Skip to main content
SpringerLink
Log in

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

  • Review Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed Central  PubMed  Google Scholar 

  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 www.cochrane-handbook.org.

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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 11:1811–1816

    PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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 111:2776–2784

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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. 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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  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 109–166

    Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

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.

Author information

Authors and Affiliations

  1. Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School (MHH), Carl-Neubergstr. 1, 30165, Hannover, Germany

    M. Port, M. Böttcher, F. Thol & A. Ganser

  2. Institute for Health Care Management and Research, University of Duisburg-Essen, Essen, Germany

    R. Schlenk

  3. Department of Internal Medicine III, University of Ulm, Ulm, Germany

    J. Wasem, A. Neumann & L. Pouryamout

Authors
  1. M. Port
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Böttcher
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F. Thol
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Ganser
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R. Schlenk
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. Wasem
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. Neumann
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. L. Pouryamout
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Port.

Additional information

M. Port, M. Böttcher, A. Neumann, and L. Pouryamout contributed equally to the work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Port, M., Böttcher, M., Thol, F. et al. 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. Ann Hematol 93, 1279–1286 (2014). https://doi.org/10.1007/s00277-014-2072-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-014-2072-6

Keywords

Search

Navigation