Abstract
FLT3-mutated acute myeloid leukemia accounts for around 30% of acute myeloid leukemia (AML). The mutation carried a poor prognosis until the rise of tyrosine kinase inhibitors (TKIs). New potent and specific inhibitors have successfully altered the course of the disease, increasing the complete response rate and the survival of patients with FLT3-mutated AML. The aim of this article is to review all the current knowledge on these game-changing drugs as well as the unsolved issues raised by their use for fit and unfit FLT3-mutated AML patients. To this end, we analyzed the results of phase I, II, III clinical trials evaluating FLT3-TKI both in the first-line, relapse monotherapy or in combination referenced in the PubMed, the American Society of Hematology, the European Hematology Association, and the Clinicaltrials.gov databases, as well as basic science reports on TKI resistance from the same databases. The review follows a chronological presentation of the different trials that allowed the development of first- and second-generation TKI and ends with a review of the current lines of evidence on leukemic blasts resistance mechanisms that allow them to escape TKI.
Highlights
Acute myeloid leukemia (AML) is the most common type of leukemia in adults [1,2].It is a heterogeneous group of hematological malignancies characterized by the clonal proliferation of immature myeloid cells in the bone marrow [1]
The 2017 European Leukemia Net classification has divided AML patients into three prognosis groups based on their oncogenetic characteristics [4]
It can either affect the juxtamembrane domain and the activation loop of the tyrosine kinase domain (TKD) (~7% of AML cases), resulting in the constitutive activation of FMS-like tyrosine kinase 3 (FLT3), or it can be an internal tandem duplication (ITD), leading to a disrupted juxtamembrane domain that has been shown to be crucial for kinase autoinhibition (~23% of AML cases) [6]
Summary
Acute myeloid leukemia (AML) is the most common type of leukemia in adults [1,2]. It is a heterogeneous group of hematological malignancies characterized by the clonal proliferation of immature myeloid cells in the bone marrow [1]. The 2017 European Leukemia Net classification has divided AML patients into three prognosis groups based on their oncogenetic characteristics [4] Among these recurrent genetic alterations, the mutations or duplication of the FMS such as tyrosine kinase 3 (FLT3) is the most frequent. Around 30% of newly diagnosed AML patients carry a genetic modification in the FLT3 gene [5] It can either affect the juxtamembrane domain and the activation loop of the tyrosine kinase domain (TKD) (~7% of AML cases), resulting in the constitutive activation of FLT3, or it can be an internal tandem duplication (ITD), leading to a disrupted juxtamembrane domain that has been shown to be crucial for kinase autoinhibition (~23% of AML cases) [6]. Phase II Phase III Phase I, Phase III (ongoing) Phase III (ongoing) Phase III (ongoing) Retrospective study Phase II study Phase I/II Phase III (failed) Preclinical Phase II, phase III Phase III (failed) Phase III (ongoing) Phase III (ongoing) Phase III (ongoing)
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