Page 72 - EJMO-9-3

Eurasian Journal of
Medicine and Oncology Molecular shift in FLT3 during AML course

to improve patient survival. The success of targeted Although induction therapy often results in similar initial
therapy in chronic myeloid leukemia, for example, complete remission rates (~70%) regardless of FLT3
where the discovery of the BCR/ABL fusion gene led to mutational status, patients harboring FLT3-ITD mutations
the development of tyrosine kinase inhibitors (TKIs), exhibit significantly higher relapse rates. One study
illustrates the transformative potential of molecularly reported a median disease-free survival of 8.4 months
guided treatments. 4 in FLT3-mutated AML versus 12.8 months in wild-type
FMS-like tyrosine kinase 3 (FLT3) mutations, first cases. Similarly, overall survival was reduced in FLT3-
11-13
described in 1996, are now recognized as the most mutated patients (12 months vs. 15 months). FLT3-ITD
5
common genetic alterations in AML. These mutations are mutations are more frequently observed in de novo AML
associated with adverse prognostic implications and poor compared to AML secondary to myelodysplasia. FLT3-
overall survival. FLT3 belongs to the class III receptor TKD mutations, on the other hand, have demonstrated
6
tyrosine kinase family. These receptors are characterized by less consistent prognostic impact. The limited number of
a membrane-bound structure comprising five extracellular patients with these mutations in published studies hinders
immunoglobulin-like domains and an intracellular catalytic the ability to draw robust conclusions. Unlike FLT3-ITD,
region. This catalytic region is divided into two kinase FLT3-TKD is not associated with elevated leukocyte
domains (TKD1 and TKD2), separated by a hydrophilic counts, possibly reflecting distinct downstream signaling
14
insert of variable length. Members of this receptor family mechanisms.
include FMS (macrophage colony-stimulating factor The therapeutic landscape of AML with FLT3 mutations
receptor), platelet-derived growth factor receptor α and has evolved significantly with the advent of targeted
7,8
β, KIT (stem cell factor receptor), and FLK-2/FLT3. agents, resulting in substantial improvements in patient
These proteins play a pivotal role in the regulation of outcomes. Phase III clinical trials in both newly diagnosed
hematopoietic cell proliferation, differentiation, and and relapsed/refractory settings have demonstrated that
survival. FLT3 inhibitors increase the likelihood of achieving

Structurally, FLT3 comprises an extracellular measurable residual disease (MRD)-negative remission,
transmembrane domain, a juxtamembrane domain (JMD) even in the absence of allogeneic hematopoietic stem cell
within the cytoplasm, and two intracellular tyrosine kinase transplantation.
domains (TKD1 and TKD2), which are connected through In the relapse setting–historically associated with
a linker segment. The JMD is further subdivided into extremely poor outcomes–the availability of FLT3 inhibitors
three functional regions: A binding site (JM-B), involved has translated into improved remission rates. and survival,
15
in receptor activation and stabilization of the inactive particularly in patients ineligible for transplantation.
conformation; a switching region (JM-S), which includes Moreover, responses to these agents have been associated
phosphorylation sites and a binding site for STAT5; with enhanced performance status and quality of life,
and a ligand segment (JM-Z). Mutant FLT3 receptors allowing some patients previously deemed unfit to become
exhibit constitutive, ligand-independent activation eligible for curative-intent transplant procedures. This
that contributes to leukemogenesis by promoting is particularly relevant, given that allogeneic stem cell
uncontrolled proliferation (class I mutations). In contrast, transplantation remains the only potentially curative
class II mutations impair hematopoietic differentiation. strategy in relapsed AML. Despite these advances, the
Importantly, class I mutations typically occur at later long-term prognosis in this patient population remains
stages of leukemogenesis and require coexisting molecular poor, with overall cure rates below 10%. Ongoing studies
16
lesions to fully transform hematopoietic progenitors into are investigating various combination regimens involving
leukemic clones. Two main classes of mutations have FLT3 inhibitors, as monotherapy–though approved in
been identified. The first comprises internal tandem many countries, including Brazil–is generally insufficient
duplications (ITDs), most commonly affecting exons 14 for achieving durable remissions in most cases. 17
and 15 within the JMD. FLT3-ITD mutations are observed Evidence suggests that FLT3 mutational profiles may
in approximately 25% of AML cases. The second class change over time, with patients either losing or acquiring
involves point mutations within the activation loop of FLT3 mutations at relapse despite their initial diagnostic
the TKD, particularly in TKD2, and occurs in about 5% status. These changes have important therapeutic
18
of cases. These are collectively referred to as FLT3-TKD implications. Several targeted agents–such as midostaurin,
mutations. 9,10 gilteritinib, and quizartinib–have been developed for
FLT3 mutations–particularly the ITD subtype–have patients with FLT3 mutations. As a result, understanding
been consistently associated with leukocytosis at diagnosis. the dynamics of FLT3 mutational status and incorporating

Volume 9 Issue 3 (2025) 64 doi: 10.36922/EJMO025150101