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Review
. 2020 Dec 23:10:612880.
doi: 10.3389/fonc.2020.612880. eCollection 2020.

FLT3 Mutations in Acute Myeloid Leukemia: Key Concepts and Emerging Controversies

Vanessa E Kennedy  1 , Catherine C Smith  1
Affiliations
Review

FLT3 Mutations in Acute Myeloid Leukemia: Key Concepts and Emerging Controversies

Vanessa E Kennedy et al. Front Oncol. .

Abstract

The FLT3 receptor is overexpressed on the majority of acute myeloid leukemia (AML) blasts. Mutations in FLT3 are the most common genetic alteration in AML, identified in approximately one third of newly diagnosed patients. FLT3 internal tandem duplication mutations (FLT3-ITD) are associated with increased relapse and inferior overall survival. Multiple small molecule inhibitors of FLT3 signaling have been identified, two of which (midostaurin and gilteritinib) are currently approved in the United States, and many more of which are in clinical trials. Despite significant advances, resistance to FLT3 inhibitors through secondary FLT3 mutations, upregulation of parallel pathways, and extracellular signaling remains an ongoing challenge. Novel therapeutic strategies to overcome resistance, including combining FLT3 inhibitors with other antileukemic agents, development of new FLT3 inhibitors, and FLT3-directed immunotherapy are in active clinical development. Multiple questions regarding FLT3-mutated AML remain. In this review, we highlight several of the current most intriguing controversies in the field including the role of FLT3 inhibitors in maintenance therapy, the role of hematopoietic cell transplantation in FLT3-mutated AML, use of FLT3 inhibitors in FLT3 wild-type disease, significance of non-canonical FLT3 mutations, and finally, emerging concerns regarding clonal evolution.

Keywords: Acute Myeloid Leukemia; FLT3 inhibitor; FLT3 inhibitor maintenance; FLT3 resistance; non-canonical FLT3 mutation.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Proposed Intrinsic and Extrinsic Mechanisms of FLT3 Inhibitor Resistance. Schematic of FLT3 inhibitor resistance mechanisms, including on-target secondary FLT3 mutations, off-target mutations in parallel and/or downstream signaling pathways, and extrinsic alterations in drug metabolism and the bone marrow microenvironment.
Figure 2
Figure 2
Established and In-Development FLT3 inhibitors, dual inhibitors, and combination agents. Schematic detailing mechanisms of action of established and in-development FLT3 inhibitors, dual and multikinase inhibitors, and combination agents.
Figure 3
Figure 3
Current Standard of Care for Treating FLT3-mutated AML in the Fit Patient.
See this image and copyright information in PMC

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