Skip to main content

Thank you for visiting 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.

Harmonization of molecular monitoring of CML therapy in Europe


The high efficacy of the standard treatment of chronic myeloid leukemia (CML) with imatinib has prompted the need for accurate methods to monitor response at levels below the landmark of complete cytogenetic remission. Quantification of BCR–ABL transcripts has proven to be the most sensitive method available, and has shown prognostic impact with regard to progression-free survival. Until recently, variations in methods used to quantify BCR–ABL made it difficult to compare results between laboratories. An international program is now underway to harmonize the reporting of results according to an international scale (IS). In this review, we consider the background to the IS and the progress that has been made to date, with a particular focus on ongoing harmonization efforts in Europe. We provide recommendations for the propagation of the IS by national or regional laboratory networks.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4


  1. Daley GQ, Van Etten RA, Baltimore D . Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 1990; 247: 824–830.

    CAS  Article  Google Scholar 

  2. Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996; 2: 561–566.

    CAS  Article  Google Scholar 

  3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology Chronic Myelogenous Leukemia, v.2.2010. (Last accessed 14 August 2009).

  4. Baccarani M, Saglio G, Goldman J, Hochhaus A, Simonsson B, Appelbaum F et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2006; 108: 1809–1820.

    CAS  Article  Google Scholar 

  5. Hughes T, Deininger M, Hochhaus A, Branford S, Radich J, Kaeda J et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 2006; 108: 28–37.

    CAS  Article  Google Scholar 

  6. Hughes T . ABL kinase inhibitor therapy for CML: baseline assessments and response monitoring. Hematology Am Soc Hematol Educ Program 2006, 211–218.

  7. Weisberg E, Manley PW, Breitenstein W, Bruggen J, Cowan-Jacob SW, Ray A et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 2005; 7: 129–141.

    CAS  Article  Google Scholar 

  8. Kantarjian HM, Giles F, Bhalla KN, Larson RA, Gattermann N, Ottmann OG et al. Nilotinib in chronic myeloid leukemia patients in chronic phase with imatinib resistance or intolerance: 2-year follow-up results of a phase 2 study. Blood 2008; 112, Abstract 3238.

  9. Cortes J, O’Brien S, Jones D, Ferrajoli A, Konopleva M, Borthakur G et al. Efficacy of nilotinib (formerly AMN107) in patients with newly diagnosed, previously untreated Philadelphia chromosome-positive chronic myelogenous leukemia in early chronic phase. Blood 2008; 112, abstract 446.

  10. Rosti G, Castagnetti F, Poerio A, Breccia M, Levato L, Capucci A et al. High and early rates of cytogenetic and molecular response with nilotinib 800 mg daily as first line treatment of Ph-positive chronic myeloid leukemia in chronic phase: results of a phase 2 trial of the GIMEMA CML working party. Blood 2008; 112, abstract 181.

  11. Baccarani M, Rosti G, Saglio G, Cortes J, Stone R, Niederwieser W et al. Dasatinib time to and durability of major and complete cytogenetic response in patients with chronic myeloid leukemia in chronic phase. Blood 2008; 112, abstract 450.

  12. Cortes J, O’Brien S, Borthakur G, Jones D, Ravandi F, Koller C et al. Efficacy of dasatanib in patients with previously untreated chronic myelogenous leukemia in early chronic phase. Blood 2008; 112, abstract 182.

  13. Hochhaus A, Müller MC, Radich J, Branford S, Hanfstein B, Rousselot P et al. Dasatinib-associated major molecular responses are rapidly achieved in patients with chronic myeloid leukemia in chronic phase following resistance, suboptimal response or intolerance on imatinib. Blood 2008; 112, abstract 1095.

  14. Branford S, Fletcher L, Cross NCP, Müller MC, Hochhaus A, Kim DW et al. Desirable performance characteristics for BCR-ABL measurement on an international reporting scale to allow consistent interpretation of individual patient response and comparison of response rates between clinical trials. Blood 2008; 112: 3330–3338.

    CAS  Article  Google Scholar 

  15. Hughes TP, Kaeda J, Branford S, Rudzki Z, Hochhaus A, Hensley ML et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 2003; 349: 1423–1432.

    CAS  Article  Google Scholar 

  16. Hughes TP, Hochhaus A, Branford S, Müller MC, Foroni L, Druker BJ et al. Reduction of BCR-ABL transcript levels at 6, 12, and 18 months correlates with long-term outcomes on imatinib at 72 mo: an analysis from the International Randomized Study of Interferon versus STI571 (IRIS) in patients with chronic phase chronic myeloid leukemia. Blood 2008; 112, abstract 334.

  17. Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006; 355: 2408–2417.

    CAS  Article  Google Scholar 

  18. Cortes J, Talpaz M, O’Brien S, Jones D, Luthra R, Shan J et al. Molecular responses in patients with chronic myelogenous leukemia in chronic phase treated with imatinib mesylate. Clin Cancer Res 2005; 11: 3425–3432.

    CAS  Article  Google Scholar 

  19. Hochhaus A, Reiter A, Saußele S, Reichert A, Emig M, Kaeda J et al. Molecular heterogeneity in complete cytogenetic responders after interferon-alpha therapy for chronic myelogenous leukemia: low levels of minimal residual disease are associated with continuing remission. Blood 2000; 95: 62–66.

    CAS  PubMed  Google Scholar 

  20. van Dongen JJ, Macintyre EA, Gabert JA, Delabesse E, Rossi V, Saglio G et al. Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Report of the BIOMED-1 Concerted Action: investigation of minimal residual disease in acute leukemia. Leukemia 1999; 13: 1901–1928.

    CAS  Article  Google Scholar 

  21. Müller MC, Saglio G, Lin F, Pfeifer H, Press RD, Tubbs RR et al. An international study to standardize the detection and quantitation of BCR-ABL transcripts from stabilized peripheral blood preparations by quantitative RT-PCR. Haematologica 2007; 92: 970–973.

    Article  Google Scholar 

  22. Zhang T, Grenier S, Nwachukwu B, Wei C, Lipton JH, Kamel-Reid S . Inter-laboratory comparison of chronic myeloid leukemia minimal residual disease monitoring: summary and recommendations. J Mol Diagn 2007; 9: 421–430.

    Article  Google Scholar 

  23. Müller MC, Erben P, Saglio G, Gottardi E, Nyvold CG, Schenk T et al. Harmonization of BCR-ABL mRNA quantification using a uniform multifunctional control plasmid in 37 international laboratories. Leukemia 2008; 22: 96–102.

    Article  Google Scholar 

  24. Saldanha J, Silvy M, Beaufils N, Arlinghaus R, Barbany G, Branford S et al. Characterization of a reference material for BCR-ABL (M-BCR) mRNA quantitation by real-time amplification assays: towards new standards for gene expression measurements. Leukemia 2007; 21: 1481–1487.

    CAS  Article  Google Scholar 

  25. Branford S, Cross NCP, Hochhaus A, Radich J, Saglio G, Kaeda J et al. Rationale for the recommendations for harmonizing current methodology for detecting BCR-ABL transcripts in patients with chronic myeloid leukaemia. Leukemia 2006; 20: 1925–1930.

    CAS  Article  Google Scholar 

  26. Krower J, Tholen D, Garber G, Goldschmidt H, Kroll M, Linnet K et al. Method Comparison and Bias Estimation Using Patient Samples: Approved Guideline Second-Edition (EP9-A2). The National Committee for Clinical Laboratory Standards: Wayne, PA, 22: 2002.

    Google Scholar 

  27. Emig M, Saussele S, Wittor H, Weisser A, Reiter A, Willer A et al. Accurate and rapid analysis of residual disease in patients with CML using specific fluorescent hybridization probes for real time quantitative RT-PCR. Leukemia 1999; 13: 1825–1832.

    CAS  Article  Google Scholar 

  28. Bland JM, Altman DG . Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986; 1: 307–310.

    CAS  Article  Google Scholar 

  29. Bland JM, Altman DG . Measuring agreement in method comparison studies. Stat Methods Med Res 1999; 8: 135–160.

    CAS  Article  Google Scholar 

  30. 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.

    CAS  Article  Google Scholar 

Download references


This work was supported by the European LeukemiaNet, sponsored by the European Union, Sixth Framework Programme, contact no. LSHC-CT-2004-503216 (European LeukemiaNet) and Novartis Pharmaceuticals as part of the EUTOS for CML collaboration, and the German José-Carreras-Foundation (AH, DJCLS H 03/01).

Author information

Authors and Affiliations


Corresponding author

Correspondence to A Hochhaus.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Müller, M., Cross, N., Erben, P. et al. Harmonization of molecular monitoring of CML therapy in Europe. Leukemia 23, 1957–1963 (2009).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • chronic myeloid leukemia
  • molecular monitoring
  • international scale
  • conversion factor
  • EUTOS for CML

Further reading


Quick links