Skip to main content
SpringerLink
Log in

Individualisierte Medizin in der Diagnostik und prognostischen Einschätzung in der akuten myeloischen Leukämie mit normalem Karyotyp bei Erwachsenen unter 65 Jahren: eine systematische Literaturrecherche und Metaanalyse zu FLT3-ITD

Diagnostic and prognostic significance of individualized medicine for acute myeloid leukemia with normal karyotype in patients younger than 65 years: a systematic review and meta-analysis with regard to FLT3-ITD

  • Originalarbeit
  • Published:
Ethik in der Medizin Aims and scope Submit manuscript

Zusammenfassung

Diagnostik und Klassifikation der akuten myeloischen Leukämie (AML) beruhen auf zytologischen und zytogenetischen Charakteristika. Eine Individualisierung der Diagnostik und Therapie wird für AML mit normalem Karyotyp (CN-AML) durch den Nachweis spezifischer Genmutationen zunehmend ermöglicht. In einem systematischen Literaturreview und Metanalyse wurde die Mutation FLT3-ITD bei CN-AML untersucht. Eine systematische Literaturrecherche aller Veröffentlichungen der Datenbanken Embase, Pubmed, Healthstar, BIOSIS, ISI Web of Knowledge und Cochrane wurde für den Zeitraum 2000 bis März 2012 im Hinblick auf die Mutation FLT3-ITD bei Patienten mit CN-AML und einem Alter von 15–65 Jahren durchgeführt. Der Literaturrecherche folgte eine Literaturselektion, eine Datenextraktion und eine qualitative sowie quantitative Informationssynthese in Form einer Metaanalyse. Achtzehn Veröffentlichungen konnten in die qualitative Analyse zur CN-AML eingeschlossen werden. Daten von 3 Publikationen zum Gesamtüberleben mit insgesamt 1.203 Patienten gingen mit Bezug auf den Marker FLT3-ITD in die Metaanalyse ein. Für FLT3-ITD zeigte sich eine statistisch signifikante schlechtere Prognose mit einer hazard ratio von 2,19 für das Gesamtüberleben bei CN-AML. FLT3-ITD ist im Vergleich zum Wildtyp mit einer schlechteren Prognose in Bezug auf den Krankheitsverlauf bei AML assoziiert. Die Analyse von FLT3 sollte bei der AML berücksichtigt werden.

Abstract

Introduction

Diagnosis and classification of acute myeloid leukemia (AML) is based on cytological criteria and cytogenetic alterations. Individualization of diagnosis and therapy of AML normal karyotype AML (CN-AML) is increasingly possible due to detection of recurrent mutations. In this systematic review and meta-analysis, we examined the mutation FLT3-ITD in CN-AML.

Methods

A systematic search of all publications listed in the electronic databases Embase, Pubmed, Healthstar, BIOSIS, ISI Web of Knowledge and Cochrane was performed from 2000 up to March 2012 for the mutations fms-related tyrosine kinase 3 (FLT3-ITD) in CN-AML patients aged 15–65 years. The literature search included data extraction, qualitative, and quantitative synthesis of information in terms of a meta-analysis.

Results

In all, 18 studies were included and qualitatively analyzed for CN-AML. Three studies were included in the quantitative meta-analysis for CN-AML incorporating 1,203 patients. The FLT3-ITD mutation versus wild type showed a statistically significant worse prognosis with a hazard ratio for overall survival of 2.19 for CN-AML. Conclusion FLT3-ITD versus wild type FLT3 is associated with worse prognosis in AML. Diagnostic workup for AML should include mutation analysis of FLT3.

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

Abb. 1
Abb. 2
Abb. 3

Literatur

  1. Arber DA, Brunning RD, Le Beau MM et al (2007) Acute myeloid leukaemia and related precursor neoplasms. In: Swerdlow SH (Hrsg) WHO classification of tumours of haematopoietic and lymphoid tissues, 4. Aufl. IARC Press, Lyon, S 109–166

  2. Bareschino MA, Schettino C, Rossi A et al (2011) Treatment of advanced non small cell lung cancer. J Thorac Dis 3:122–133. doi:10.3978/j.issn.2072-1439.2010.12.08

    Google Scholar 

  3. 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

    Google Scholar 

  4. Chapman PB, Hauschild A, Robert C et al (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364:2507–2516. doi:10.1056/NEJMoa1103782

    Google Scholar 

  5. 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

    Google Scholar 

  6. 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

    Google Scholar 

  7. Döhner 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

    Google Scholar 

  8. Döhner K, Döhner H (2008) Molecular characterization of acute myeloid leukemia. Haematologica 93:976–982

    Article  PubMed  Google Scholar 

  9. 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 

  10. 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

    Google Scholar 

  11. 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  PubMed  CAS  Google Scholar 

  12. 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

    Article  PubMed  CAS  Google Scholar 

  13. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. doi:10.1016/j.cell.2011.02.013

    Google Scholar 

  14. 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

    Google Scholar 

  15. 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

    Article  PubMed  CAS  Google Scholar 

  16. 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) study. Blood 111:5371–5379. doi:10.1182/blood-2007-11-124958

    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

    Google Scholar 

  18. 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

    Google Scholar 

  19. Marcucci G, Haferlach T, Döhner 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

    Google Scholar 

  20. O’Brien SG, Guilhot F, Larson RA et al (2003) Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348:994–1004. doi:10.1056/NEJMoa022457

    Google Scholar 

  21. 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

    Google Scholar 

  22. 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

    Google Scholar 

  23. Taskesen E, Bullinger L, Corbacioglu A et al (2010) 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

    Google Scholar 

  24. 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

    Google Scholar 

  25. 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

    Google Scholar 

  26. 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

    Google Scholar 

  27. 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

    Google Scholar 

  28. 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

    Google Scholar 

  29. Yanada M, Matsuo K, Suzuki T, Kiyoi H, Naoe T (2005) Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia 19:1345–1349. doi:10.1038/sj.leu.2403838

    Google Scholar 

Download references

Interessenkonflikt

Die Autoren geben an, dass keine Interessenkonflikte bestehen.

Author information

Authors and Affiliations

  1. Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation, Medizinische Hochschule Hannover, Carl Neubergstr. 1, 30625, Hannover, Deutschland

    Matthias Port, Miriam Böttcher,  Felicitas Thol &  Arnold Ganser

  2. Lehrstuhl für Medizinmanagement, Universität Duisburg-Essen, Campus Essen, Essen, Deutschland

    Nicole Trachte,  Jürgen Wasem, Laura Pouryamout M.A. &  Anja Neumann

Authors
  1. Matthias Port
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Miriam Böttcher
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Felicitas Thol
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nicole Trachte
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jürgen Wasem
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Arnold Ganser
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Laura Pouryamout M.A.
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Anja Neumann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Matthias Port.

Additional information

Matthias Port, Miriam Böttcher, Laura Pouryamout und Anja Neumann haben gleichberechtigt zur Publikation beigetragen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Port, M., Böttcher, M., Thol, F. et al. Individualisierte Medizin in der Diagnostik und prognostischen Einschätzung in der akuten myeloischen Leukämie mit normalem Karyotyp bei Erwachsenen unter 65 Jahren: eine systematische Literaturrecherche und Metaanalyse zu FLT3-ITD. Ethik Med 25, 183–193 (2013). https://doi.org/10.1007/s00481-013-0271-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00481-013-0271-7

Schlüsselwörter

Keywords

Search

Navigation