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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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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DOI: https://doi.org/10.1038/leu.2012.105
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