Annals of Hematology

, Volume 93, Issue 8, pp 1279–1286 | Cite as

Prognostic significance of FLT3 internal tandem duplication, nucleophosmin 1, and CEBPA gene mutations for acute myeloid leukemia patients with normal karyotype and younger than 60 years: a systematic review and meta-analysis

  • M. Port
  • M. Böttcher
  • F. Thol
  • A. Ganser
  • R. Schlenk
  • J. Wasem
  • A. Neumann
  • L. Pouryamout
Review Article


Diagnosis and classification of acute myeloid leukemia (AML) are based on morphology and genetics. An increasing number of gene mutations have been found, and some are used for risk classification in AML patients with normal karyotype (cytogenetically normal (CN)-AML). In this systematic review and meta-analysis, we examined three frequent mutations in CN-AML: mutations of fms-related tyrosine kinase 3 (FLT3-ITD), mutated nucleophosmin (NPM1), and mutations of the CCAAT enhancer-binding protein alpha (CEBPA) gene. A systematic literature search of publications listed in the electronic databases (Embase, Pubmed, Healthstar, BIOSIS, ISI Web of Knowledge and Cochrane) from 2000 up to March 2012 was performed (Fig. 1). Nineteen studies were included and qualitatively analyzed. Two to four studies entered the quantitative meta-analysis incorporating 1,378 to 1,942 patients with CN-AML. Meta-analysis for overall survival (OS) and relapse-free survival (RFS) showed FLT3-ITD to predict an unfavorable prognosis, with hazard ratios (HR) of 1.86 and 1.75, respectively. In contrast, meta-analysis of the impact of NPM1 and CEBPA mutations on OS yielded an HR of 0.56 for each mutation, while analysis of impact on RFS produced HRs of 0.37 and 0.42, respectively. This systematic review and meta-analysis aimed to evaluate the prognostic value of mutations in the NPM1, CEBPA, and FLT3 genes. FLT3-ITD was associated with worse prognosis, whereas mutations in NPM1 and CEBPA genes were associated with a favorable prognosis.


Acute myeloid leukemia Normal karyotype Mutations of fms-related tyrosine kinase 3 Mutated nucleophosmin Mutations of the CEBPA gene Meta-analysis 



This work was supported by the Bundesministerium für Bildung und Forschung/Germany.

We are very thankful to Michael Morgan carefully reading the manuscript.

Conflict of interest

All authors have no conflict of interest to declare.


  1. 1.
    Dohner H, Estey EH, Amadori S et al (2010) Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 115:453–474. doi: 10.1182/blood-2009-07-235358 PubMedCrossRefGoogle Scholar
  2. 2.
    Grimwade D, Hills RK, Moorman AV et al (2010) Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 116:354–365. doi: 10.1182/blood-2009-11-254441 PubMedCrossRefGoogle Scholar
  3. 3.
    Marcucci G, Haferlach T, Dohner H (2011) Molecular genetics of adult acute myeloid leukemia: prognostic and therapeutic implications. J Clin Oncol 29:475–486. doi: 10.1200/JCO.2010.30.2554 PubMedCrossRefGoogle Scholar
  4. 4.
    Schlenk RF, Döhner K, Krauter JJ et al (2008) Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 358:1909–1918. doi: 10.1056/NEJMoa074306 PubMedCrossRefGoogle Scholar
  5. 5.
    Vardiman JW, Thiele J, Arber DA et al (2009) The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 114:937–951. doi: 10.1182/blood-2009-03-209262 PubMedCrossRefGoogle Scholar
  6. 6.
    Liberati A, Altman DG, Tetzlaff J et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 339:b2700–b2700. doi: 10.1136/bmj.b2700 PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Higgins J, Green S (eds) Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. doi: Available from
  8. 8.
    Boissel N, Renneville A, Biggio V et al (2005) Prevalence, clinical profile, and prognosis of NPM mutations in AML with normal karyotype. Blood 106:3618–3620. doi: 10.1182/blood-2005-05-2174 PubMedCrossRefGoogle Scholar
  9. 9.
    Damm F, Heuser M, Morgan M et al (2011) Integrative prognostic risk score in acute myeloid leukemia with normal karyotype. Blood 117:4561–4568. doi: 10.1182/blood-2010-08-303479 PubMedCrossRefGoogle Scholar
  10. 10.
    Damm F, Heuser M, Morgan M et al (2010) Single nucleotide polymorphism in the mutational hotspot of WT1 predicts a favorable outcome in patients with cytogenetically normal acute myeloid leukemia. J Clin Oncol 28:578–585. doi: 10.1200/JCO.2009.23.0342 PubMedCrossRefGoogle Scholar
  11. 11.
    Dohner K, Schlenk RF, Habdank M et al (2005) Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood 106:3740–3746. doi: 10.1182/blood-2005-05-2164 PubMedCrossRefGoogle Scholar
  12. 12.
    Dunna NR, Rajappa S, Digumarti R et al (2010) Fms like tyrosine kinase (FLT3) and nucleophosmin 1 (NPM1) mutations in de novo normal karyotype acute myeloid leukemia (AML). Asian Pac J Cancer Prev 11:1811–1816PubMedGoogle Scholar
  13. 13.
    Fröhling S, Schlenk RF, Stolze I et al (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. doi: 10.1200/JCO.2004.06.060 PubMedCrossRefGoogle Scholar
  14. 14.
    Gale RE, Green C, Allen C et al (2008) The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood 111:2776–2784PubMedCrossRefGoogle Scholar
  15. 15.
    Heuser M, Beutel G, Krauter J et al (2006) High meningioma 1 (MN1) expression as a predictor for poor outcome in acute myeloid leukemia with normal cytogenetics. Blood 108:3898–3905. doi: 10.1182/blood-2006-04-014845 PubMedCrossRefGoogle Scholar
  16. 16.
    Kim YK, Kim HJN, Lee SR et al (2010) Prognostic significance of nucleophosmin mutations and FLT3 internal tandem duplication in adult patients with cytogenetically normal acute myeloid leukemia. Korean J Hematol 45:36–45. doi: 10.5045/kjh.2010.45.1.36 PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Langer C, Marcucci G, Holland KB et al (2009) Prognostic importance of MN1 transcript levels, and biologic insights from MN1-associated gene and microRNA expression signatures in cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. J Clin Oncol 27:3198–3204. doi: 10.1200/JCO.2008.20.6110 PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Langer C, Radmacher MD, Ruppert AS et al (2008) 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) st. Blood 111:5371–5379. doi: 10.1182/blood-2007-11-124958 PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Marcucci G, Maharry K, Radmacher MD et al (2008) Prognostic significance of, and gene and microRNA expression signatures associated with, CEBPA mutations in cytogenetically normal acute myeloid leukemia with high-risk molecular features: a Cancer and Leukemia Group B Study. J Clin Oncol 26:5078–5087. doi: 10.1200/JCO.2008.17.5554 PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Paschka P, Marcucci G, Ruppert AS et al (2008) 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 26:4595–4602. doi: 10.1200/JCO.2007.15.2058 PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Taskesen E, Bullinger L, Corbacioglu A, et al. (2011) Prognostic impact, concurrent genetic mutations and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML: further evidence for CEBPA double mutant AML as a distinctive disease entity. Blood 117:2469–2475. doi: 10.1182/blood-2010-09-307280
  22. 22.
    Thiede C, Koch S, Creutzig E et al (2006) Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood 107:4011–4020. doi: 10.1182/blood-2005-08-3167 PubMedCrossRefGoogle Scholar
  23. 23.
    Virappane P, Gale R, Hills R et al (2008) 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 26:5429–5435. doi: 10.1200/JCO.2008.16.0333 PubMedCrossRefGoogle Scholar
  24. 24.
    Wagner K, Damm F, Goehring G et al (2010) Impact of IDH1 R132 mutations and an IDH1 single nucleotide polymorphism in cytogenetically normal acute myeloid leukemia: SNP rs11554137 is an adverse prognostic factor. J Clin Oncol 28:2356–2364. doi: 10.1200/JCO.2009.27.6899 PubMedCrossRefGoogle Scholar
  25. 25.
    Whitman SP, Ruppert AS, Radmacher MD et al (2008) 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 111:1552–1559. doi: 10.1182/blood-2007-08-107946 PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Arber DA, Brunning RD, Le Beau MM et al (2008) Acute myeloid leukaemia and related precursor neoplasms. In: Swerdlow SH, Campo E, Harris NL (eds) WHO Classif. Tumours Haematop. Lymphoid Tissues, 4th edn. IARC Press, Lyon, pp 109–166Google Scholar
  27. 27.
    Yanada M, Matsuo K, Suzuki T et al (2005) Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leuk Off J Leuk Soc Am Leuk Res Fund UK 19:1345–1349. doi: 10.1038/sj.leu.2403838 CrossRefGoogle Scholar
  28. 28.
    Thol F, Damm F, Lüdeking A et al (2011) Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. J Clin Oncol 29:2889–2896. doi: 10.1200/JCO.2011.35.4894 PubMedCrossRefGoogle Scholar
  29. 29.
    Thol F, Damm F, Wagner K et al (2010) Prognostic impact of IDH2 mutations in cytogenetically normal acute myeloid leukemia. Blood 116:614–616. doi: 10.1182/blood-2010-03-272146 PubMedCrossRefGoogle Scholar
  30. 30.
    Schnittger S, Schoch C, Kern W et al (2005) Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood 106:3733–3739. doi: 10.1182/blood-2005-06-2248 PubMedCrossRefGoogle Scholar
  31. 31.
    Schlenk RF, Taskesen E, van Norden Y et al (2013) The value of allogeneic and autologous hematopoietic stem cell transplantation in prognostically favorable acute myeloid leukemia with double mutant CEBPA. Blood 122:1576–1582. doi: 10.1182/blood-2013-05-503847 PubMedCrossRefGoogle Scholar
  32. 32.
    Schneider F, Hoster E, Schneider S et al (2012) Age-dependent frequencies of NPM1 mutations and FLT3-ITD in patients with normal karyotype AML (NK-AML). Ann Hematol 91:9–18. doi: 10.1007/s00277-011-1280-6 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • M. Port
    • 1
  • M. Böttcher
    • 1
  • F. Thol
    • 1
  • A. Ganser
    • 1
  • R. Schlenk
    • 2
  • J. Wasem
    • 3
  • A. Neumann
    • 3
  • L. Pouryamout
    • 3
  1. 1.Department of Hematology, Hemostasis, Oncology, and Stem Cell TransplantationHannover Medical School (MHH)HannoverGermany
  2. 2.Institute for Health Care Management and ResearchUniversity of Duisburg-EssenEssenGermany
  3. 3.Department of Internal Medicine IIIUniversity of UlmUlmGermany

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