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

routine reassessment using polymerase chain reaction more pronounced when comparing academic centers to
(PCR) and next-generation sequencing (NGS) may inform community-based institutions, likely reflecting unequal
prognosis and guide therapeutic strategies. In some cases, access to molecular diagnostics and variable awareness
such reassessment may enable the use of FLT3 inhibitors, regarding the clinical utility of these tests. 24,25
which can enable the patient to undergo curative treatment Additional data from a cohort at the Hospital das
- bone marrow transplant. Clínicas of the Federal University of Bahia (UFBA)
Beyond their prognostic therapeutic value, FLT3 revealed that nearly half (47%) of patients could not be
mutations have also been investigated as potential adequately risk-stratified according to the 2022 European
markers for disease monitoring. Currently, treatment Leukemia Net guidelines due to the absence of molecular
response is often assessed through flow cytometry-based data. Furthermore, only 21% of patients had any molecular
immunophenotyping to detect MRD through abnormal reassessment throughout their disease. Although the
2
surface markers. This approach has been validated as recommendation to perform FLT3 testing in all CN-AML
a prognostic tool that correlates with relapse risk and cases dates back to 2010, this gap in implementation
treatment response. The combination of flow cytometry underscores a persistent challenge in real-world practice.
18
with molecular assays—such as PCR and NGS—further These shifts in the mutational profile underscore the need
enhances prognostic accuracy. Some mutations, such as for routine molecular reassessment, especially in the
those in the NPM1 gene, are considered reliable MRD setting of relapse or refractory disease.
markers. However, the role of FLT3 mutations in this
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context remains controversial due to their unstable Given the increasing availability of FLT3-targeted
behavior during disease evolution. therapies, identifying the mutational status at each
disease stage is critical. Previous studies suggest that FLT3
Reassessment of FLT3 mutational status at relapse is mutations may emerge at relapse in initially FLT3-wild
critical, given its profound therapeutic implications. The type patients. Timely identification of an actionable FLT3
clinical course of patients with FLT3-mutated relapse mutation may significantly impact therapeutic decision-
who do not receive a FLT3 inhibitor is uniformly poor, making and alter the clinical course—even offering curative
and targeted therapy may represent the only viable options in otherwise adverse scenarios. Understanding
option for disease control or remission. Importantly, this shift is critical for tailoring therapy.
evidence suggests that FLT3 mutations may emerge at
relapse in patients who were FLT3-wild type at diagnosis, This study aims to systematically evaluate published
highlighting the dynamic nature of the leukemic clone. evidence on the dynamics of FLT3 mutations in adult
Although current data remain limited and somewhat patients with AML, comparing the mutation status at
inconclusive, they underscore the necessity of routine diagnosis and relapse or refractory disease. The objectives
molecular reassessment during disease progression. are to (i) quantify the FLT3 mutation shift rate, (ii)
These dynamic shifts in clonal architecture have profound distinguish changes between FLT3-ITD and FLT3-TKD
clinical implications. The acquisition of new mutations— subtypes, (iii) assess methodological variability, (iv)
either within FLT3 or in other oncogenic drivers—can explore corresponding clinical implications, and (v)
lead to increased proliferation, therapeutic resistance, provide evidence-based recommendations for routine
and disease aggressiveness. For example, secondary FLT3- molecular retesting.
TKD mutations (e.g., N676K, F691L, A627P, Y842C) 2. Methods
may arise during treatment with midostaurin or second-
generation FLT3 inhibitors, conferring resistance. 20-22 In 2.1. Search strategy
parallel, mutations in other genes, such as ASXL1, WT1, An initial literature search was conducted in June 2020
and KMT2A, may further impair prognosis and treatment using the PubMed database to identify studies relevant
responsiveness. 23 to the research area. Search terms were selected based on
Despite current recommendations advocating Medical Subject Headings (MeSH) and included: “fms-like
for comprehensive molecular profiling in all cases of tyrosine kinase 3” OR “Fetal Liver Kinase-2” OR “Fetal
newly diagnosed AML—particularly in patients with Liver Kinase 2” OR “Fetal Liver Kinase-3” OR “Fetal Liver
cytogenetically normal AML (CN-AML)—the universal Kinase 3” OR “CD135 Antigens” OR “Antigens, CD135”
implementation of FLT3 testing remains suboptimal. OR “CD135 Antigen” OR “Antigen, CD135” OR “Stem
Retrospective registry data have indicated that in some Cell Tyrosine Kinase 1” OR “FLT3” AND “Leukemia,
centers, only 77% of patients with CN-AML underwent Myeloid, Acute”[MeSH] OR “Acute Myeloid Leukemia”
FLT3 mutational analysis. Alarmingly, this disparity is OR “ANLL” OR “Leukemia, Acute Myelogenous” OR

Volume 9 Issue 3 (2025) 65 doi: 10.36922/EJMO025150101