Targeting FLT3 Mutations in Acute Myeloid Leukemia.

Riad El Fakih,Yousef Hawsawi,Maamoun Alsermani,Mona Hassanein,Walid Rasheed

doi:10.3390/cells7010004

Riad El Fakih, Yousef Hawsawi + Show 3 more

Open Access

https://doi.org/10.3390/cells7010004

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Journal: Cells	Publication Date: Jan 8, 2018
Citations: 31	License type: CC BY 4.0

Affiliation: King Faisal Specialist Hospital & Research Centre

Abstract

The FMS-like tyrosine kinase 3 (FLT3) pathway has an important role in cellular proliferation, survival, and differentiation. Acute myeloid leukemia (AML) patients with mutated FLT3 have a large disease burden at presentation and a dismal prognosis. A number of FLT3 inhibitors have been developed over the years. The first-generation inhibitors are largely non-specific, while the second-generation inhibitors are more specific and more potent. These inhibitors are used to treat patients with FLT3-mutated AML in virtually all disease settings including induction, consolidation, maintenance, relapse, and after hematopoietic cell transplantation (HCT). In this article, we will review the use of FLT3 inhibitors in AML.

Highlights

The FMS-like tyrosine kinase 3 (FLT3) gene, which is located on chromosome 13q12, encodes the FLT3 tyrosine kinase receptor expressed on the surface of CD34+ hematopoietic stem cells and other immature hematopoietic progenitors
Like other class III members, upon activation, the FLT3 tyrosine kinase promotes the activation of downstream pathways involving phosphatidylinositol-3 kinase (PI3K), AKT, mammalian target of rapamycin, RAS, and extracellular signal-related kinase (ERK) (Figure 1)
Studies have shown that patients with a low FLT3-internal tandem duplication (ITD) allelic ratios (

Summary

Introduction

The FMS-like tyrosine kinase 3 (FLT3) gene, which is located on chromosome 13q12, encodes the FLT3 tyrosine kinase receptor expressed on the surface of CD34+ hematopoietic stem cells and other immature hematopoietic progenitors It is a type-1 transmembrane receptor tyrosine kinase consisting of an extracellular domain, transmembrane domain, and an intracellular tyrosine kinase domain. Patients with a high FLT3-ITD allelic ratios (≥0.5) carry a dismal prognosis in the absence of an NPM1 mutation [4,5,6], and these are considered as one of the adverse risk groups in the 2017. Another study enrolled 380 AML patients, 12% of whom had an FLT3-ITD mutation, and showed no impact of FLT3-ITD on the outcome of the elderly. FLT3 A activation elderly patients number pathway of trials already published and multiple other trials are underway to investigate the effects of targeting FLT3 on the outcomes of AML patients

Targeting FLT3 Mutations in AML

Non-Selective FLT3 Inhibitors

Tandutinib

Sorafenib

Selective FLT3 Inhibitors

Findings

Future Directions