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Gilteritinib enhances graft-versus-leukemia effects against FLT3-ITD mutant leukemia after allogeneic hematopoietic stem cell transplantation

Bone Marrow Transplantation volume 57, pages 775–780 (2022)Cite this article

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Abstract

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a potentially curative therapy for FLT3 internal tandem duplication mutant (FLT3-ITD+) acute myeloid leukemia, but relapse rate is high. A recent study showed that sorafenib, a first generation FLT3 and multikinase inhibitor, enhanced graft-versus-leukemia (GVL) effects against FLT3-ITD+ leukemia via interleukin-15 (IL-15) production. However, it remains to be clarified whether this effect could be mediated by selective FLT3 inhibition. We investigated whether gilteritinib, a selective FLT3 inhibitor, could enhance GVL effects against FLT3-ITD transfected Ba/F3 leukemia (Ba/F3-FLT3-ITD) in mice. Oral administration of gilteritinib from day +5 to +14 after allo-SCT reduced expression of the co-inhibitory receptors PD-1 and TIGIT on donor CD8+ T cells and enhanced IL-15 expression in Ba/F3-FLT3-ITD. Bioluminescent imaging using luciferase-transfected Ba/F3-FLT3-ITD demonstrated that gilteritinib significantly suppressed leukemia expansion after allo-SCT, whereas it did not impact the morbidity or mortality of graft-versus-host disease (GVHD), resulting in significant improvement of overall survival. In conclusion, short-term administration of gilteritinib after allo-SCT enhanced GVL effects against FLT3-ITD+ leukemia without exacerbating GVHD.

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Fig. 1: FLT3-ITD inhibitors promote IL-15 expression in Ba/F3-FLT3-ITD cells.
Fig. 2: Gilteritinib enhances GVL effects against Ba/F3-FLT3-ITD-luc leukemia.

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Acknowledgements

We gratefully acknowledge Dr. Gerard Grosveld (Department of Genetics, St. Jude Children’s Research Hospital) for providing pMSCV-lus-IRES-YFP plasmid and Dr. Inder Verma (Addgene) for providing pCL-Eco.

Funding

This study was supported by JSPS KAKENHI (21K08409 to DH, 21390295 to TT, 20K17366 to HO, 21K16259 to TA, JP21H02775 to MN), Japan Society of Hematology Research Fund (TT), the Center of Innovation Program from JST (TT).

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  1. These authors contributed equally: Zixuan Zhang, Yuta Hasegawa.

Authors and Affiliations

  1. Department of Hematology, Hokkaido University Faculty of Medicine, Graduate School of Medicine, Sapporo, 060-8638, Japan

    Zixuan Zhang, Yuta Hasegawa, Daigo Hashimoto, Hajime Senjo, Ryo Kikuchi, Xuanzhong Chen, Kazuki Yoneda, Tomoko Sekiguchi, Takashi Ishio, Takahide Ara, Hiroyuki Ohigashi, Masao Nakagawa & Takanori Teshima

  2. Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Japan

    Tatsuya Kawase & Hirofumi Tsuzuki

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Contributions

DH and TT developed the conceptual framework of the study, designed the experiments, analyzed the data and wrote the paper. ZZ and YH conducted experiments, analyzed data, and wrote the paper. HS, RK, XC, KY, TS, TK, HT, TI, TA, and HO conducted experiments. MN supervised experiments.

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Correspondence to Daigo Hashimoto.

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Competing interests

TT received a research grant from Kyowa Kirin, Chugai, Sanofi, Astellas, TEIJIN PHARMA, Fuji Pharma, NIPPON SHINYAKU, Personal Fees from Novartis, Merck, Kyowa Kirin, Takeda, Pfizer, Bristol-Myers Squibb, Non-Financial Support from Janssen, Novartis.

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Zhang, Z., Hasegawa, Y., Hashimoto, D. et al. Gilteritinib enhances graft-versus-leukemia effects against FLT3-ITD mutant leukemia after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 57, 775–780 (2022). https://doi.org/10.1038/s41409-022-01619-4

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