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Potential targeting of FLT3 acute myeloid leukemia
Ferrata Storti Foundation
Haematologica 2021 Volume 106(3):671-681
Alexander J. Ambinder and Mark Levis
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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-mutat- ed 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 prog- nosis, 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 testing to guide the targeting of FLT3, and novel immunotherapeutic approaches.
Introduction
FLT3 (FMS-Like Tyrosine kinase-3) is a type 3 receptor tyrosine kinase that plays an important role in the expansion of multi-potent progenitor cells within the bone marrow (BM).1,2 It is also among the most commonly mutated genes in acute myeloid leukemia (AML).3 In an AML patient with a FLT3-activating mutation, the clinician is immediately faced with a variety of challenges and questions. These patients routinely present critically ill with hyperleukocytosis. Management deci- sions must be made rapidly, and trial participation is often difficult to arrange. There is agreement that FLT3 inhibitors need to be incorporated into treatment, but how should that be done if a patient is receiving a lower-intensity regimen such as a hypomethylating agent (HMA) with or without venetoclax? What impact does the FLT3 mutant allelic burden have on treatment decisions? What about co-muta- tions like NPM1 or DNMT3A? Should the patient receive an allogeneic transplant? A FLT3-activating mutation might be present at diagnosis and absent at relapse, or vice versa. A FLT3 mutation can impair the responses to other targeted agents like IDH inhibitors or venetoclax. Nothing seems to complicate the management of an AML patient more than the presence of a FLT3 mutation. This receptor’s activity, both mutated and non-mutated, is intertwined throughout this disease, and the potential benefits of targeting it in more refined ways is just beginning to be real- ized.
Why FLT3 is important to target in acute myeloid leukemia
FLT3 receptor’s natural ligand is FLT3 ligand (FL). Binding of the ligand leads to homodimerization of the receptor, autophosphorylation, and the transduction of pro-survival and proliferative signals via the RAS/MAPK, JAK/STAT5 and PI3K/AKT pathways.4,5 In healthy individuals, FLT3 is expressed by a limited subset of hematopoietic stem cells (HSC), multipotent progenitors (MPP), common lym- phoid progenitors (CLP), common myeloid progenitors (CMP), and mature dendrit-
Correspondence:
ALEXANDER J AMBINDER
aambind1@jhmi.edu
MARK LEVIS
mlevisma@jhmi.edu
Received: May 4, 2020. Accepted: July 7, 2020. Pre-published: July 23, 2020.
https://doi.org/10.3324/haematol.2019.240754
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