Prevalence and Clinical Significance of FLT3 and NPM1 Mutations in Acute Myeloid Leukaemia Patients of Assam, India

Abstract

Acute Myeloid Leukaemia (AML) is one of the common forms of haematological malignancy in adults. We analysed the prevalence and clinical significance of FMS-like tyrosine kinase 3 (FLT3) and Nucleophosmin 1 (NPM1) mutations in AML patients of North East India. Co-prevalence and clinical significance of three recurrent chromosomal translocations namely t(15; 17), t(8; 21), t(16; 16) and expression of epidermal growth factor receptor (EGFR), flow markers were also documented and co-related with disease progress. We analysed bone marrow aspirates or peripheral blood samples from 165 newly diagnosed AML patients. All clinical samples were analysed by Real Time PCR and DNA sequencing based assays. NPM1 was the most frequently detected mutation in the study population (46/165 = 27.90%, 95% CI 20.75-35.05). FLT3 mutations were detected in 27/165 (16.40%, 95% CI 10.45-22.35) patients with internal tandem duplication (FLT3-ITD) in 24/165 (14.60%, 95% CI 8.91-20.29) and FLT3-D835 in 3/165 (1.80%, 95% CI 0-4.13) patients. NPM1 mutations were associated with a higher complete remission rate and longer overall survival ( < 0.01) compared to FLT3-ITD whereas FLT3-ITD showed adverse impact with poor survival rate ( < 0.01), leukocytosis ( < 0.01) and a packed bone marrow. EGFR expression was more in patients with NPM1 mutation compared to FLT3 mutation ( = 0.09). Patients with FLT3 and NPM1 mutations uniformly expressed CD13 and CD33 whereas CD34 was associated with poor prognosis ( ≤ 0.01) in patients with NPM1 mutation. FLT3-ITD was associated with inferior overall survival. However the clinical significance of FLT3-D835 was not clear due to small number of samples. NPM1 mutation showed better prognosis with increased response to treatment in the absence of FLT3-ITD.

<p>Combined Expression of CD34 and FLT3-Internal Tandem Duplication Mutation Predicts Poor Response to Treatment in Acute Myeloid Leukemia</p>

“…Although cytogenetics is the most valuable prognostic marker in AML, however in patients with normal karyotype, molecular tasting like FLT3-ITD mutation has an important role as a prognostic risk stratification for those patients, and therefore optimizing better therapeutic approaches. 21 The current study demonstrated that FLT3-ITD mutation represented 17.6% of the assessed Egyptian AML patients. This percentage was comparable to other studies which reported the prevalence of FLT3-ITD mutation which were 17.4%, 15.9%, and14.6% in Latin American, Chinese, and Indian patients, respectively.…”

“…Also, Wang et al 32 concluded a significant increase in the BM blast cell count and TLC in AML patients with FLT3-ITD mutation. On the other hand, Bhattacharyya et al 21 detected a significant increase in the TLC in AML patients with FLT3-ITD mutation, however no significant association with PB or BM blast cell count.…”

“…This percentage was comparable to other studies which reported the prevalence of FLT3-ITD mutation which were 17.4%, 15.9%, and14.6% in Latin American, Chinese, and Indian patients, respectively. [21][22][23] However, it was higher in South Korea (22.4%) and Australia (30.8%), while it was lower in Poland (8%) and Saudi Arabia (11.6%). [24][25][26][27] In line with many previously published studies, 28,30 it was reported that t (15,17) and chromosome 8 trisomy were the most significant recurrent alterations associated with FLT3-ITD mutation.…”

“…This percentage was comparable to other studies which reported the prevalence of FLT3-ITD mutation which were 17.4%, 15.9%, and14.6% in Latin American, Chinese, and Indian patients, respectively. 21 – 23 However, it was higher in South Korea (22.4%) and Australia (30.8%), while it was lower in Poland (8%) and Saudi Arabia (11.6%). 24 – 27 …”

“…Also, Wang et al 32 concluded a significant increase in the BM blast cell count and TLC in AML patients with FLT3-ITD mutation. On the other hand, Bhattacharyya et al 21 detected a significant increase in the TLC in AML patients with FLT3-ITD mutation, however no significant association with PB or BM blast cell count. The present data also showed an increased incidence of disease relapse, inferior overall survival, and disease-free survival rates in patients with FLT3-ITD mutation compared to patients with wild FLT3.…”