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.

  • Letter to the Editor
  • Published:

Prognostic value of minimal residual disease by real-time quantitative PCR in acute myeloid leukemia with CBFB-MYH11 rearrangement: the French experience

Leukemia volume 24, pages 1386–1388 (2010)Cite this article

Subjects

Acute myeloid leukemia (AML) with inversion of chromosome 16 inv(16)(p13q22) or balanced translocation t(16;16)(p13;q22), which results in the fusion of CBFB to MYH11, is closely associated with a favorable outcome compared with other AML subtypes, especially when patients are treated with high-dose cytarabine (HD-AraC) consolidation therapy. However, relapse still occurs in 30–40% of cases and a significant number of patients subsequently die. An adequate prediction of relapse risk could justify alternative therapy strategies in first complete remission (CR), including allogeneic hematopoietic stem cell transplantation. Prognostic factors for risk of relapse in this AML subset are still a matter of debate. Mutations in receptor tyrosine kinase genes, including c-KIT and FLT3, are present in about 20–30% of inv(16)/t(16;16) AML cases. In a recent report of the Cancer and Leukemia Group B, the relapse risk was higher for patients with c-KIT mutations.1 Minimal residual disease (MRD) monitoring is of growing importance for risk stratification and early detection of relapse in AML. Previous studies reported the feasibility and the potential prognostic impact of MRD detection using real-time PCR or quantitative real-time PCR (RQ-PCR), but produced conflicting results. Low MRD level after induction or following completion of the entire chemotherapy program was associated with a lower risk of relapse.2, 3, 4 Schnittger et al.5 previously described a strong prognostic impact of the initial fusion transcript level by creating a score based on the median expression ratio after consolidation therapy and the 75th percentile of the expression ratio at diagnosis. However, no study has defined an absolute threshold for the early molecular response, which could be used for outcome prediction. Furthermore, no prognostic analysis taking into account all previous prognostic factors including MRD and mutational profile is available and the clinical relevance of monitoring MRD by RQ-PCR is still a matter of debate in this AML subset.

In this study, we retrospectively analyzed the prognostic value of sequential MRD assessment by RQ-PCR in patients with CBFB-MYH11-positive AML with known c-KIT, FLT3 and RAS mutational status. A total of 59 AML patients with inv(16)/t(16;16) diagnosed between 1993 and 2008 in 14 French University Hospitals and who achieved first CR using cooperative group multicenter trials were retrospectively analyzed. The main characteristics of the patients are described in Table 1. In agreement with the declaration of Helsinki, patients or their guardians (for children) gave informed consent for the use of their samples in research studies. Patients were treated according to the clinical trials of the Acute Leukemia French Association (ALFA) or the European Organisation for the Research and Treatment of Cancer (EORTC) cooperative groups for adult cases and of the Leucémies Aiguës Myéloblastiques de l’Enfant (LAME) Cooperative Group for pediatric cases. Although these trials evolved during the patient recruitment period, HD-AraC was given during consolidation to 79% of patients. Intensification chemotherapy followed by autologous stem cell transplantation was used as consolidation therapy in four patients. Two pediatric cases received allogeneic hematopoietic stem cell transplantation with a matched related donor in first CR; CR status and survival data were censored at the time of transplant in both cases. Peripheral blood (PB) and bone marrow (BM) samples were collected at diagnosis, at CR achievement (MRD1), after the first consolidation course (MRD2), after the end of consolidation chemotherapy (MRD3) and every 3–6 months thereafter. The decrease in MRD2 (ΔMRD2) was defined as MRD2/CBFB-MYH11 transcript level at diagnosis. A total of 515 consecutive PB or BM samples were centralized and prospectively analyzed according to the same techniques in three French laboratories (CHRU of Lille, Paris Necker and Paris Saint-Louis Hospitals). RQ-PCR was performed following the Europe Against Cancer program recommendations for CBFB-MYH11 fusion transcripts.6 As the genomic break points within the CBFB and MYH11 genes are variable, at least 11 different types of CBFB-MYH11 fusion transcripts (that is, A to K) have been described, although the type A largely predominates. Specifics primers were used to detect A, D and E transcripts, that is, the most common ones. A specific reverse primer was designed (5′-CGTAGACACGTTGAGCTTCTGC-3′) for the detection of type J transcript. Results were expressed by the ratio CBFB-MYH11 copy number/ABL copy number × 100 (%), according to a standard curve established with serial dilutions of CBFB-MYH11 and ABL Ipsogen plasmids. FLT3, c-KIT and RAS mutations were detected in BM or PB samples as previously reported.7

Table 1 Patient characteristics
Full size table

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

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1

References

  1. 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.

    Article  CAS  Google Scholar 

  2. 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.

    Article  CAS  Google Scholar 

  3. Guerrasio A, Pilatrino C, De Micheli D, Cilloni D, Serra A, Gottardi E et al. Assessment of minimal residual disease (MRD) in CBFbeta/MYH11-positive acute myeloid leukemias by qualitative and quantitative RT-PCR amplification of fusion transcripts. Leukemia 2002; 16: 1176–1181.

    Article  CAS  Google Scholar 

  4. Perea G, Lasa A, Aventin A, Domingo A, Villamor N, Queipo de Llano MP et al. Prognostic value of minimal residual disease (MRD) in acute myeloid leukemia (AML) with favorable cytogenetics [t(8;21) and inv(16)]. Leukemia 2006; 20: 87–94.

    Article  CAS  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  Google Scholar 

  6. Gabert J, Beillard E, van der Velden VH, Bi W, Grimwade D, Pallisgaard N et al. Standardization and quality control studies of ‘real-time’ quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia—a Europe Against Cancer program. Leukemia 2003; 17: 2318–2357.

    Article  CAS  Google Scholar 

  7. Boissel N, Leroy H, Brethon B, Philippe N, de Botton S, Auvrignon A et al. Incidence and prognostic impact of c-Kit, FLT3, and Ras gene mutations in core binding factor acute myeloid leukemia (CBF-AML). Leukemia 2006; 20: 965–970.

    Article  CAS  Google Scholar 

  8. Stentoft J, Hokland P, Ostergaard M, Hasle H, Nyvold CG . Minimal residual core binding factor AMLs by real time quantitative PCR—initial response to chemotherapy predicts event free survival and close monitoring of peripheral blood unravels the kinetics of relapse. Leuk Res 2006; 30: 389–395.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by the North-West Canceropole (Onco-Hematology Axis) and the Fondation de France (Leukemia Committee).

Author information

Authors and Affiliations

  1. Service des Maladies du Sang, CHRU de Lille, Lille, France

    R Guièze

  2. Inserm, U837, Team 3, Lille, France

    R Guièze, A Renneville, M Cheok & C Preudhomme

  3. University of Lille Nord de France, Lille, France

    R Guièze, A Renneville & C Preudhomme

  4. University of Clermont 1, EA3846, Clermont-Ferrand, France

    R Guièze

  5. CHU de Clermont-Ferrand, Hôtel-Dieu, Service d’Hématologie Clinique Adulte et de Thérapie Cellulaire, Clermont-Ferrand, France

    R Guièze

  6. Institut de Recherche sur le Cancer de Lille, Lille, France

    A Renneville, M Cheok & C Preudhomme

  7. Laboratoire d’Hématologie, CHRU de Lille, Lille, France

    A Renneville & C Preudhomme

  8. Hématologie Biologique, Hôpital Saint-Louis, Université Paris 7, Paris, France

    J-M Cayuela & F Sigaux

  9. Hématologie Biologique, Hôpital Necker, AP-HP, Université Paris Descartes, Paris, France

    R B Abdelali & E A Macintyre

  10. EA 3518, Université de Paris 7,

    N Boissel & H Dombret

  11. Hématologie Adulte, Hôpital Saint-Louis, Paris, France

    N Boissel & H Dombret

  12. Hématologie Clinique, Institut Gustave Roussy, Villejuif, France

    S de Botton

  13. Service d’Hématologie Clinique adultes, Hôpital Necker AP-HP, Université Paris Descartes, Paris, France

    M-T Rubio

  14. Hématologie Pédiatrique, Hôpital Jeanne de Flandres, CHRU de Lille, Lille, France

    F Mazingue

  15. Service d’Hématologie Clinique, Hôpital Avicenne, Université Paris 13, Bobigny, France

    P Fenaux

Authors
  1. R Guièze
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Renneville
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J-M Cayuela
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R B Abdelali
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. N Boissel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S de Botton
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M-T Rubio
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. F Mazingue
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. E A Macintyre
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M Cheok
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. F Sigaux
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. P Fenaux
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. H Dombret
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. C Preudhomme
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C Preudhomme.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Guièze, R., Renneville, A., Cayuela, JM. et al. Prognostic value of minimal residual disease by real-time quantitative PCR in acute myeloid leukemia with CBFB-MYH11 rearrangement: the French experience. Leukemia 24, 1386–1388 (2010). https://doi.org/10.1038/leu.2010.112

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2010.112

This article is cited by

Search

Advanced search

Quick links