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Acute Leukemias

Prevalence and dynamics of bcr-abl kinase domain mutations during imatinib treatment differ in patients with newly diagnosed and recurrent bcr-abl positive acute lymphoblastic leukemia

Leukemia volume 26, pages 1475–1481 (2012)Cite this article

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Abstract

Imatinib is highly effective in newly diagnosed, but not in relapsed, Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). BCR-ABL tyrosine kinase domain (TKD) mutations are associated with acquired imatinib resistance, but their role in primary resistance is uncertain. Using highly sensitive ligation-PCR and denaturing high-performance liquid chromatography (DHPLC), we identified baseline TKD mutations in 21% and 42% of imatinib-naïve patients with newly diagnosed (n=26) or recurrent (n=65) Ph+ ALL, respectively (P=ns). Within 4 weeks of starting the imatinib treatment, absolute levels of mutant bcr-abl transcripts increased significantly in patients with advanced, but not with de novo, Ph+ ALL. The net expansion of pre-existing mutant clones during imatinib treatment resulted in the rapid appearance of initially undetectable TKD mutations, which after 4 weeks were detectable in 70% of patients with advanced disease. There was a high degree of concordance between the type of mutations detected at relapse and during initial imatinib treatment. The profoundly different outgrowth dynamics of leukemic clones with bcr-abl mutations in imatinib-treated patients who differ in their disease history, provides clinical–translational evidence for a contributory role of non-mutational resistance mechanisms, possibly induced by prior chemotherapy. Moreover, the prevalence of pre-existing, clinically relevant TKD may have been underestimated in tyrosine kinase inhibitor-naïve patients with Ph+ ALL.

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Acknowledgements

We thank Doreen Badowski, Brigitte Gehrke, Tamara Klan and Sandra Markovic for excellent technical assistance.

Supported by grants from the Deutsche Jose Carreras Leukämiestiftung (R06/25v), BMBF Competence Network ‘Acute Leukemias’ Grant No. 01G19971, the German Genome Research Network (NGFN), the Wilhelm Sander Stiftung and the Adolf-Messer Foundation, Germany, and from Novartis Pharma AG, Nürnberg, Germany.

Author contributions

HP designed the study, performed experiments, analyzed data and wrote the manuscript. BW conducted the clinical study, analyzed data and wrote the manuscript. AS, SW, JM and TL performed experiments and analyzed data. AB conducted the clinical study and analyzed data. AG, MS, MS, UD, PB, LW and HS enrolled and treated patients. DH designed the study and wrote the manuscript. OGO designed the study, conducted the clinical trial, analyzed data and wrote the manuscript.

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Authors and Affiliations

  1. Department of Medicine, Hematology/Oncology, Goethe University, Frankfurt, Germany

    H Pfeifer, S Wystub, B Wassmann, A Binckebanck, L Wunderle, H Serve, P Brück, A Schmidt, D Hoelzer & O G Ottmann

  2. Department of Hematology and Oncology, Center for Internal Medicine, University of Leipzig, Leipzig, Germany

    T Lange & J Maier

  3. Department of Medicine, St. Johannes Hospital, Duisburg, Germany

    A Giagounidis

  4. Department of Hematology and Oncology, University of Münster, Münster, Germany

    M Stelljes

  5. Department of Hematology and Oncology, Eberhardt-Karls University, Tübingen, Germany

    M Schmalzing

  6. Department of Hematology and Oncology, Center for Internal Medicine, University of Essen, Essen, Germany

    U Dührsen

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  1. H Pfeifer
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Correspondence to O G Ottmann.

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Competing interests

OG Ottmann received research support and honoraria for advisory board activities and scientific presentations from Novartis and Bristol-Myers-Squibb. The remaining authors declare no conflict of interest.

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Pfeifer, H., Lange, T., Wystub, S. et al. Prevalence and dynamics of bcr-abl kinase domain mutations during imatinib treatment differ in patients with newly diagnosed and recurrent bcr-abl positive acute lymphoblastic leukemia. Leukemia 26, 1475–1481 (2012). https://doi.org/10.1038/leu.2012.5

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