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Ferrata Storti Foundation
Haematologica 2021 Volume 106(3):664-670
Maintenance therapy for FLT3-ITD-mutated acute myeloid leukemia
Department of Internal Medicine, Hematology, Oncology and Immunology, Philipps University Marburg and University Hospital Giessen and Marburg, Campus Marburg, Marburg, Germany
ABSTRACT
FLT3-ITD is a constitutively activated variant of the FLT3 tyrosine kinase receptor. Its expression in acute myeloid leukemia (AML) is associated with a poor prognosis. Due to this, the development of tyrosine kinase inhibitors (TKI) blocking FLT3-ITD became a rational therapeutic concept. This review describes key milestones in the clinical development of different FLT3-specific TKI with a particular focus on FLT3-TKI maintenance therapy in remission after allogeneic hematopoietic stem cell transplantation (HCT). Recent evidence from randomized trials using sorafenib in FLT3-ITD mutat- ed AML provided a proof of concept that targeted post-HCT maintenance therapy could become a new treatment paradigm in AML.
Why FLT3 as a therapeutic target in acute myeloid leukemia?
AML is a clonal stem cell malignancy. Although AML prognosis is governed by genomic features,1-3 therapeutic targeting of recurrently mutated genes is a com- plex task.4 For example, while mutations in epigenetic regulator genes such as DNMT3A or ASXL1 are recurrently detected in AML5 and are linked to a dismal prognosis,3,6 the same mutations are also very frequently found in hematopoietic stem cells of healthy elderly individuals with 'clonal' (so-called 'age-related hematopoiesis' or CHIP/ARCH-associated mutations).7,8 Thus, although ARCH mutations seem to be instrumental drivers of clonal progression towards AML,5,8 their detection in AML per se does not qualify them as therapeutic targets in AML.9 This is because the expression of mutant oncoproteins is therapeutically exploitable only if their inhibition induces differentiation, restricts growth, or reduces viability of the AML bulk. A perfect target oncoprotein in AML is the con- stitutively activated FLT3 receptor tyrosine kinase which results from mutations in the FMS-like tyrosine kinase 3 (FLT3) gene. FLT3 mutations emerge very late dur- ing AML pathogenesis.3,10 They are found in approximately 30% of all AML patients and can be either FLT3-tyrosine kinase point mutations (FLT3-TKD) or FLT3 internal tandem duplication mutations (FLT3-ITD).11 Only FLT3-ITD muta- tions are associated with a poor outcome in AML.12,13 FLT3-TKD and FLT3-ITD cause uncontrolled signaling through the ERK-signaling, PI3-kinase signaling, and, in the case of FLT3-ITD, also STAT5-signaling,14 and drive stem cell transforma- tion.15,16 By 'hijacking' the signal transduction machinery of AML cells, FLT3 onco- proteins generate a strong dependence on FLT3-signaling pathways to sustain sur- vival. As a result, AML cells undergo apoptosis in vitro and in vivo when FLT3 sig- naling output is blocked by a TKI.17,18 Dependence on FLT3 oncoproteins provided the biological rationale for the clinical development of FLT3 inhibitors in FLT3- mutated AML (reviewed by Kindler et al.18 and Daver et al.19).
In this review, I will discuss evidence that illustrates the value of FLT3-TKI when used as maintenance therapy in remission after allogeneic hematopoietic stem cell transplantation (HCT) compared with its use outside the context of a HCT.
The main characteristics and approval status of currently developed FLT3 inhibitors are shown in Table 1.
A long road for FLT3-TKI in acute myeloid leukemia
In spite of the preclinical data showing a promising activity of FLT3 inhibitors in FLT3-mutated AML, it has proven difficult to translate these preclinical results into
Andreas Burchert
Correspondence:
ANDREAS BURCHERT
burchert@staff.uni-marburg.de
Received: August 25, 2020. Accepted: January 7, 2021. Pre-published: January 21, 2021.
https://doi.org/10.3324/haematol.2019.240747
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