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Molecular monitoring

    Martin C Müller

    Martin C Müller is Professor and Specialist in Internal Medicine and Hematology/Oncology at the University Hospital of Mannheim, Heidelberg University, Germany. Having research interests in mechanisms of response and resistance to therapy as well as the monitoring of residual disease in chronic myeloid leukemia, he has been the author/coauthor of more than 70 peer-reviewed publications. He is responsible for the outpatient care of chronic myeloid leukemia patients and is Head of the Molecular Laboratory.

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    ,
    Christian Dietz

    Christian Dietz received his PhD degree in biology from the Heidelberg University in 2011. He started as Project Manager in the Clinical Trial Center at the Department of Hematology and Oncology at the University Medical Center Mannheim, Heidelberg University. Furthermore, he is the responsible Laboratory Manager and Quality Management Officer in the Molecular Laboratory at Heidelberg University.

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    Benjamin Hanfstein

    Benjamin Hanfstein is Investigator of numerous clinical trials at the Chronic Myeloid Leukemia Center, University Hospital of Mannheim, Heidelberg University. Responsible for molecular monitoring of patients on tyrosine kinase inhibitor treatment, he gathered outstanding experience in PCR methods and mutational analysis. His vivid research interest is focused on genetic markers and their kinetics for early identification of treatment failures.

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    Published Online:22 Jul 2013https://doi.org/10.2217/ebo.13.179
    Abstract:

    The introduction of tyrosine kinase inhibitors as standard treatment of chronic myeloid leukemia was paralleled by the establishment of molecular diagnostics to routinely assess the activity of disease. The quantitative measurement of the BCR-ABL oncogene levels allows the exact determination of the individual treatment response, which correlates with prognosis and makes chronic myeloid leukemia a disease that is manageable like few others. PCR diagnostics can be performed from blood samples and surpass the sensitivity of conventional cytogenetics, which is of particular importance since the majority of patients today achieve very deep responses. In case of resistance, the detection of BCR-ABL mutations has become the major tool to guide second-line tyrosine kinase inhibitor treatment.

    References

    • 1  Hehlmann R , Hochhaus A , Baccarani M . Chronic myeloid leukaemia . Lancet 370 (9584) , 342 – 350 (2007) .
      Medline CASGoogle Scholar
    • 2  Cross NC , Melo JV , Feng L , Goldman JM . An optimized multiplex polymerase chain reaction (PCR) for detection of BCR-ABL fusion mRNAs in haematological disorders . Leukemia 8 (1) , 186 – 189 (1994) .
      Medline CASGoogle Scholar
    • 3  Deininger MW , Goldman JM , Melo JV . The molecular biology of chronic myeloid leukemia . Blood 96 (10) , 3343 – 3356 (2000) .
      Medline CASGoogle Scholar
    • 4  Hochhaus A , Reiter A , Skladny H et al. A novel BCR-ABL fusion gene (e6a2) in a patient with Philadelphia chromosome-negative chronic myelogenous leukemia . Blood 88 (6) , 2236 – 2240 (1996) .
      Medline CASGoogle Scholar
    • 5  Cross NC , White HE , Müller MC , Saglio G , Hochhaus A . Standardized definitions of molecular response in chronic myeloid leukemia . Leukemia 26 (10) , 2172 – 2175 (2012) .
      Medline CASGoogle Scholar
    • 6  Emig M , Saussele S , Wittor H 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 13 (11) , 1825 – 1832 (1999) .
      Medline CASGoogle Scholar
    • 7  Branford S , Rudzki Z , Harper A et al. Imatinib produces significantly superior molecular responses compared to interferon alfa plus cytarabine in patients with newly diagnosed chronic myeloid leukemia in chronic phase . Leukemia 17 (12) , 2401 – 2409 (2003) .
      Medline CASGoogle Scholar
    • 8  Baccarani M , Cortes J , Pane F et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet . J. Clin. Oncol. 27 (35) , 6041 – 6051 (2009) .
      Medline CASGoogle Scholar
    • 9  Sobrinho-Simoes M , Wilczek V , Score J , Cross NC , Apperley JF , Melo JV . In search of the original leukemic clone in chronic myeloid leukemia patients in complete molecular remission after stem cell transplantation or imatinib . Blood 116 (8) , 1329 – 1335 (2010) .
      Medline CASGoogle Scholar
    • 10  Kiss TL , Xu WM , Jamal N , Messner HA . Comparative testing of peripheral blood and bone marrow for BCR-ABL transcripts in patients post allogeneic bone marrow transplantation and during interferon treatment for chronic myeloid leukemia . Leuk. Lymphoma 34 (5–6) , 493 – 500 (1999) .
      Medline CASGoogle Scholar
    • 11  Thorn I , Olsson-Stromberg U , Ohlsen C et al. The impact of RNA stabilization on minimal residual disease assessment in chronic myeloid leukemia . Haematologica 90 (11) , 1471 – 1476 (2005) .
      MedlineGoogle Scholar
    • 12  Müller MC , Hordt T , Paschka P et al. Standardization of preanalytical factors for minimal residual disease analysis in chronic myelogenous leukemia . Acta Haematol. 112 (1–2) , 30 – 33 (2004) .
      MedlineGoogle Scholar
    • 13  Beillard E , Pallisgaard N , Van Der Velden VH et al. Evaluation of candidate control genes for diagnosis and residual disease detection in leukemic patients using ‘real-time’ quantitative reverse-transcriptase polymerase chain reaction (RQ-PCR) – a Europe against cancer program . Leukemia 17 (12) , 2474 – 2486 (2003) .
      Medline CASGoogle Scholar
    • 14  Hughes TP , Kaeda J , Branford S et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia . N. Engl. J. Med. 349 (15) , 1423 – 1432 (2003) .
      Medline CASGoogle Scholar
    • 15  Hughes T , Deininger M , Hochhaus A 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 108 (1) , 28 – 37 (2006) .
      Medline CASGoogle Scholar
    • 16  Branford S , Fletcher L , Cross NC 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 112 (8) , 3330 – 3338 (2008) .
      Medline CASGoogle Scholar
    • 17  Müller MC , Cross NC , Erben P et al. Harmonization of molecular monitoring of CML therapy in Europe . Leukemia 23 (11) , 1957 – 1963 (2009) .
      Medline CASGoogle Scholar
    • 18  White HE , Matejtschuk P , Rigsby P et al. Establishment of the first World Health Organization International Genetic Reference Panel for quantitation of BCR-ABL mRNA . Blood 116 (22) , e111 – e117 (2010) .
      Medline CASGoogle Scholar
    • 19  Müller MC , Munjal U , Erben P et al. Stability of conversion factors for BCR-ABL monitoring – implications for the frequency of validation rounds . Blood 116 (21) , 893 (2010) .
      MedlineGoogle Scholar
    • 20  Hughes TP , Hochhaus A , Branford S et al. 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 (2010) .
      Medline CASGoogle Scholar
    • 21  Hehlmann R , Lauseker M , Jung-Munkwitz S et al. 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 (2011) .
      Medline CASGoogle Scholar
    • 22  Hanfstein B , Müller MC , Hehlmann R et al. 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 (2012) .
      Medline CASGoogle Scholar
    • 23  Marin D , Ibrahim AR , Lucas C et al. 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 (2012) .
      Medline CASGoogle Scholar
    • 24  Hochhaus A , Boqué C , Bradley-Garelik MB . Molecular response kinetics and BCR-ABL reduction in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) receiving dasatinib vs imatinib: DASISION 3-year follow-up . Haematologica 97 (Suppl. 1) , Abstract 0192 (2012) .
      Google Scholar
    • 25  Hochhaus A , Guilhot F , Al-Ali K , Rosti G . Early BCR-ABL transcript levels predict future molecular response and long-term outcomes in newly-diagnosed patients with chronic myeloid leukemia in chronic phase: analysis of ENESTnd 3-year data . Haematologica 97 (Suppl. 1) , Abstract 0584 (2012) .
      Google Scholar
    • 26  Mahon FX , Rea D , Guilhot J et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial . Lancet Oncol. 11 (11) , 1029 – 1035 (2010) .
      Medline CASGoogle Scholar
    • 27  Hochhaus A , La Rosee P , Müller MC , Ernst T , Cross NC . Impact of BCR-ABL mutations on patients with chronic myeloid leukemia . Cell Cycle 10 (2) , 250 – 260 (2011) .
      Medline CASGoogle Scholar
    • 28  Branford S , Rudzki Z , Parkinson I et al. Real-time quantitative PCR analysis can be used as a primary screen to identify patients with CML treated with imatinib who have BCR-ABL kinase domain mutations . Blood 104 (9) , 2926 – 2932 (2004) .
      Medline CASGoogle Scholar
    • 29  Press RD , Willis SG , Laudadio J , Mauro MJ , Deininger MW . Determining the rise in BCR-ABL RNA that optimally predicts a kinase domain mutation in patients with chronic myeloid leukemia on imatinib . Blood 114 (13) , 2598 – 2605 (2009) .
      Medline CASGoogle Scholar
    • 30  Soverini S , Hochhaus A ,
      Nicolini FE
      et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet . Blood 118 (5) , 1208 – 1215 (2011) .
      Medline CASGoogle Scholar
    • 31  Parker WT , Lawrence RM , Ho M et al. Sensitive detection of BCR-ABL1 mutations in patients with chronic myeloid leukemia after imatinib resistance is predictive of outcome during subsequent therapy . J. Clin. Oncol. 29 (32) , 4250 – 4259 (2011) .
      Medline CASGoogle Scholar