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Acute Leukemias

High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses

Leukemia volume 26, pages 2353–2359 (2012)Cite this article

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Abstract

Preliminary evidence suggests that the multikinase inhibitor sorafenib has clinical activity in FLT3-ITD-positive (FLT3-ITD) acute myeloid leukemia (AML). However, the quality and sustainability of achievable remissions and clinical variables that influence the outcome of sorafenib monotherapy are largely undefined. To address these questions, we evaluated sorafenib monotherapy in 65 FLT3-ITD AML patients treated at 23 centers. All but two patients had relapsed or were chemotherapy-refractory after a median of three prior chemotherapy cycles. Twenty-nine patients (45%) had undergone prior allogeneic stem cell transplantation (allo-SCT). The documented best responses were: hematological remission in 24 patients (37%), bone marrow remission in 5 patients (8%), complete remission (with and without normalization of peripheral blood counts) in 15 patients (23%) and molecular remission with undetectable FLT3-ITD mRNA in 10 patients (15%), respectively. Seventeen of the patients without prior allo-SCT (47%) developed sorafenib resistance after a median treatment duration of 136 days (range, 56–270 days). In contrast, allo-SCT patients developed sorafenib resistance less frequently (38%) and significantly later (197 days, range 38–225 days; P=0.03). Sustained remissions were seen exclusively in the allo-SCT cohort. Thus, sorafenib monotherapy has significant activity in FLT3-ITD AML and may synergize with allogeneic immune effects to induce durable remissions.

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Acknowledgements

We are particularly thankful to Michael Lübbert for critically reading the manuscript and Thomas Pabst, Kristina Siegloch, Julian Sprague for contributing their patients. This work was supported by the Deutsche Forschungsgemeinschaft (DFG) Klinische Forschergruppe KFO210 TP1 (to AB) and TP3 (to AN), the Transregio SFB 17 (to AB und AN), the Behring Röntgen Foundation TP51-0057 (to AB) by a research grant of the University Medical Center Gießen and Marburg TP 24/2010 (to AB), the LOEWE-consortium ‘Tumor and Inflammation’ (to AB and AN) and the German Carreras Leukemia Foundation AH 06-01 and AR 08-05v (to AN) and R 11-03 (to SS).

SKM treated the patients, performed the research, analyzed the data, compiled the figures and helped in writing the paper. All co-investigators treated patients, collected and provided clinical data. AB treated patients, designed and coordinated the research, analyzed the data and wrote the paper. AN coordinated the research and discussed the data. All authors critically reviewed and edited the manuscript.

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Authors and Affiliations

  1. Philipps Universität Marburg, Universitätsklinikum Gießen und Marburg, Standort Marburg, Klinik für Hämatologie, Onkologie und Immunologie, Marburg, Germany

    S K Metzelder, A Neubauer & A Burchert

  2. Department of Hematology, Oncology and Clinical Immunology, Medical Faculty, University of Duesseldorf, Duesseldorf, Germany

    T Schroeder

  3. Department of Hematology/Oncology, University of Freiburg, Freiburg, Germany

    A Finck

  4. Abteilung für Hämatologie/Onkologie, Universitätsklinikum Jena, Jena, Germany

    S Scholl

  5. Department of Medical Oncology, Inselspital and University of Bern, Bern, Switzerland

    M Fey

  6. Department of Internal Medicine III, Technische Univerisität München, München, Germany

    K Götze

  7. Department of Hematology, Singapore General Hospital, Singapore, Singapore

    Y C Linn

  8. Onkologische Schwerpunktpraxis Bremerhaven, Bremerhaven, Germany

    M Kröger

  9. Universitätsmedizin Mannheim, III. Medizinische Klinik, Mannheim, Germany

    A Reiter

  10. Department of Hematology/Oncology, Eberhard Karls-University Tübingen, Tübingen, Germany

    H R Salih

  11. Otto-von-Guericke-Universität Magdeburg, Klinik für Hämatologie/Onkologie, Magdeburg, Germany

    T Heinicke

  12. Abteilung für Hämatologie, Asklepios Klinik St. Georg, Onkologie und Stammzelltransplantation, Hamburg, Germany

    R Stuhlmann

  13. Onkologische Schwerpunktpraxis Leer-Emden, Leer-Emden, Germany

    L Müller

  14. St Johannes Hospital, Medizinische Klinik 2, Duisburg, Germany

    A Giagounidis

  15. Department of Hematology, Oncology, and Pneumology, University Medical Center Mainz, Mainz, Germany

    R G Meyer

  16. Schwarzwald-Baar Klinikum, Klinik für Hämatologie/Onkologie, Villingen-Schwenningen, Germany

    W Brugger

  17. Abteilung für Hämatologie, Robert-Bosch-Krankenhaus, Onkologie und Klinische Immunologie, Stuttgart, Germany

    M Vöhringer

  18. Department of Medicine, University of Heidelberg, Heidelberg, Germany

    P Dreger

  19. Department of Hematology and Oncology, University of Vermont, Burlington, VT, USA

    M Mori

  20. Department of Palliative Medicine, Seirei Hamamatsu General Hospital, Shizuoka, Japan

    M Mori

  21. Department of Hematology, Oncology and Hemostaseology, University Clinical Center, Leipzig, Germany

    N Basara

  22. Klinikum Nürnberg, Medizinische Klinik 5, Medizinische Onkologie, Hämatologie und Stammzelltransplantation, Nürnberg, Germany

    K Schäfer-Eckart

  23. Depatment of Hematology/Oncology, Marienhospital Herne, Ruhr-University Bochum, Herne, Germany

    B Schultheis

  24. Department of Hematology and Oncology, Charité, University Hospital Berlin, Campus Benjamin Franklin, Berlin, Germany

    C Baldus

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  1. S K Metzelder
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  2. T Schroeder
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  3. A Finck
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  15. R G Meyer
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  17. M Vöhringer
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  19. M Mori
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  20. N Basara
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  24. A Neubauer
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Correspondence to A Burchert.

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Additional information

Presented in part as abstract at the 51st and 52nd annual meeting of the American Society of Hematology, New Orleans, LA, 2009 and Orlando, FL, 2010.

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Metzelder, S., Schroeder, T., Finck, A. et al. High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses. Leukemia 26, 2353–2359 (2012). https://doi.org/10.1038/leu.2012.105

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