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Review
. 2022 Sep;116(3):341-350.
doi: 10.1007/s12185-022-03352-6. Epub 2022 Apr 23.

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

Francesca Biavasco  1 , Robert Zeiser  2
Affiliations
Review

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

Francesca Biavasco et al. Int J Hematol. 2022 Sep.

Abstract

The curative potential of allogeneic hematopoietic cell transplantation (allo-HCT) for acute myeloid leukemia (AML) relies on the graft-versus-leukemia (GVL)-effect. Relapse after allo-HCT occurs in a considerable proportion of patients, and has a dismal prognosis with very limited curative potential, especially for patients with FLT-ITD-mutated AML. Since the first description of sorafenib for treatment of FLT3-ITD-mutated AML, several clinical trials have tried to determine the efficacy of FLT3 inhibitors for preventing and treating AML relapse after allo-HSCT, but many questions regarding differences among compounds and mechanisms of action remain unanswered. This review provides an overview on the established and evolving use of FLT3 inhibitors to prevent or treat relapse of AML in the context of allo-HCT, focusing on the recently discovered immunogenic potential of some FLT3 inhibitors and addressing the possible mechanisms of leukemia drug-escape.

Keywords: Acute myeloid leukemia; Allogeneic hematopoietic stem cell transplantation; FLT3-ITD; Gilteritinib; Midostaurin; Relapse; Sorafebin.

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Conflict of interest statement

F.B. has no conflict of interest to declare. R.Z. received honoraria from Novartis, Sanofi and Mallinckrodt outside of the submitted work.

Figures

Fig. 1
Fig. 1
Mechanism of action of type I and type II FLT3 inhibitors and downstream effects. Proposed mechanism through which sorafenib/gilteritinib leads to increased IL-15 transcription. Inhibition of FLT3 receptor tyrosine kinase signaling reduces ATF4 production. Reduced ATF4 levels result in less inhibition of IRF7 phosphorylation and activation. Active p-IRF7 can translocate to the nucleus, where it activates IL-15 transcription. IL-15 activates CD8 T cells and NK cells.
See this image and copyright information in PMC

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