Identification of FLT3-TKD Mutation in a Patient with Acute Myeloid Leukemia: Evidence Suggesting Possible Germline Origin
Authors: Di Stefano Marcos , Ramos Oscar Enrico , Larrea Esteban David , Silva Sofia Stefany , Luna Beatriz , Arias Calvachi Claudia Patricia 
Published: December 2024

Acute myeloid leukemia (AML) is a hematological malignancy characterized with an abnormal increase of blast cells to over 20%, with different survival rates of less than or more than 5 years, depending on factors such as age, leukocytosis, type of treatment, molecular characteristics, and other factors. The molecular characteristic is especially important for a specific mutation in FLT3 occurs in approximately 30% of all patients with AML. Which has two types of mutation of FLT3: Internal tandem duplications (FLT3-ITD) mutation in the juxtamembrane domain leads to uncontrolled proliferation of AML blast, and point mutations within the activation loop of the tyrosine kinase domain (FLT3-TKD), affecting D835 in most cases and has a lower incidence AML (approximately 7-10% of all cases).
To detect molecular alterations using we employed Next-Generation Sequencing (NGS) to evaluate punctual mutations in patients with complex neoplastic disorders. FLT3-ITD are more common and are associated with a worse prognosis, playing a clear role in the progression of the disease. In contrast, the prognostic impact of FLT3-TKD mutations is not as well defined, generally considered prognostically neutral, have been associated with a favorable prognosis in some reports, especially in specific mutation combinations (e.g., together with mutant NPM1).
We present a 34-year-old patient with a subtype of AML, previously detected with inversion 16 (CBFB/MYH11) by RT-qPCR, belonging to the favorable-risk category, with a rare case of relapse. Consequently, to gather more information about this patient, Next-Generation Sequencing (NGS) was requested on a specific panel with genes important for myeloid disorders. This identified a FLT3-TKD point mutation (c.2503G&gt;C), followed by inv (16), providing a better understanding of the patient. The variant allele frequency was 43.36% with a depth of 5316, associated with the database with Tier 1, indicating a variant with significant clinical importance according to the American Society of Clinical Oncology (ASCO) / College of American Pathologists (CAP) / (Association for Molecular Pathology (AMP) for Cancer Variant Classification.
It's important to note that the inv (16) does not affect the risk classification when FLT3-TKD is present, constitutes a favorable prognosis by risk stratification for patients with AML. The alteration in FLT3-TKD, despite not having a well-defined hereditary character in cancer, raises suspicion of a possible germline mutation due to the allele's high- frequency, furthermore, there are no current studies in Ecuador. This case highlights the importance of distinguishing the origin of mutation, have genetic counseling and take new sample for a molecular profile, especially in underrepresented populations such as the Ecuadorian one, and resaler the importance for take more investigation, given that studies with criterion beneficial prognosis with FLT3-TKD in different populations.