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

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.

Successful Pre- and Post-transplant Administration of Gilteritinib in a Patient with Relapsed and Refractory Acute Myeloid Leukemia Undergoing Allogeneic Peripheral Blood Stem Cell Transplantation

“…Bone marrow aspirate revealed hypercellularity with 85.6% myeloblasts. A G-banded metaphase analysis showed a normal karyotype (46, XX [20]), suggesting the absence of additional aberrant chromosomal abnormalities. Therefore, the patient was diagnosed with relapsed AML.…”

“…A G-banded metaphase analysis showed a normal karyotype [46, XX (20)]. The nucleophosmin member 1 mutation was detected, but FLT3 internal tandem duplications and CCAAT/enhancer-binding protein A mutations were not detected.…”

FLT3-inhibitor therapy for prevention and treatment of relapse after allogeneic hematopoietic cell transplantation

“…Sorafenib, however, is a multi-tyrosine kinase inhibitor. To answer the question if also a selective FLT3 inhibitor could enhance GvL-effect, Zhang and colleagues studied IL-15 production and T cell activation in a mouse model of FLT3-ITD-positive AML relapse after allo-HCT treated with gilteritinib with or without T lymphocyte infusion [ 21 ]. Upon FLT3 inhibition, an increased production of IL-15 and a reduction of exhaustion T cell marker could be identified.…”

“…Upon FLT3 inhibition, an increased production of IL-15 and a reduction of exhaustion T cell marker could be identified. Interestingly, a short-term administration of gilteritinib alone was not able to suppress leukemia growth in the absence of T lymphocytes [ 21 ].…”

“…1 ) [ 20 ]. The connection between FLT3 inhibition and IL-15 production in the GVL context was reproduced by the group of Teshima using gilteritinib [ 21 ].…”