oa Molecular Diagnosis and Vaccines - Prognostic significance of activating FLT3 mutations in adults with acute myeloid leukemia



The aim of the present study was to investigate the frequency of FLT3 activating mutations; Internal tandem duplication (ITD)& the point mutation in exon 20 at aspartate (Asp) residue 835 within the tyrosine kinase domain (D835) in acute myloid leukemia (AML) and their correlation to prognostic factors and clinical outcomes. The study was conducted on 50 (23 males and 27 females) adult patients with newly diagnosed AML. Twenty apparently healthy and haematologically normal individuals of matched age and sex were also studied to verify the possibility of the occurrence of FLT3 mutations in normal subjects. We evaluated patients after induction chemotherapy which consisted of the standard 3+7 induction regimen. The evaluation was done in accordance with standard criteria for complete remission (CR), remission failure (RF) or remission death (RD) after 28 days from induction chemotherapy. Detection of FLT3 mutation was done by polymerase chain reaction (PCR) for the (ITD) mutation and by restriction fragment length polymorphism mediated polymerase chain reaction (RFLPPCR) for the (D835) mutation. We analyzed FLT3 mutations according to age, sex, WBC, FAB subtypes, percentage (%) of blast cells in peripheral blood (PB) and bone marrow (BM) and response to induction therapy. Tandem duplication (ITD) was found in (18/50) 36.0%. There were (9/18) 50.0% males and (9/18) 50.0% females, with no significant correlation between age or sex and FLT3-ITD. On the other hand only (3/50) cases were positive for FLT3-D835 6.0%. The three positive cases were males. A statistically significant relationship was found between D835 and male sex while no significant relation was found with age. The total white blood cell count (WBCs) was the only parameter that showed a significant increase in positive FLT3-ITD and FLT3-D835. Neither hemoglobin levels nor Blast % in PB or BM had significant difference between positive and negative cases of FLT3-ITD and FLT3-D835. On the other hand a significant relationship between FLT3-ITD and FAB subtype was found, while all positive FLT3-D835 cases were of M3 subtype. Among the 16 positive cases with ITD that could be followed after induction, only 3 achieved induction remission. In contrast, none of the 3 cases with FLT3-D835 mutation achieved induction remission. A statistically significant relationship was found between FLT3/ITD, FLT3-D835 mutation and failure to achieve induction remission. It is concluded that the prevelance of FLT3/ITD in our study population is a little higher than that reported else where, while that of FLT3-D835 is almost similar. FLT3 mutations are identified as poor prognostic factors in Adult AML as regards remission rate. Further study on a larger scale is recommended.


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