Oncotarget

Research Papers:

Evaluation of gilteritinib in combination with chemotherapy in preclinical models of FLT3-ITD+ acute myeloid leukemia

Yoko Ueno _, Masamichi Mori, Yoshiteru Kamiyama, Rika Saito, Naoki Kaneko, Eriko Isshiki, Sadao Kuromitsu and Masahiro Takeuchi

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Oncotarget. 2019; 10:2530-2545. https://doi.org/10.18632/oncotarget.26811

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Abstract

Yoko Ueno1, Masamichi Mori1, Yoshiteru Kamiyama1, Rika Saito1, Naoki Kaneko1, Eriko Isshiki2, Sadao Kuromitsu1 and Masahiro Takeuchi1

1Drug Discovery Research, Astellas Pharma, Inc., Ibaraki, Japan

2Biological Research Division, Astellas Research Technologies Co., Ltd., Ibaraki, Japan

Correspondence to:

Yoko Ueno, email: yoko.ueno@astellas.com

Keywords: acute myeloid leukemia; FLT3 inhibition; internal tandem duplication; combination therapy; apoptosis

Received: January 02, 2019    Accepted: March 04, 2019    Published: April 02, 2019

ABSTRACT

Activating internal tandem duplication (ITD) and tyrosine kinase domain (TKD) point mutations in Fms-like tyrosine kinase 3 (FLT3) occur in approximately 30% of patients with acute myeloid leukemia (AML), and confer a poor prognosis with standard cytarabine/anthracycline or azacitidine-based chemotherapy regimens. Gilteritinib is a highly-specific, potent FLT3/AXL inhibitor with demonstrated activity against FLT3-ITD and FLT3-TKD mutations. Compared with salvage chemotherapy, treatment with once-daily oral gilteritinib demonstrated a clinical benefit in patients with FLT3-mutated relapsed/refractory AML, which led to its recent approval in Japan and the United States. We investigated the effects of gilteritinib combined with cytarabine plus daunorubicin/idarubicin, or combined with azacitidine in human FLT3-ITD–positive (FLT3-ITD+) AML cell lines and xenografted mouse models. Gilteritinib induced G1 arrest and apoptosis in a dose-dependent manner. The addition of cytarabine, daunorubicin, idarubicin, or azacitidine potentiated apoptosis. Gilteritinib alone or combined with cytarabine, daunorubicin, idarubicin, or azacitidine, inhibited anti-apoptotic protein expression in MV4-11 cells. In xenografted mice, administration of cytarabine, idarubicin, or azacitidine in combination with gilteritinib had little impact on plasma or intratumor PK profiles of gilteritinib, cytarabine, idarubicin, or azacitidine. Gilteritinib combined with chemotherapy reduced tumor volume to a greater extent than either gilteritinib or chemotherapy alone. Of note, the addition of cytarabine plus daunorubicin/idarubicin led to tumor regression in mice, with complete regression observed in six out of eight mice in both triple combination groups. These findings support the investigation of gilteritinib combined with chemotherapy in patients with FLT3-ITD+ AML, including those who are ineligible for intensive chemotherapy.


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