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Optimizing Early Prediction Of Outcome In CML Using The Exact Decline Of BCR-ABL Transcript Levels Within 3 Months Of Imatinib Treatment As a Prognostic Marker
Journal article

Optimizing Early Prediction Of Outcome In CML Using The Exact Decline Of BCR-ABL Transcript Levels Within 3 Months Of Imatinib Treatment As a Prognostic Marker

  • Hanfstein, Benjamin III. Medizinische Klinik, Universitätsmedizin Mannheim, Universität Heidelberg, Mannheim, Germany,
  • Shlyakhto, Valeria III. Medizinische Klinik, Universitätsmedizin Mannheim, Universität Heidelberg, Mannheim, Germany,
  • Lauseker, Michael Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Ludwig-Maximilians-Universität, München, Germany,
  • Hehlmann, Rüdiger III. Medizinische Klinik, Universitätsmedizin Mannheim, Universität Heidelberg, Mannheim, Germany,
  • Saussele, Susanne III. Medizinische Klinik, Universitätsmedizin Mannheim, Universität Heidelberg, Mannheim, Germany,
  • Erben, Philipp III. Medizinische Klinik, Universitätsmedizin Mannheim, Universität Heidelberg, Mannheim, Germany,
  • Dietz, Christian III. Medizinische Klinik, Universitätsmedizin Mannheim, Universität Heidelberg, Mannheim, Germany,
  • Fabarius, Alice III. Medizinische Klinik, Universitätsmedizin Mannheim, Universität Heidelberg, Mannheim, Germany,
  • Proetel, Ulrike III. Medizinische Klinik, Universitätsmedizin Mannheim, Universität Heidelberg, Mannheim, Germany,
  • Schnittger, Susanne MLL Münchner Leukämielabor, München, Germany,
  • Krause, Stefan W. Medizinische Klinik 5, Universitätsklinikum, Erlangen, Germany,
  • Schubert, Jörg Klinik für Hämatologie, Onkologie und Palliativmedizin, Evangelische Krankenhaus, Hamm, Germany,
  • Einsele, Hermann Medizinische Klinik und Poliklinik II, Universitätsklinikum, Würzburg, Germany,
  • Hänel, Mathias Klinik für Innere Medizin III, Klinikum, Chemnitz, Germany,
  • Dengler, Jolanta Innere Medizin V, Universitätsklinikum, Heidelberg, Germany,
  • Falge, Christiane Medizinische Klinik 5, Klinikum Nord, Nürnberg, Germany,
  • Kanz, Lothar Innere Medizin II, Universitätsklinikum, Tübingen, Germany,
  • Neubauer, Andreas Klinik für Innere Medizin, Schwerpunkt Hämatologie, Onkologie und Immunologie, Universitätsklinikum, Marburg, Germany,
  • Kneba, Michael II. Medizinische Klinik und Poliklinik im Städtischen Krankenhaus, Universitätsklinikum Schleswig-Holstein, Kiel, Germany,
  • Stegelmann, Frank Klinik für Innere Medizin III, Universitätsklinikum, Ulm, Germany,
  • Pfreundschuh, Michael Klinik für Innere Medizin I, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany,
  • Waller, Cornelius F. Klinik für Innere Medizin I, Universitätsklinikum, Freiburg, Germany,
  • Spiekermann, Karsten Medizinische Klinik und Poliklinik III, Klinikum der Universität, München, Germany,
  • Baerlocher, Gabriela M. Universitätsklinik für Hämatologie und hämatologisches Zentrallabor, Inselspital, Bern, Switzerland,
  • Pfirrmann, Markus Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Ludwig-Maximilians-Universität, München, Germany,
  • Hasford, Joerg Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Ludwig-Maximilians-Universität, München, Germany,
  • Hofmann, Wolf-Karsten III. Medizinische Klinik, Universitätsmedizin Mannheim, Universität Heidelberg, Mannheim, Germany,
  • Hochhaus, Andreas Klinik für Innere Medizin II, Abt. Hämatologie und Intern. Onkologie, Universitätsklinikum, Jena, Germany
  • Müller, Martin C. III. Medizinische Klinik, Universitätsmedizin Mannheim, Universität Heidelberg, Mannheim, Germany,
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Published in:
  • Blood. - American Society of Hematology. - 2013, vol. 122, no. 21, p. 253-253
Immunology
Cell Biology
Biochemistry
Hematology
English Abstract

Introduction
Early assessment of BCR-ABL transcript levels at 3 months allows the prediction of survival and may serve as a trigger for treatment intensification in CML patients with slow response to imatinib. The exact decline of BCR-ABL transcript levels within the first 3 months of treatment is defined by the ratio BCR-ABL transcripts at 3 months to BCR-ABL transcripts at baseline. This ratio might better reflect the individual biology of disease and its susceptibility to tyrosine kinase inhibition.


Methods
A total of 408 chronic phase CML patients (pts) with baseline and 3 month blood samples available in one single laboratory were investigated. Pts with pre-treatment before first blood sampling were excluded (imatinib with or without hydroxyurea, n=58; hydroxyurea only, n=49). A total of 301 evaluable pts (median age 52 years, range 18-85, 41% female) were treated with an imatinib-based therapy within the CML-Study IV. Median follow-up was 4.8 years. Transcript levels of BCR-ABL, total ABL, and beta-glucuronidase (GUS) were determined by quantitative RT-PCR. Exploratory landmark analyses were performed with regard to overall and progression-free survival (OS, PFS) to evaluate the prognostic significance of (i) BCR-ABL/GUS before treatment, (ii) the individual reduction of transcripts given by (BCR-ABL/GUS at 3 months) / (BCR-ABL/GUS before treatment), and (iii) the 3-month 10% BCR-ABLIS landmark.


Results
The median BCR-ABL/GUS ratio was 15.5% at diagnosis (0.06-107) and 0.63% at 3 months (0-84) reflecting a decline to the 0.04-fold (1.4 log reduction).
i) No prognostic cut-off could be identified for BCR-ABL/GUS before treatment.
ii) A reduction to the 0.35-fold of the initial BCR-ABL transcript level at diagnosis (0.46 log reduction) was identified as best cut-off according to a hazard ratio of 5.6 (95%-CI 2.3-13.4, p<0.001 for PFS). Using this cut-off a high-risk group of 48 pts (16% of pts, 5-year PFS and OS: 77% and 83%) was separated from a good-risk group of 253 pts (84% of pts, 5-year PFS and OS: 96% and 98%).
iii) As a comparison we investigated the 10% BCR-ABLIS landmark at 3 months with a hazard ratio of 2.4 (95%-CI 1.0-5.8, p=0.06 for PFS). With this landmark a high-risk group of 67 pts (22% of pts, 5-year PFS and OS: 87% and 90%) was separated from a good-risk group of 234 pts (78% of pts, 5-year PFS and OS: 95% and 97%).


Conclusion
A two-group risk stratification according to the individual reduction of BCR-ABL transcripts to the 0.35-fold of pre-treatment levels yields a superior separation of risk groups with a 5-year difference of 19% for PFS and 15% for OS. This predictive marker might identify patients at risk more precisely than 3-month 10% BCR-ABLIS.


Disclosures:
Hehlmann: BMS: Consultancy, Research Funding; Novartis: Research Funding. Saussele:Novartis: Honoraria, Research Funding, Travel Other; BMS: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding, Travel Other; BMS: Consultancy, Honoraria, Research Funding; ARIAD: Consultancy, Honoraria; Pfizer: Consultancy. Müller:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.ch/global/documents/9730
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