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

• Published in: Bone marrow transplantation (Basingstoke) Vol. 57; no. 5; pp. 775 - 780
• Main Authors: Zhang, Zixuan, Hasegawa, Yuta, Hashimoto, Daigo, Senjo, Hajime, Kikuchi, Ryo, Chen, Xuanzhong, Yoneda, Kazuki, Sekiguchi, Tomoko, Kawase, Tatsuya, Tsuzuki, Hirofumi, Ishio, Takashi, Ara, Takahide, Ohigashi, Hiroyuki, Nakagawa, Masao, Teshima, Takanori
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2022; Nature Publishing Group
• Subjects: 13/21; 13/31; 38/35; 42/109; 42/44; 45/77; 59/5; 631/250/1904; 64/60; 692/699/1541/1990/283/1897; Acute myeloid leukemia; Aniline Compounds; Animals; CD8 antigen; CD8-Positive T-Lymphocytes; Cell Biology; fms-Like Tyrosine Kinase 3 - genetics; Graft versus host disease; Graft vs Leukemia Effect; Graft-versus-host reaction; Grafting; Hematology; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Inhibitors; Interleukin 15; Interleukins; Internal Medicine; Leukemia; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - therapy; Lymphocytes; Lymphocytes T; Medicine; Medicine & Public Health; Mice; Morbidity; Mutants; Mutation; Oral administration; PD-1 protein; Public Health; Pyrazines; Stem cell transplantation; Stem Cells; Transplantation; Transplantation, Homologous
• ISSN: 0268-3369; 1476-5365
• DOI: 10.1038/s41409-022-01619-4

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.