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Outcome of FLT3-ITD-positive acute myeloid leukemia: impact of allogeneic stem cell transplantation and tyrosine kinase inhibitor treatment

  • Original Article – Clinical Oncology
  • Published:
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Abstract

Background

Activating mutations of the receptor tyrosine kinase FLT3 (fms-related tyrosine kinase 3) reflect the most frequent molecular aberration in acute myeloid leukemia (AML). In particular, FLT3 internal tandem duplications (FLT3-ITD) are characterized by an unfavorable prognosis and allogeneic stem cell transplantation (allogeneic SCT) in first complete remission is recommended. In case of imminent or frank relapse following allogeneic SCT, treatment with FLT3 tyrosine kinase inhibitors (TKI) constitutes a promising clinical approach to induce hematologic remission without conventional chemotherapy.

Patients and methods

We retrospectively analyzed the response to induction chemotherapy and the outcome of 76 patients with FLT3-ITD-positive AML including 50 patients who underwent allogeneic SCT. Furthermore, efficacy of TKI treatment was evaluated in 18 patients (median age 54 years, range 21–74) with relapsed or refractory FLT3-ITD-positive AML.

Results

Response to induction chemotherapy in 76 FLT3-ITD-positive AML patients was characterized by a complete remission (CR) rate of 68%. In total, 50 of 76 patients (66%) underwent allogeneic SCT including 40 patients (80%) in CR. Relapse of AML was observed in 21 of 47 patients (45%) after allogeneic SCT with a median relapse-free survival (RFS) of 13 months (range 3–224) for patients with CR prior to or at day +30 after SCT. Myeloablative conditioning resulted in an improved median RFS of 29 months (4–217) as compared to a reduced intensity conditioning protocol prior to allogeneic SCT with a RFS of 8 months (1–197, P = 0.048), respectively. Median OS of FLT3-ITD-positive AML was 17 months (5–225) for patients who received an allogeneic SCT as compared to 9 months (1–184) for patients who did not undergo SCT. Response of FLT3-ITD-positive AML to sorafenib was characterized by only 3 of 18 patients achieving a bone marrow response (17%), while there was no response to second-line treatment with ponatinib.

Conclusion

This “real-life” data reflect the continuing challenge of FLT3-ITD-positive AML and confirm the poor outcome even after allogeneic SCT. Furthermore, efficacy of TKI treatment of relapsed or refractory FLT3-ITD AML is still limited and requires substantial improvement, e.g., by the introduction of second-generation inhibitors targeting constitutively active FLT3.

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Acknowledgements

This work was in part supported by a grant (M.F.) from the “Interdisciplinary Center of Clinical Research” (IZKF) Jena, Germany.

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  1. Volker Schmidt & Herbert G. Sayer

    Present address: HELIOS Klinikum Erfurt, Erfurt, Germany

Authors and Affiliations

  1. Klinik für Innere Medizin II (Abteilung Hämatologie und Internistische Onkologie), Universitätsklinikum Jena, Am Klinikum 1, 07740, Jena, Germany

    Maximilian Fleischmann, Ulf Schnetzke, Karin G. Schrenk, Volker Schmidt, Herbert G. Sayer, Inken Hilgendorf, Andreas Hochhaus & Sebastian Scholl

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  1. Maximilian Fleischmann
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Correspondence to Sebastian Scholl.

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IH received travel sponsoring for congress attendance by Medac. The authors declare no conflict of interest.

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All procedures were in accordance with ethical standards of the institutional research committee and with the Declaration of Helsinki. The study has been approved by the Jena University Hospital Ethics Committee (4871-07/16). Written informed consent was obtained from all patient included in this study.

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Fleischmann, M., Schnetzke, U., Schrenk, K.G. et al. Outcome of FLT3-ITD-positive acute myeloid leukemia: impact of allogeneic stem cell transplantation and tyrosine kinase inhibitor treatment. J Cancer Res Clin Oncol 143, 337–345 (2017). https://doi.org/10.1007/s00432-016-2290-5

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