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Impact of FLT3-ITD location on sensitivity to TKI-therapy in vitro and in vivo

Leukemia volume 30, pages 1220–1225 (2016)Cite this article

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FLT3-internal-tandem-duplication (ITD)-mutated acute myeloid leukemia (AML) is difficult to treat and the majority of patients experience relapse within a short period of time after discontinuation of chemotherapy.1 Current therapeutic options include experimental trials using FLT3-tyrosine kinase-inhibitors (TKI) or allogeneic stem cell transplantation. Inhibitors that are currently investigated in advanced clinical trials with promising clinical responses include midostaurin (PKC412) and quizartinib (AC220). Most recently, Röllig and colleagues reported on a large multicenter trial where combination of chemotherapy with the FLT3-inhibitor sorafenib improved progression free survival in younger patients with AML (abstract #6, ASH annual meeting, 2014).2 Resistance-mediating mutations emerging upon long-term exposure to these inhibitors have confirmed mutated FLT3-kinase as a valid therapeutic target.3, 4 Recently, we identified a subgroup of FLT3 length-mutations (~30% of patients that harbor an ITD mutation) with the ITD being located in the tyrosine kinase domain 1 (TKD1).5, 6 Multivariate analysis of clinical data revealed that location of FLT3-ITDs within the β1-sheet of TKD1 is an independent unfavorable prognostic factor (that may even outweigh other prognostically relevant determinants such as allelic ratio)5 and predicts resistance to chemotherapy and inferior survival. A recent report by Schnittger et al.7 could not find a strict association with functional domains but confirmed that ITD-mutations localized more 5′ were associated with better outcome than more 3′ mutations.

In AML, it is of major clinical interest to identify patients that may benefit from targeted therapies in the future. So far, the significance of FLT3-kinase inhibitors in AML therapy remains a matter of current debate.

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Acknowledgements

This work was supported by a grant from the German Research Council (DFG) FI405/5-1 to TF and FHH, and BU 1339/5-1 to LB and KD; the DFG graduate school GRK 1167 (P17) to TF and a Heisenberg-Stipend to LB (BU 1339/3-1). Part of this work was also funded by the German Cancer Aid (Deutsche Krebshilfe e.V.; grants #110058 and #110062 to TF). SAA was supported by NCI grant CA66996 and the Leukemia and Lymphoma Society. FHH was supported by the EHA/ASH TRTH program 2012.

Author contributions

PAT, TSM, AP, TMS, AB, ZW, AJD and SW. Designed research, performed research and collected data. LB, SAA, KD, FHH and TF. Analyzed and interpreted data and performed statistical analysis. FHH wrote the manuscript.

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Author notes

  1. T Fischer and F H Heidel: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology and Oncology, Center of Internal Medicine, Otto-von-Guericke University Magdeburg, Magdeburg, Saxony-Anhalt, Germany

    P Arreba-Tutusaus, T S Mack, T M Schnöder, A Polanetzki, A Ballaschk, T Fischer & F H Heidel

  2. Department of Internal Medicine III, University of Ulm, Ulm, Baden-Württemberg, Germany

    L Bullinger & K Döhner

  3. Department of Pediatric Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

    L Bullinger, Z Wang, A J Deshpande & S A Armstrong

  4. Department of Cardiology and Angiology, Center of Internal Medicine, Otto-von-Guericke University Magdeburg, Magdeburg, Saxony-Anhalt, Germany

    S Weinert

  5. Tumor Initiation and Maintenance, Sanford Burnham Medical Research Institute, La Jolla, CA, USA

    A J Deshpande

  6. Human Oncology and Pathogenesis Program and Department of Pediatrics, Memorial Sloan-Kettering Cancer Institute, New York, NY, USA

    S A Armstrong

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Correspondence to F H Heidel.

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Arreba-Tutusaus, P., Mack, T., Bullinger, L. et al. Impact of FLT3-ITD location on sensitivity to TKI-therapy in vitro and in vivo. Leukemia 30, 1220–1225 (2016). https://doi.org/10.1038/leu.2015.292

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