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. 2022 May;57(5):775-780.
doi: 10.1038/s41409-022-01619-4. Epub 2022 Feb 28.

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

Zixuan Zhang #  1 , Yuta Hasegawa #  1 , Daigo Hashimoto  2 , Hajime Senjo  1 , Ryo Kikuchi  1 , Xuanzhong Chen  1 , Kazuki Yoneda  1 , Tomoko Sekiguchi  1 , Tatsuya Kawase  3 , Hirofumi Tsuzuki  3 , Takashi Ishio  1 , Takahide Ara  1 , Hiroyuki Ohigashi  1 , Masao Nakagawa  1 , Takanori Teshima  1
Affiliations
Free article

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

Zixuan Zhang et al. Bone Marrow Transplant. 2022 May.
Free article

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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