Gilteritinib enhances graft-versus-leukemia effects against FLT3-ITD mutant leukemia after allogeneic hematopoietic stem cell transplantation
Gilteritinib enhances graft-versus-leukemia effects against FLT3-ITD mutant leukemia after allogeneic hematopoietic stem cell transplantation
复制标题
DOI：
10.1038/s41409-022-01619-4
复制
发表时间：
2022-02-28
影响因子：
4.8
通讯作者：
Teshima, Takanori
中科院分区：
文献类型：
--
作者：
Zhang, Zixuan;Hasegawa, Yuta;Teshima, Takanori
异基因造血干细胞移植（allo-SCT）是治疗FLT 3-ITD+急性髓系白血病的有效方法，但复发率高。最近的一项研究表明，索拉非尼（第一代FLT 3和多激酶抑制剂）通过产生白细胞介素-15（IL-15）增强了抗FLT 3-ITD+白血病的移植物抗白血病（GVL）作用。然而，这种作用是否可以通过选择性FLT 3抑制来介导仍有待澄清。我们研究了gilteritinib（一种选择性FLT 3抑制剂）是否可以增强小鼠对FLT 3-ITD转染Ba/F3白血病（Ba/F3-FLT 3-ITD）的GVL效应。allo-SCT后第+5天至+14天口服gilteritinib可减少供体CD 8（+）T细胞上共抑制受体PD-1和TIGIT的表达，并增强Ba/F3-FLT 3-ITD中IL-15的表达。使用经端粒酶转染的Ba/F3-FLT 3-ITD进行的生物发光成像表明，gilteritinib可显著抑制allo-SCT后的白血病扩展，但不影响移植物抗宿主病（GVHD）的发病率或死亡率，从而显著改善总生存期。总之，allo-SCT后短期给予gilteritinib可增强GVL对FLT 3-ITD+白血病的作用，而不会加重GVHD。
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.