Page 78 - EJMO-9-3

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

inclusion criteria in most studies. Consequently, only A study conducted in the United States demonstrated
descriptive analysis was feasible. In addition, the impact of a lower rate of testing for AML patients in academic
FLT3 allelic burden on prognosis could not be assessed due centers compared to community centers. This discrepancy
to a lack of extractable data. may reflect the heterogeneous incorporation of testing
In all studies included in the present review, FLT3 technologies across treatment facilities and a potentially
mutation detection was performed using PCR, the most lower rate of molecular testing requests by medical teams
widely adopted method in clinical practice. With the in community settings, as academic institutions often
advancement of molecular diagnostics, more sensitive require more frequent medical updates.
techniques have emerged, offering enhanced mutation In Brazil, the public healthcare system, known as
detection and broader genomic insights beyond the the Unified Health System (SUS), faces significant
scope of conventional PCR. NGS, for example, has gained challenges in the incorporation of new technologies,
traction in AML diagnostics; however, its sensitivity in even within academic centers. For example, cytogenetic
detecting FLT3-ITD mutations is limited by mutation size analysis—recommended since the 1980s—is still not fully
and allele frequency. Moreover, studies have highlighted implemented in the public system. This was evidenced in
variability even among PCR-based assays. The PCR a study conducted at the academic center of the University
method of choice for this type of assessment is fragment Hospital of Bahia, where only 60% of patients underwent
analysis PCR, which is more modern and sensitive. In karyotype analysis at diagnosis. While investment in
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the present review, some of the included studies were technological infrastructure is essential, parallel efforts
older and employed gel-based PCR, which may have are required to enhance continuous medical education,
contributed to false-negative results. In the context of ensuring that healthcare providers recognize the clinical
clinical research, there has been a growing trend toward utility of molecular data for risk stratification and
combining PCR and NGS methodologies, thereby therapeutic decision-making.
improving mutation detection and enabling more refined A key limitation of this systematic review is that the
genomic characterization. As previously reported, 47,48 this screening of titles and abstracts was performed by a single
hybrid approach holds clinical relevance in identifying investigator, which may have introduced selection bias and
resistance profiles to TKIs and may become the new gold potentially resulted in the exclusion of relevant studies. As
standard for FLT3 mutation analysis.
is widely recognized, systematic reviews require rigorous
FLT3 inhibitors have demonstrated promising methodology, ideally involving independent review by
results in clinical trials and are increasingly integrated multiple researchers to minimize bias. Moreover, some
into therapeutic protocols, with regulatory approvals studies were excluded due to missing or incomplete data.
in multiple regions. In Brazil, midostaurin is currently This review could not be registered on the PROSPERO
approved for newly diagnosed patients harboring FLT3- platform, as it currently only accepts registrations
ITD or FLT3-TKD mutations, based on the RATIFY of systematic reviews and meta-analyses involving
study, which demonstrated an improvement in overall interventions. The present work is classified as a systematic
survival and event-free survival compared to placebos. For review and meta-analysis with aggregation of prevalence
relapsed/refractory AML, gilteritinib has been approved data, in which the total proportion of FLT3-mutated and
for patients with FLT3 mutations, based on the ADMIRAL FLT3-wildtype patients was calculated. As a descriptive
study, which reported an overall survival of 9.3 months prevalence meta-analysis, it is not possible to perform
compared to 5.6 months with salvage chemotherapy. 49 statistical analyses to assess heterogeneity or publication
Our findings demonstrated a mutational status change bias. This methodological choice was based on the clinical
in 14% of patients, highlighting the importance of routine relevance of the data, which focused on mutation frequency.
molecular reassessment at relapse. Despite its relevance, To strengthen the findings, future studies should involve
access to FLT3 mutational status testing remains limited more than one reviewer and incorporate complementary
in many clinical settings. In the Brazilian public healthcare clinical outcome data to enable more robust statistical
system, previous data have indicated that up to 79% of analyses.
patients lack adequate molecular characterization due 5. Conclusion
to infrastructural and technological constraints. In
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the present review, approximately 5% of patients had The characterization of FLT3 mutation status and subtype
incomplete molecular data. The disparity is even more in AML represents one of the most robust molecular models
pronounced when comparing academic versus non- for supporting diagnosis, refining disease pathophysiology,
academic centers—a global challenge in cancer care. guiding risk stratification, and informing therapeutic

Volume 9 Issue 3 (2025) 70 doi: 10.36922/EJMO025150101