Lower frequency of <scp>NPM</scp>1 and <scp>FLT</scp>3‐<scp>ITD</scp> mutations in a South African adult <i>de novo </i><scp>AML</scp> cohort

Marshall, Robyn; Tlagadi, A.; Bronze, Michelle; Kana, Vibha; Naidoo, Strinivasen; Wiggill, Tracey; Carmona, Sergio

doi:10.1111/ijlh.12204

Cited by 15 publications

(11 citation statements)

References 30 publications

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“…In patients with FLT3 and NPM1 mutations, the associations of other genetic alterations have also been evaluated to understand any possible role in disease outcome. The prevalence of FLT3 and NPM1 mutations found in this population was in coherence with other studies (Asian and Western) despite geographic and ethnic differences (Tables 3, 4) [19][20][21][22][23][24][25][26][27][28][29][30].…”

Section: Discussionsupporting

confidence: 90%

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

Bhattacharyya

Nath

Saikia

et al. 2017

Indian J Hematol Blood Transfus

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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.

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Section: Discussionsupporting

confidence: 90%

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

Bhattacharyya

Nath

Saikia

et al. 2017

Indian J Hematol Blood Transfus

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“…This suggests that the gene mutations assessed for on the microarray might be population specific and are therefore not being detected. In 2014, Marshall et al reported a lower frequency of known NPM1 and FLT3 -ITD mutations in a South African AML cohort and suggested that race-specific mutations might contribute to AML pathogenesis and also to the lower frequency of detection of these mutations [ 14 ]. They further concluded that NPM1 mutation frequency increases with population age and that their cohort had a considerably younger median age at diagnosis, which might contribute to the lower frequency of NPM1 mutations observed in their study.…”

Section: Discussionmentioning

confidence: 99%

Application of the AMLprofiler Diagnostic Microarray in the South African Setting

Kappala

Alessandrini

Matlhako

et al. 2017

Stem Cells International

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Acute myeloid leukemia (AML) is characterized by proliferation of the myeloid lineage and accumulation of immature hematopoietic cells in the bone marrow and is typified by marked heterogeneity both in response to treatment and survival. AMLprofiler is a qualitative in vitro diagnostic microarray incorporating seven molecular biomarkers used to diagnose and predict posttherapy survival rates. In this study, we compared AMLprofiler to routine AML diagnostic methodologies employed in South Africa, focusing on consistency of the results, cost, and time to result. RNA was isolated from bone marrow and peripheral blood samples from patients with de novo AML and was processed using Affymetrix Gene Profiling Reagent kits. The results from AMLprofiler and standard methodologies were highly comparable. In addition, many samples were determined to be positive for biomarkers not routinely investigated in South Africa, namely, CEBPA double mutants, NPM1 variants, and altered expression levels of BAALC and EVI1. 38% of samples presented with no positive biomarker; AMLprofiler nonetheless enabled 26% of AML patients to be classified into either favorable or poor prognostic categories. This study highlights the comprehensive nature of the microarray. Decreased time to result and refinement of risk stratification are notable benefits.

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“…This mutation is much less common 2-8% in pediatric AML and about 7.5% in younger median age AML cases [13,14,18,19]. Notably, Incidence of the NPM1 mutations is age-dependent as the mutation has not yet been identified in children younger than 3 years old, whereas the frequency is 10-19% in children older than 3 years and exceeds 30% in children older than 10 years [20,21].…”

Section: Npm1 Mutationsmentioning

confidence: 99%

Distinct Gene Mutations, their Prognostic Relevance and Molecularly Targeted Therapies in Acute Myeloid Leukemia (AML)

Tayyab¹

2014

J Cancer Sci Ther

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Acquired genetic alterations which include balanced and unbalanced chromosome aberrations and submicroscopic gene mutations and changes in gene expression strongly influenced by pretreatment clinical features and prognosis of adults patients with acute myeloid leukemia (AML). Cytogenetic profiling separate AML patients into three broad prognostic groups: favorable, intermediate and adverse. The cytogenetic risk classifications vary to some extent for younger adult patients and for those aged 60 years or older. In many cases, patients with specific cytogenetic rearrangement such as those with a normal karyotype or those with either RUNX1-RUNX1T1 or CBFB-MYH11 feature of core-binding factor (CBF) can be further subdivided into prognostic categories depend on the presence or absence of specific gene mutations or changes in gene expression. Advancement in the understanding of cancer genetic and discovery of recurrent mutations in AML provide opportunity to develop targeted therapies and improve the clinical outcome. The identified gene mutations, mainly targetable lesions are gain of function mutations of JAK2 and cKIT and FLT3 in APL have been associated with clinical features and/ or outcome of patients with these AML subtypes. These data emphasize the significance of genetic testing for common translocations for diagnosis, prognosis and increasingly targeted therapy in acute leukemia. Notably, these several molecular genetic alterations constitute a variety of diverse new targets for salvage therapies. These approaches intend to develop targeted treatment concepts that depend on interference with molecular genetics or epigenetic mechanisms. This report provides an overview on characteristic gene mutations, discuss their biological functions and Prognostic significance, which serve as basis for selected therapy approaches now or might represent options for such approaches in the future and expected to have a role in treating AML subtypes with characteristic molecular alterations.

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Lower frequency of NPM1 and FLT3‐ITD mutations in a South African adult de novo AML cohort

Cited by 15 publications

References 30 publications

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

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

Application of the AMLprofiler Diagnostic Microarray in the South African Setting

Distinct Gene Mutations, their Prognostic Relevance and Molecularly Targeted Therapies in Acute Myeloid Leukemia (AML)

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