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.

Minimal Residual Disease

Clinical implications of minimal residual disease monitoring by quantitative polymerase chain reaction in acute myeloid leukemia patients bearing nucleophosmin (NPM1) mutations

Abstract

To explore the validity and prognostic significance of minimal residual disease detection by quantitative polymerase chain reaction (qPCR) in patients of acute myeloid leukemia (AML) bearing Nucleophosmin (NPM1) mutations, we quantified mutants in 194 bone marrow samples from 38 patients with a median follow-up time of 20.6 months. Following induction chemotherapy, a median of 2.78 log decline in mutant copy number was observed. Relapse was always accompanied by significant increase of mutant numbers (P<0.001). After achieving complete remission (CR), the mutant copy number was significantly higher in patients with subsequent relapse than in those remaining in continuous CR (P<0.001). Presence of detectable mutants after treatment predicted relapse if no further chemotherapy was administered. Furthermore, the patients with any rise of mutant signals during serial follow-up had 3.2-fold increase of relapse risk compared to those with persistently low or undetectable signals (P<0.001). Patients who could achieve mutant reduction to <0.1% of internal control had significantly longer overall survival (OS) (P=0.004) and relapse-free survival (RFS) (P<0.001). Failure to achieve 2 logs of reduction after consolidation predicted shorter OS (P=0.01) and RFS (P=0.001). In conclusion, qPCR monitoring may have prognostic impact in AML patients with NPM1 mutations.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Tallman MS, Gilliland DG, Rowe JM . Drug therapy for acute myeloid leukemia. Blood 2005; 106: 1154–1163.

    Article  CAS  PubMed  Google Scholar 

  2. 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.

    Article  PubMed  Google Scholar 

  3. Jurcic JG, Nimer SD, Scheinberg DA, DeBlasio T, Warrell Jr RP, Miller Jr WH . Prognostic significance of minimal residual disease detection and PML/RAR-alpha isoform type: long-term follow-up in acute promyelocytic leukemia. Blood 2001; 98: 2651–2656.

    Article  CAS  PubMed  Google Scholar 

  4. 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.

    Article  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.

    Article  CAS  PubMed  Google Scholar 

  6. 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.

    Article  CAS  PubMed  Google Scholar 

  7. Menssen HD, Siehl JM, Thiel E . Wilms tumor gene (WT1) expression as a panleukemic marker. Int J Hematol 2002; 76: 103–109.

    Article  CAS  PubMed  Google Scholar 

  8. 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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. 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.

    Article  CAS  PubMed  Google Scholar 

  11. Boissel N, Renneville A, Biggio V, Philippe N, Thomas X, Cayuela JM et al. Prevalence, clinical profile, and prognosis of NPM mutations in AML with normal karyotype. Blood 2005; 106: 3618–3620.

    CAS  PubMed  Google Scholar 

  12. Alcalay M, Tiacci E, Bergomas R, Bigerna B, Venturini E, Minardi SP et al. Acute myeloid leukemia bearing cytoplasmic nucleophosmin (NPMc+ AML) shows a distinct gene expression profile characterized by up-regulation of genes involved in stem-cell maintenance. Blood 2005; 106: 899–902.

    Article  CAS  PubMed  Google Scholar 

  13. Verhaak RG, Goudswaard CS, van Putten W, 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.

    Article  CAS  PubMed  Google Scholar 

  14. 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.

    Article  PubMed  Google Scholar 

  15. Chou WC, Tang JL, Lin LI, Yao M, Tsay W, Chen CY et al. Nucleophosmin mutations in de novo acute myeloid leukemia: the age-dependent incidences and the stability during disease evolution. Cancer Res 2006; 66: 3310–3316.

    Article  CAS  PubMed  Google Scholar 

  16. Falini B, Martelli MP, Bolli N, Bonasso R, Ghia E, Pallotta MT et al. Immunohistochemistry predicts nucleophosmin (NPM) mutations in acute myeloid leukemia. Blood 2006; 108: 1999–2005.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  18. 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.

    Article  CAS  PubMed  Google Scholar 

  19. 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.

    Article  CAS  PubMed  Google Scholar 

  20. Shih LY, Huang CF, Wu JH, Lin TL, Dunn P, Wang PN et al. Internal tandem duplication of FLT3 in relapsed acute myeloid leukemia: a comparative analysis of bone marrow samples from 108 adult patients at diagnosis and relapse. Blood 2002; 100: 2387–2392.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by Grants NTUH 93-N015, NTUH 95-000404, NSC 94-2314-B-002-307 and NSC 95-2314-B-002-234-MY2 from National Science Council and Department of Medical Research in National Taiwan University Hospital (Taiwan).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to H-F Tien.

Additional information

Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chou, WC., Tang, JL., Wu, SJ. et al. Clinical implications of minimal residual disease monitoring by quantitative polymerase chain reaction in acute myeloid leukemia patients bearing nucleophosmin (NPM1) mutations. Leukemia 21, 998–1004 (2007). https://doi.org/10.1038/sj.leu.2404637

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2404637

Keywords

This article is cited by

Search

Quick links