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Identification of a secondary FLT3/A848P mutation in a patient with FLT3-ITD-positive blast phase CMML and response to sunitinib and sorafenib

Leukemia volume 24, pages 1523–1525 (2010)Cite this article

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FLT3 kinase inhibitors display clinical activity in the treatment of AML.2, 3, 4, 5, 6 Although responses were short-lived in many patients,2, 3 sustained responses were reported, including single cases of complete molecular remissions.6 Moreover, a single case of a patient with PKC412-resistant AML and a FLT3-ITD/N676K resistance mutation has been described,7 supporting the significance of FLT3 as drug target in AML. Ongoing clinical trials evaluate the activity of FLT3 inhibitors added to standard chemotherapy in AML.

The FLT3-ITD/A848P mutation identified in our patient mediated strong sorafenib and sunitinib resistance in vitro, but did not affect response to PKC412 (Figure 1c), an FLT3 inhibitor currently evaluated in clinical trials. Consequently, our patient at the time of relapse upon selection of the FLT3-ITD/A848P mutation might have been benefited from PKC412. The finding of a FLT3-ITD/N676K exchange in the first part of the FLT3 tyrosine kinase domain (TK1) in the PKC412-resistant patient by Heidel et al.7 and the identification of FLT3-ITD/A848P (TK2) in our patient resistant to sorafenib and sunitinib well accords to in vitro data suggesting that PKC412 might be more vulnerable to TK1 exchanges, whereas sorafenib might be more prone to mutations of TK2.8, 9 Thus, sequential therapy with different FLT3 inhibitors might be an option, like it is common practice with Abl kinase inhibitors in the treatment of CML.

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Acknowledgements

This work was supported by Bundesministerium für Bildung und Forschung grant NGFNplus 01GS0878.

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  1. 3. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, München, Germany

    N von Bubnoff, C Rummelt, H Menzel, M Sigl, C Peschel & J Duyster

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Correspondence to N von Bubnoff.

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von Bubnoff, N., Rummelt, C., Menzel, H. et al. Identification of a secondary FLT3/A848P mutation in a patient with FLT3-ITD-positive blast phase CMML and response to sunitinib and sorafenib. Leukemia 24, 1523–1525 (2010). https://doi.org/10.1038/leu.2010.122

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