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Equivalence of BCR-ABL transcript levels with complete cytogenetic remission in patients with chronic myeloid leukemia in chronic phase

  • Original Article – Clinical Oncology
  • Published:
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Abstract

Purpose

Chronic myeloid leukemia (CML) patients are monitored by both cytogenetic and molecular assessments, although present guidelines appear to switch from cytogenetic to molecular criteria. Due to the increasing use of molecular measurements, it was the aim of this work to identify a BCR-ABL level according to the international scale (BCR-ABLIS) as an equivalent substitute for complete cytogenetic remission (CCyR).

Methods

In total, 1,329 paired data from 557 patients of the German CML-Study IV were evaluated. The data set was divided into a learning set and a validation set. The best cutoff was determined applying a minimal p value approach to the Fisher test.

Results

In the learning set, we found BCR-ABLIS values between 0.2 and 1.1 % were well suited for predicting a CCyR. In the validation set, the cutoff level of 1 % led to a mean concordance rate of 90.1 %.

Conclusions

Our results suggest that there is no one-to-one cutoff for BCR-ABLIS representing CCyR, but we advise to use the 1 % BCR-ABLIS in order to avoid misclassification of CCyR patients.

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References

  • Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, Cervantes F, Clark RE, Cortes JE, Guilhot F, Hjorth-Hansen H, Hughes TP, Kantarjian HM, Kim D-W, Larson RA, Lipton JH, Mahon FX, Martinelli G, Mayer J, Müller MC, Niederwieser D, Pane F, Radich JP, Rousselot P, Saglio G, Saußele S, Schiffer C, Silver R, Simonsson B, Steegmann J-L, Goldman JM, Hehlmann R (2013) European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 122(6):872–884

    Article  PubMed  CAS  Google Scholar 

  • Cross NCP, White HE, Müller MC, Saglio G, Hochhaus A (2012) Standardized definitions of molecular response in chronic myeloid leukemia. Leukemia 26(10):2172–2175

    Article  PubMed  CAS  Google Scholar 

  • Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N, Deininger MWN, Silver RT, Goldman JM, Stone RM, Cervantes F, Hochhaus A, Powell BL, Gabrilove JL, Rousselot P, Reiffers J, Cornelissen JJ, Hughes T, Agis H, Fischer T, Verhoef G, Shepherd J, Saglio G, Gratwohl A, Nielsen JL, Radich JP, Simonsson B, Taylor K, Baccarani M, So C, Letvak L, Larson RA (2006) Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355(23):2408–2417

    Article  PubMed  CAS  Google Scholar 

  • Hanfstein B, Müller MC, Hehlmann R, Erben P, Lauseker M, Fabarius A, Schnittger S, Haferlach C, Gohring G, Proetel U, Kolb HJ, Krause SW, Hofmann WK, Schubert J, Einsele H, Dengler J, Hanel M, Falge C, Kanz L, Neubauer A, Kneba M, Stegelmann F, Pfreundschuh M, Waller CF, Branford S, Hughes TP, Spiekermann K, Baerlocher GM, Pfirrmann M, Hasford J, Sausele S, Hochhaus A (2012) Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML). Leukemia 26(9):2096–2102

    Article  PubMed  CAS  Google Scholar 

  • Hehlmann R, Lauseker M, Jung-Munkwitz S, Leitner A, Müller MC, Pletsch N, Proetel U, Haferlach C, Schlegelberger B, Balleisen L, Hänel M, Pfirrmann M, Krause SW, Nerl C, Pralle H, Gratwohl A, Hossfeld DK, Hasford J, Hochhaus A, Saußele S (2011) Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-alpha in newly diagnosed chronic myeloid leukemia. J Clin Oncol 29(12):1634–1642

    Article  PubMed  CAS  Google Scholar 

  • Hehlmann R, Müller MC, Lauseker M, Hanfstein B, Fabarius A, Schreiber A, Proetel U, Pletsch N, Pfirrmann M, Haferlach C, Schnittger S, Einsele H, Dengler J, Falge C, Kanz L, Neubauer A, Kneba M, Stegelmann F, Pfreundschuh M, Waller CF, Spiekermann K, Baerlocher GM, Ehninger G, Heim D, Heimpel H, Nerl C, Krause SW, Hossfeld DK, Kolb HJ, Hasford J, Saußele S, Hochhaus A, Group ftSatGC-S (2013) Deep molecular response (MR4.5) is reached by the majority of patients treated with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: results from the randomized CML-Study IV. J Clin Oncol 32(5):415–423

  • Hochhaus A, Lin F, Reiter A, Skladny H, Mason PJ, van Rhee F, Shepherd PC, Allan NC, Hehlmann R, Goldman JM, Cross NC (1996) Quantification of residual disease in chronic myelogenous leukemia patients on interferon-alpha therapy by competitive polymerase chain reaction. Blood 87(4):1549–1555

    PubMed  CAS  Google Scholar 

  • Hochhaus A, Reiter A, Reichert A, Saussele S, Emig M, Kaeda J, Schultheis B, Berger U, Shepherd PCA, Allan NC, Hehlmann R, Goldman JM, Cross NCP (2000) 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 95(1):62–66

    PubMed  CAS  Google Scholar 

  • Hochhaus A, Hughes TP, Saglio G, Guilhot F, Al-Ali HK, Rosti G, Nakaseko C, De Souza CA, Kemp C, Fan X, Hoenekopp A, Larson RA, Kantarjian HM (2012) Outcome of patients with chronic myeloid leukemia in chronic phase (CML-CP) based on early molecular response and factors associated with early response: 4-year follow-up data from ENESTND (Evaluating Nilotinib Efficacy and Safety in Clinical Trials Newly Diagnosed Patients) [abstract]. Blood 120(21):Abstract 167

  • Hook EB (1977) Exclusion of chromosomal mosaicism: tables of 90%, 95% and 99% confidence limits and comments on use. Am J Hum Genet 29(1):94–97

    PubMed  CAS  PubMed Central  Google Scholar 

  • Hughes TP, Branford S (2009) Monitoring disease response to tyrosine kinase inhibitor therapy in CML. ASH Educ Program Book 1:477–487

    Google Scholar 

  • Hughes TP, Hochhaus A, Branford S, Müller MC, Kaeda JS, Foroni L, Druker BJ, FO Guilhot, Larson RA, O’Brien SG, Rudoltz MS, Mone M, Wehrle E, Modur V, Goldman JM, Radich JP, on behalf of the Ii (2010) Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS). Blood 116(19):3758–3765

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Jabbour E, Kantarjian H, O’Brien S, Shan J, Quintas-Cardama A, Faderl S, Garcia-Manero G, Ravandi F, Rios MB, Cortes J (2011) The achievement of an early complete cytogenetic response is a major determinant for outcome in patients with early chronic phase chronic myeloid leukemia treated with tyrosine kinase inhibitors. Blood 118(17):4541–4546

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Marin D, Ibrahim AR, Lucas C, Gerrard G, Wang L, Szydlo RM, Clark RE, Apperley JF, Milojkovic D, Bua M, Pavlu J, Paliompeis C, Reid A, Rezvani K, Goldman JM, Foroni L (2012) Assessment of BCR-ABL1 transcript levels at 3 months is the only requirement for predicting outcome for patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. J Clin Oncol 30(3):232–238

    Article  PubMed  CAS  Google Scholar 

  • Müller MC, Cross NCP, Erben P, Schenk T, Hanfstein B, Ernst T, Hehlmann R, Branford S, Saglio G, Hochhaus A (2009) Harmonization of molecular monitoring of CML therapy in Europe. Leukemia 23(11):1957–1963

    Article  PubMed  Google Scholar 

  • Saglio G, Kantarjian HM, Shah N, Jabbour EJ, Quintas-Cardama A, Steegmann JL, Boque C, Chuah C, Pavlovsky C, Mayer J, Ukropec J, Wildgust M, Hochhaus A (2012) Early response (molecular and cytogenetic) and long-term outcomes in newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): exploratory analysis of DASISION 3-year data [abstract]. Blood 120(21):Abstract 1675

  • Silverman BW (1986) Density estimation for statistics and data analysis. Chapman and Hall, London

    Book  Google Scholar 

  • Simon J (1997) Resampling: the new statistics, 2nd edn. Wadsworth, Boston

    Google Scholar 

Download references

Conflict of interest

The CML-Study IV is supported by the Deutsche Krebshilfe (Grant Nos. 106642 and 109588), Novartis, Nürnberg, Germany, Kompetenznetz für Akute and Chronische Leukämien (BMBF 01GI0270), José-Carreras Leukämiestiftung (DJCLS H09/01f, H06/04v,H03/01, R05/23), and the European LeukemiaNet (LSHC-CT-2004-503216). No direct payments to authors were done. C.H.: MLL Munich Leukemia Laboratory: Equity Ownership. S.S.C.: MLL Munich Leukemia Laboratory: Equity Ownership. A.H.: Novartis, BMS, MSD, Ariad, Pfizer: Consultancy, Honoraria, Research Funding. M.C.M.: Novartis, BMS, Ariad: Consultancy, Honoraria, Research Funding.

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Authors and Affiliations

  1. Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Ludwig-Maximilians-Universität, Munich, Germany

    Michael Lauseker, Markus Pfirrmann & Joerg Hasford

  2. III. Medizinische Universitätsklinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Pettenkoferstr. 22, 68169, Mannheim, Germany

    Benjamin Hanfstein, Alice Fabarius, Susanne Saußele, Christian T. Dietz, Philipp Erben, Rüdiger Hehlmann & Martin C. Müller

  3. MLL Münchner Leukämielabor, Munich, Germany

    Claudia Haferlach & Susanne Schnittger

  4. Institut für Zell- und Molekularpathologie, Medizinische Hochschule Hannover, Hannover, Germany

    Brigitte Schlegelberger

  5. Abteilung für Hämatologie/Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany

    Andreas Hochhaus

Authors
  1. Michael Lauseker
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  2. Benjamin Hanfstein
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  3. Claudia Haferlach
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  4. Susanne Schnittger
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  5. Markus Pfirrmann
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  6. Alice Fabarius
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  7. Brigitte Schlegelberger
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  8. Susanne Saußele
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  9. Christian T. Dietz
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  10. Philipp Erben
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  11. Rüdiger Hehlmann
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  12. Joerg Hasford
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  13. Andreas Hochhaus
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  14. Martin C. Müller
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Corresponding author

Correspondence to Martin C. Müller.

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Lauseker, M., Hanfstein, B., Haferlach, C. et al. Equivalence of BCR-ABL transcript levels with complete cytogenetic remission in patients with chronic myeloid leukemia in chronic phase. J Cancer Res Clin Oncol 140, 1965–1969 (2014). https://doi.org/10.1007/s00432-014-1746-8

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  • DOI: https://doi.org/10.1007/s00432-014-1746-8

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