RESUMEN
The FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) is one of the most prevalent mutations, affecting between 20 and 30 percent of cases in patients with acute myeloid leukemia (AML). The Patients with a FLT3-ITD mutation have a poor prognosis. In the present study, we investigated the FLT3 (ITD-TKD) mutations in 100 newly adult Syrian patients with AML-Normal karyotype (NK). Our results revealed that prevalence of FLT3-ITD mutation was 24%. Interestingly, 20 patients had a typical duplication mutation and four patients had different mutations. From those four mentioned patients, two of them carried a 39 base pair (bp) duplication in different location: (c.1838_1877dup39, p.591-603dup) and (c.1836_1874 dup 39, p.591-603dup), the third patient, showed FLT3-ITD duplication and a newly insertion together, this insertion was not demonstrated before: (c.1842_1865dup24, c.1865_1866insGAA). Finally, the fourth patient exhibited a duplication of 21bp (c.1855_1875dup21, p.597-603dup). In addition, statistically significant differences were observed for the relation between the presence of FLT3-ITD mutation and lactate dehydrogenase (LDH) level, overall survival (OS), relapse, and event free survival (EFS). We demonstrated that our patients with FLT3-ITD mutation had a poor prognosis. Also, the frequency of FLT3-TKD mutation was low 2% and no compound between the two mutations was found, as individuals showed to carry the two mutations were not detected. These findings are likely useful for a better understanding of molecular leukemogenetic steps in AML-NK patients and may be beneficial for clinical relevance for risk grouping, study design and choice of therapy in Syrian population.
RESUMEN
OBJECTIVE: Among all types of hematological neoplasms, acute myeloid leukemia (AML) has the highest death rate. Recently, cytogenetic and molecular genetics are crucial in the management, as a consequence of their effect on AML pathogenesis, classification, risk-stratification, prognosis and treatment. METHODS: 100 Syrian adults with Normal Karyotype (NK) newly diagnosed AML patients were included in this study, all cases confirmed histologically and immunohistochemically. Patients were divided into six subgroups using flow cytometry and cytological results. Polymerase chain reaction (PCR) was performed on exon 11-12 for FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD), exon 12 for Nucleophosmin1 (NPM1), and exon 23 for DNA methyltransferase 3A (DNMT3A) using target primers, the electropherograms were analyzed for gene mutations by comparing with the reference DNA sequence. Data were compared and aligned with different sequences using the NCBI BLAST Assembled Genomes tool. RESULTS: FLT3-ITD, NPM1 and DNMT3A were detected in 24%, 22 % and 4% patients respectively. M2 subtype had the most frequent incidence of diagnosis in AML. FLT3-ITD mutation patients had the highest mean of death cases, while the DNMT3A mutation patients had the lowest. On the other hand, the highest mean of remission was in patients with NPM1 mutation and the lowest in the carriers of the FLT3-ITD mutation. It was observed that the mean relapsed patients with FLT3-ITD and DNMT3A mutation was 3.4 and 2 months respectively, with no significant differences between (FLT3-ITD and DNMT3A) carriers and non-carriers relapsed. On the contrary, the mean relapsed for NPM1 mutation carriers was 2.4 months with significant statistical differences. The mean survival time for patients with FLT3-ITD and NPM1 mutation was 5.9 months and 5.85 months respectively, with significant correlation. Between it was 5.88 months in DNMT3A patients with no significant differences. Finally, It was noted that the mean event free survival (EFS) of FLT3-ITD mutation patients was 4.818 months and the mean EFS of NPM1 mutation patients was 4.805 months, with significant statistical differences (p<0.05) between the mutation patients and non-mutated patients regarding to EFS, While this mean was not statistically significant in patients carrying DNMT3A mutation. CONCLUSION: Patients with FLT3-ITD and NPM1 mutations have the worst prognosis, where the presence of those mutations was significantly related to overall survival (OS) and EFS. Our study reflects that DNMT3A was not an extremely bad prognostic effect as an independent factor. We can declare according to this study that genetic mutation and variants detection could easily be incorporated into the regimen evaluation of AML patients.
