytic leukemia: report on two new cases and review of the literature. Leuk Lymphoma 1996; 21: 137–142.

    CAS  PubMed  Google Scholar 

  88. Bernasconi P, Orlandi E, Cavigliano P, Calatroni S, Boni M, Astori C et al. Translocation (8;16) in a patient with acute myelomonocytic leukemia, occurring after treatment with fludarabine for a low-grade non-Hodgkin's lymphoma. Haematologica 2000; 85: 1087–1091.

    CAS  PubMed  Google Scholar 

  89. Savasan S, Mohamed AN, Lucas DR, Dugan MC, Ryan JR, Ravindranath Y . Acute myeloid leukaemia with t(8;16)(p11;p13) in a child after intrauterine X-ray exposure. Br J Haematol 1996; 94: 702–704.

    CAS  PubMed  Google Scholar 

  90. Murati A, Gervais C, Carbuccia N, Finetti P, Cervera N, Adelaide J et al. Genome profiling of acute myelomonocytic leukemia: alteration of the MYB locus in MYST3-linked cases. Leukemia 2009; 23: 85–94.

    CAS  PubMed  Google Scholar 

  91. Quesnel B, Kantarjian H, Bjergaard JP, Brault P, Estey E, Lai JL et al. Therapy-related acute myeloid leukemia with t(8;21), inv(16), and t(8;16): a report on 25 cases and review of the literature. J Clin Oncol 1993; 11: 2370–2379.

    CAS  PubMed  Google Scholar 

  92. Gervais C, Murati A, Helias C, Struski S, Eischen A, Lippert E et al. Acute myeloid leukaemia with 8p11 (MYST3) rearrangement: an integrated cytologic, cytogenetic and molecular study by the groupe francophone de cytogenetique hematologique. Leukemia 2008; 22: 1567–1575.

    CAS  PubMed  Google Scholar 

  93. Demuynck H, Verhoef GE, Zachee P, Vandenberghe P, Van OA, Paridaens R et al. Therapy-related acute myeloid leukemia with t(8;16)(p11;p13) following anthracycline-based therapy for nonmetastatic osteosarcoma. Cancer Genet Cytogenet 1995; 82: 103–105.

    CAS  PubMed  Google Scholar 

  94. Schichman SA, Caligiuri MA, Strout MP, Carter SL, Gu Y, Canaani E et al. ALL-1 tandem duplication in acute myeloid leukemia with a normal karyotype involves homologous recombination between Alu elements. Cancer Res 1994; 54: 4277–4280.

    CAS  PubMed  Google Scholar 

  95. Silva FP, Lind A, Brouwer-Mandema G, Valk PJ, Giphart-Gassler M . Trisomy 13 correlates with RUNX1 mutation and increased FLT3 expression in AML-M0 patients. Haematologica 2007; 92: 1123–1126.

    CAS  PubMed  Google Scholar 

  96. Dicker F, Haferlach C, Kern W, Haferlach T, Schnittger S . Trisomy 13 is strongly associated with AML1/RUNX1 mutations and increased FLT3 expression in acute myeloid leukemia. Blood 2007; 110: 1308–1316.

    CAS  PubMed  Google Scholar 

  97. Schnittger S, Schoch C, Kern W, Mecucci C, Tschulik C, Martelli MF et al. Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood 2005; 106: 3733–3739.

    CAS  PubMed  Google Scholar 

  98. Dohner K, Schlenk RF, Habdank M, Scholl C, Rucker FG, Corbacioglu A et al. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood 2005; 106: 3740–3746.

    PubMed  Google Scholar 

  99. Verhaak RG, Goudswaard CS, van PW, Bijl MA, Sanders MA, Hugens W et al. Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance. Blood 2005; 106: 3747–3754.

    CAS  PubMed  Google Scholar 

  100. Thiede C, Koch S, Creutzig E, Steudel C, Illmer T, Schaich M et al. Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood 2006; 107: 4011–4020.

    CAS  PubMed  Google Scholar 

  101. Scholl S, Theuer C, Scheble V, Kunert C, Heller A, Mugge LO et al. Clinical impact of nucleophosmin mutations and Flt3 internal tandem duplications in patients older than 60 years with acute myeloid leukemia. Eur J Haematol 2008; 80: 208–215.

    CAS  PubMed  Google Scholar 

  102. Pabst T, Mueller BU, Zhang P, Radomska HS, Narravula S, Schnittger S et al. Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia. Nat Genet 2001; 27: 263–270.

    CAS  PubMed  Google Scholar 

  103. Frohling S, Schlenk RF, Stolze I, Bihlmayr J, Benner A, Kreitmeier S et al. CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: prognostic relevance and analysis of cooperating mutations. J Clin Oncol 2004; 22: 624–633.

    PubMed  Google Scholar 

  104. Gilliland DG, Griffin JD . Role of FLT3 in leukemia. Curr Opin Hematol 2002; 9: 274–281.

    PubMed  Google Scholar 

  105. Kiyoi H, Towatari M, Yokota S, Hamaguchi M, Ohno R, Saito H et al. Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product. Leukemia 1998; 12: 1333–1337.

    CAS  PubMed  Google Scholar 

  106. Whitman SP, Ruppert AS, Radmacher MD, Mrozek K, Paschka P, Langer C et al. FLT3 D835/I836 mutations are associated with poor disease-free survival and a distinct gene-expression signature among younger adults with de novo cytogenetically normal acute myeloid leukemia lacking FLT3 internal tandem duplications. Blood 2008; 111: 1552–1559.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Bornhauser M, Illmer T, Schaich M, Soucek S, Ehninger G, Thiede C . Improved outcome after stem-cell transplantation in FLT3/ITD-positive AML. Blood 2007; 109: 2264–2265.

    PubMed  Google Scholar 

  108. Doubek M, Muzik J, Szotkowski T, Koza V, Cetkovsky P, Kozak T et al. Is FLT3 internal tandem duplication significant indicator for allogeneic transplantation in acute myeloid leukemia? An analysis of patients from the Czech Acute Leukemia Clinical Register (ALERT). Neoplasma 2007; 54: 89–94.

    CAS  PubMed  Google Scholar 

  109. Gale RE, Hills R, Kottaridis PD, Srirangan S, Wheatley K, Burnett AK et al. No evidence that FLT3 status should be considered as an indicator for transplantation in acute myeloid leukemia (AML): an analysis of 1135 patients, excluding acute promyelocytic leukemia, from the UK MRC AML10 and 12 trials. Blood 2005; 106: 3658–3665.

    CAS  PubMed  Google Scholar 

  110. Meijer E, Cornelissen JJ . Allogeneic stem cell transplantation in acute myeloid leukemia in first or subsequent remission: weighing prognostic markers predicting relapse and risk factors for non-relapse mortality. Semin Oncol 2008; 35: 449–457.

    CAS  PubMed  Google Scholar 

  111. Schnittger S, Kinkelin U, Schoch C, Heinecke A, Haase D, Haferlach T et al. Screening for MLL tandem duplication in 387 unselected patients with AML identify a prognostically unfavorable subset of AML. Leukemia 2000; 14: 796–804.

    CAS  PubMed  Google Scholar 

  112. Libura M, Asnafi V, Tu A, Delabesse E, Tigaud I, Cymbalista F et al. FLT3 and MLL intragenic abnormalities in AML reflect a common category of genotoxic stress. Blood 2003; 102: 2198–2204.

    CAS  PubMed  Google Scholar 

  113. Olesen LH, Nyvold CG, Aggerholm A, Norgaard JM, Guldberg P, Hokland P . Delineation and molecular characterization of acute myeloid leukemia patients with coduplication of FLT3 and MLL. Eur J Haematol 2005; 75: 185–192.

    CAS  PubMed  Google Scholar 

  114. Paschka P, Marcucci G, Ruppert AS, Mrozek K, Chen H, Kittles RA et al. Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B study. J Clin Oncol 2006; 24: 3904–3911.

    CAS  PubMed  Google Scholar 

  115. Schnittger S, Kohl TM, Haferlach T, Kern W, Hiddemann W, Spiekermann K et al. KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival. Blood 2006; 107: 1791–1799.

    CAS  PubMed  Google Scholar 

  116. Stirewalt DL, Kopecky KJ, Meshinchi S, Appelbaum FR, Slovak ML, Willman CL et al. FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia. Blood 2001; 97: 3589–3595.

    CAS  PubMed  Google Scholar 

  117. King-Underwood L, Pritchard-Jones K . Wilms’ tumor (WT1) gene mutations occur mainly in acute myeloid leukemia and may confer drug resistance. Blood 1998; 91: 2961–2968.

    CAS  PubMed  Google Scholar 

  118. Summers K, Stevens J, Kakkas I, Smith M, Smith LL, Macdougall F et al. Wilms’ tumour 1 mutations are associated with FLT3-ITD and failure of standard induction chemotherapy in patients with normal karyotype AML. Leukemia 2007; 21: 550–551.

    CAS  PubMed  Google Scholar 

  119. Weisser M, Kern W, Rauhut S, Schoch C, Hiddemann W, Haferlach T et al. Prognostic impact of RT-PCR-based quantification of WT1 gene expression during MRD monitoring of acute myeloid leukemia. Leukemia 2005; 19: 1416–1423.

    CAS  PubMed  Google Scholar 

  120. Bienz M, Ludwig M, Leibundgut EO, Mueller BU, Ratschiller D, Solenthaler M et al. Risk assessment in patients with acute myeloid leukemia and a normal karyotype. Clin Cancer Res 2005; 11: 1416–1424.

    CAS  PubMed  Google Scholar 

  121. Marcucci G, Maharry K, Whitman SP, Vukosavljevic T, Paschka P, Langer C et al. High expression levels of the ETS-related gene, ERG, predict adverse outcome and improve molecular risk-based classification of cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol 2007; 25: 3337–3343.

    CAS  PubMed  Google Scholar 

  122. Heuser M, Beutel G, Krauter J, Dohner K, von NN, Schlegelberger B et al. High meningioma 1 (MN1) expression as a predictor for poor outcome in acute myeloid leukemia with normal cytogenetics. Blood 2006; 108: 3898–3905.

    CAS  PubMed  Google Scholar 

  123. Shimoni A, Nagler A . Clinical implications of minimal residual disease monitoring for stem cell transplantation after reduced intensity and nonmyeloablative conditioning. Acta Haematol 2004; 112: 93–104.

    PubMed  Google Scholar 

  124. Leroy H, de BS, Grardel-Duflos N, Darre S, Leleu X, Roumier C et al. Prognostic value of real-time quantitative PCR (RQ-PCR) in AML with t(8;21). Leukemia 2005; 19: 367–372.

    CAS  PubMed  Google Scholar 

  125. Krauter J, Gorlich K, Ottmann O, Lubbert M, Dohner H, Heit W et al. 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 2003; 21: 4413–4422.

    CAS  PubMed  Google Scholar 

  126. Marcucci G, Caligiuri MA, Dohner H, Archer KJ, Schlenk RF, Dohner K et al. Quantification of CBFbeta/MYH11 fusion transcript by real time RT-PCR in patients with inv(16) acute myeloid leukemia. Leukemia 2001; 15: 1072–1080.

    CAS  PubMed  Google Scholar 

  127. Barragan E, Pajuelo JC, Ballester S, Fuster O, Cervera J, Moscardo F et al. Minimal residual disease detection in acute myeloid leukemia by mutant nucleophosmin (NPM1): comparison with WT1 gene expression. Clin Chim Acta 2008; 395: 120–123.

    CAS  PubMed  Google Scholar 

  128. Bacher U, Badbaran A, Fehse B, Zabelina T, Zander A, Kroger N . Quantitative monitoring of NPM1 mutations provides a valid minimal residual disease parameter following allogeneic stem cell transplantation. J Exp Hematol 2009; 37: 135–142.

    CAS  Google Scholar 

  129. Cloos J, Goemans BF, Hess CJ, van Oostveen JW, Waisfisz Q, Corthals S et al. Stability and prognostic influence of FLT3 mutations in paired initial and relapsed AML samples. Leukemia 2006; 20: 1217–1220.

    CAS  PubMed  Google Scholar 

  130. Ellisen LW, Carlesso N, Cheng T, Scadden DT, Haber DA . The Wilms tumor suppressor WT1 directs stage-specific quiescence and differentiation of human hematopoietic progenitor cells. EMBO J 2001; 20: 1897–1909.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Keilholz U, Menssen HD, Gaiger A, Menke A, Oji Y, Oka Y et al. Wilms’ tumour gene 1 (WT1) in human neoplasia. Leukemia 2005; 19: 1318–1323.

    CAS  PubMed  Google Scholar 

  132. Cilloni D, Gottardi E, De Micheli D, Serra A, Volpe G, Messa F et al. Quantitative assessment of WT1 expression by real time quantitative PCR may be a useful tool for monitoring minimal residual disease in acute leukemia patients. Leukemia 2002; 16: 2115–2121.

    CAS  PubMed  Google Scholar 

  133. Haferlach T, Kohlmann A, Kern W, Hiddemann W, Schnittger S, Schoch C . Gene expression profiling as a tool for the diagnosis of acute leukemias. Semin Hematol 2003; 40: 281–295.

    CAS  PubMed  Google Scholar 

  134. Bullinger L, Dohner K, Bair E, Frohling S, Schlenk RF, Tibshirani R et al. Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukaemia. N Engl J Med 2004; 350: 1605–1616.

    CAS  PubMed  Google Scholar 

  135. Radmacher MD, Marcucci G, Ruppert AS, Mrozek K, Whitman SP, Vardiman JW et al. Independent confirmation of a prognostic gene-expression signature in adult acute myeloid leukemia with a normal karyotype: a Cancer and Leukemia Group B study. Blood 2006; 108: 1677–1683.

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Bullinger L, Rucker FG, Kurz S, Du J, Scholl C, Sander S et al. Gene-expression profiling identifies distinct subclasses of core binding factor acute myeloid leukemia. Blood 2007; 110: 1291–1300.

    CAS  PubMed  Google Scholar 

  137. Raponi M, Lancet JE, Fan H, Dossey L, Lee G, Gojo I et al. A 2-gene classifier for predicting response to the farnesyltransferase inhibitor tipifarnib in acute myeloid leukemia. Blood 2008; 111: 2589–2596.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to U Bacher.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bacher, U., Haferlach, C., Schnittger, S. et al. Interactive diagnostics in the indication to allogeneic SCT in AML. Bone Marrow Transplant 43, 745–756 (2009). https://doi.org/10.1038/bmt.2009.54

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2009.54

Keywords

This article is cited by

Search

Quick links