Potential targeting of FLT3 acute myeloid leukemia

Abstract

Aberrant FLT3 receptor signaling is common in acute myeloid leukemia (AML) and has important implications for the biology and clinical management of the disease. Patients with FLT3-mutated AML frequently present with critical illness, are more likely to relapse after treatment, and have worse clinical outcomes than their FLT3 wild type counterparts. The clinical management of FLT3-mutated AML has been transformed by the development of FLT3 inhibitors, which are now in use in the frontline and relapsed/refractory settings. However, many questions regarding the optimal approach to the treatment of these patients remain. In this paper, we will review the rationale for targeting the FLT3 receptor in AML, the impact of FLT3 mutation on patient prognosis, the current standard of care approaches to FLT3-mutated AML management, and the diverse array of FLT3 inhibitors in use and under investigation. We will also explore new opportunities and strategies for targeting the FLT3 receptor. These include targeting the receptor in patients with non-canonical FLT3 mutations or wild type FLT3, pairing FLT3 inhibitors with other novel therapies, using minimal residual disease (MRD) testing to guide the targeting of FLT3, and novel immunotherapeutic approaches.

A Novel FLT3 Y842D Mutation Carriers a Potentially Highly Sensitivity to Midostaurin? Case Report and Literature Review

“…Mutant FLT3 contained two kinds of mutation forms, internal tandem duplication (ITD) in juxtamembrane domain and point mutation within the activation loop of tyrosine kinase domain (TKD) [2] . FLT3 mutation occurred in 30% of de novo AML patients and accounted for the most predominant mutation type in AML [1] . Notably, FLT3-ITD was considered as an independent unfavorable risk factor in AML, for patients with FLT3-ITD always be resistant to chemotherapy and present a higher relapse rate and more early death cases.…”

“…FMS-like tyrosine kinase 3 (FLT3) is a type 3 receptor tyrosine kinase. Certain alteration of this protein can constitutively active receptor tyrosine kinase causing uncontrolled proliferation, reduced apoptosis, and malignant transformation of myeloid cells [1] . Thus, mutant FLT3 is well known as a promising target for molecular therapy in acute myeloid leukemia (AML) [1,2] .…”

“…Certain alteration of this protein can constitutively active receptor tyrosine kinase causing uncontrolled proliferation, reduced apoptosis, and malignant transformation of myeloid cells [1] . Thus, mutant FLT3 is well known as a promising target for molecular therapy in acute myeloid leukemia (AML) [1,2] . FLT3 mutation occurred in 30% of de novo AML, with internal tandem duplication (FLT3-ITD) in juxtamembrane domain observed in 75% of mutant patients and point mutation within the activation loop of tyrosine kinase domain (FLT3-TKD) in the rest of 25% patients [3] .…”

Upfront Treatment of FLT3-Mutated AML: A Look Back at the RATIFY Trial and Beyond

“…Beyond the support for upfront use of midostaurin observed in the RATIFY trial, it has been suggested ( 6 , 18 ) that the optimal sequencing of FLT3-inhibition may be to utilize multikinase inhibitor in the upfront setting when the disease is known to be polyclonal ( 19 ) and to save a more targeted FLT3 inhibitor for the time of relapse when the disease may have fewer clones and may be more dependent on FLT3 signaling. It is important to note that this suggestion is merely theoretical.…”

Phosphoproteomic Characterization of Primary AML Samples and Relevance for Response Toward FLT3-inhibitors

“… 2 The presence of FLT3 -ITD is predictive for response to FLT3-TKIs, 3 yet 41%–56% of FLT3 -WT patients respond to FLT3 -TKIs, indicating alternative possibilities of FLT3 pathway activation or TKI off-target effects leading to unexpected treatment response. 4 Others have identified genomic and global phosphorylation markers associated with FLT3-TKI response in FLT3 -WT AML. 5 , 6 As the primary targets of currently approved FLT3-TKIs are tyrosine (Y) kinases, we hypothesized that the direct evaluation of tyrosine kinome could reveal phosphorylation markers associated with FLT3-TKI response.…”