Profiling FLT3 Mutations in Mexican Acute Myeloid Leukemia Pediatric Patients: Impact on Overall Survival

Abstract

Background: Acute myeloid leukemia (AML) is the second most frequent leukemia in childhood. The FLT3 gene participates in hematopoietic stem cell proliferation. FLT3 mutations are recurrent in AML and influence prognosis. In Mexican pediatric AML patients, FLT3 mutational profile, and their clinical impact have not been evaluated. Aim of the study: This study aimed to identify the profile of FLT3 mutations in pediatric patients with de novo AML and to assess their possible influence on overall survival (OS) and other clinical features. Methods: Massive parallel target sequencing of FLT3 was performed in 80 patients. Results: FLT3 mutations [internal tandem duplication (ITD) or tyrosine kinase domain (TKD)] were identified in 24% of them. OS was significantly lower in FLT3 ^POS cases than in FLT3 ^NEG (p = 0.03). The average OS for FLT3 ^POS was 1.2 vs. 2.2 years in FLT3 ^NEG. There were no significant differences in the children's sex, age, percentage of blasts in bone marrow aspirate, or white blood cell count in peripheral blood at diagnosis between both groups. No differences were identified stratifying by the mutational load (high > 0.4) or type of mutation. The negative effect of FLT3 mutations was also observed in patients with acute promyelocytic leukemia (APL). Conclusions: FLT3 mutational profile is described in Mexican pediatric AML patients for the first time. Mutated FLT3 negatively impacts the outcome of AML patients, even considering the APL group. The clinical benefit from treatment with tyrosine kinase inhibitors in the FLT3 ^POS pediatric patients needs to be assessed in clinical trials. FLT3 testing may contribute to better risk stratification in our pediatric AML patients.

Keywords: AML; FLT3; Mexican; pediatric; risk-stratification; survival.

Figure 1

FMS-like tyrosine kinase 3 (FLT3) gene encodes a 993-amino-acid protein, consisting of five functional domains: an immunoglobulin-like extracellular domain, a transmembrane domain, a juxtamembrane domain (JMD), one interrupted tyrosine kinase domain (TKD), and a small C-terminal domain. Internal tandem duplications (ITDs) were the most common mutations in the FLT3^POS patients with insertions from 21 to 111 bp that mainly occurred in JMD, although two ITDs were found in the β1 sheet of TKD1. *Asp600del was positioned in exon 14 of the JMD, but it is not considered as an ITD, because no nucleotide duplication occurred. TKD activating mutations were located within the activation loop of the TKD2. Most of them were single-nucleotide variations resulting in amino acid changes at positions 835, 839, and 842. Two activating mutations caused by deletions were also identified in the TKD2.

Figure 2

Prognosis impact of FLT3 mutation. (A) Overall survival (OS) was analyzed considering FLT3–ITD or FLT3–TKD patients vs. the FLT3^NEG negative group. FLT3^POS patients (TKD or ITD) showed a significantly reduced OS as compared with those without FLT3 mutation. (B) No significant difference in OS was found between FLT3–ITD and TKD groups of patients. ITD, internal tandem duplication; TKD, tyrosine kinase domain.