Mild chronic graft‐versus‐host disease may alleviate poor prognosis associated with FLT3 internal tandem duplication for adult acute myeloid leukemia following allogeneic stem cell transplantation with myeloablative conditioning in first complete remission: a retrospective study

Abstract

Internal tandem duplication (ITD) of the FLT3 gene (Fms-like tyrosine kinase 3) is the most commonly found mutation in acute myeloid leukemia (AML). The significance of FLT3-ITD at diagnosis was retrospectively estimated for allo-HSCT (allogeneic hematopoietic stem cell transplantation) outcomes in 140 patients, median age of 38, undergoing allo-HSCT after myeloablative conditioning in first complete remission of AML. FLT3-ITD was detected at AML diagnosis in 42/140 (30%) of included into this study patients. At 3 years, relapse incidence (RI) following allo-HSCT in AML patients with intermediate or normal karyotype was significantly higher in those FLT3-ITD positive than FLT3-ITD negative [52.9 vs. 20.4%, P = 0.002]. Additionally, patients with mild chronic graft-versus-host disease (cGvHD) had significantly lower RI compared to patients with moderate or severe grade cGvHD or those not experiencing cGvHD, respectively, 4.8 vs. 36.0 vs. 27.8%, P = 0.032. FLT3-ITD was harboring a poor prognosis in AML with intermediate or normal karyotype and significantly increased risk of relapse following allo-HSCT. It appears that allo-HSCT does not cure patients with FLT3-ITD, unless they develop symptoms of mild cGvHD and graft versus leukemia, which may decrease RI.

Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells

“…Consistent with these findings, others have reported the production of IL-15 by acute leukemia cells 34,35 , however no strategy has been found to date to directly increase IL-15 production in the malignant cells themselves. Our observation is clinically highly relevant, because the relapse rate in patients with FLT3 -ITD + AML is 52% at 3 years after allo-HCT and the prognosis for these relapsed patients is poor 36 . We also extended the previous clinical observation of a synergistic effect for sorafenib and allo-HCT in FLT3-ITD + AML 5 by delineating the immunological mechanism behind this observation, thereby providing a scientific rationale for using sorafenib to treat FLT3-ITD + AML-relapse.…”

Incubation of Immune Cell Grafts With MAX.16H5 IgG1 Anti-Human CD4 Antibody Prolonged Survival After Hematopoietic Stem Cell Transplantation in a Mouse Model for Fms Like Tyrosine Kinase 3 Positive Acute Myeloid Leukemia

“…Regarding these promising results, we decided to investigate whether the antibody-induced GVHD prevention and retained anti-tumor effect can be translated into an Fms like tyrosine kinase 3 (FLT3, CD135) internal tandem duplication (ITD) positive acute myeloid leukemia (AML) C3H mouse model since acute GVHD affects 45–53% of AML patients carrying FLT3 mutations ( 30 , 31 ). FLT3 is involved in proliferation, survival, and differentiation processes of hematopoietic cells and in the development of B and T cells [reviewed in 32 )].…”