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Examination of the FLT3 and NPM1 mutational status in patients with acute myeloid leukemia from southeastern Poland.

ABSTRACT: INTRODUCTION:Acute myeloid leukemia (AML) is a genetically heterogeneous disease at both the cytogenetic and molecular levels. In AML cells many chromosomal aberrations are observed, some of them being characteristic of a particular subtype of patients, and others being less significant. Besides chromosomal abnormalities, the leukemic cells can have a variety of mutations involving individual genes. The aim of this work was to investigate the frequencies of molecular alterations with the focus on FLT3-ITD and NPM1 mutations in AML patients of different age groups living in a southeastern region of Poland. MATERIAL AND METHODS:The study group comprised 50 consecutive AML patients. We analyzed bone marrow samples by conventional cytogenetics. Cytogenetic evaluation in selected cases was complemented by the FISH technique. The internal tandem mutation in the FLT3 gene was identified using polymerase chain reaction (PCR), and the NPM1 mutation was assessed by direct nucleotide sequencing. RESULTS:The studies using classical cytogenetics showed chromosomal aberrations in 32 (64%) patients. In 18 cases no changes in the karyotype were found by conventional karyotyping. FLT3-ITD mutation was detected in 4 (8%) patients and mutation of NPM1 in 3 patients with AML (6%). CONCLUSIONS:The incidence of both mutations in our study group was lower than described elsewhere. We have confirmed that FLT3-ITD occurred more commonly in older patients and it was associated with shorter overall survival. By contrast, mutation of exon 12 of the NPM1 gene seems to be a good prognostic factor in AML patients with normal karyotype.

SUBMITTER: Koczkodaj D

PROVIDER: S-EPMC4754359 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Examination of the FLT3 and NPM1 mutational status in patients with acute myeloid leukemia from southeastern Poland.

Koczkodaj Dorota D Zmorzyński Szymon S Michalak-Wojnowska Małgorzata M Wąsik-Szczepanek Ewa E Filip Agata A AA

Archives of medical science : AMS 20160202 1

<h4>Introduction</h4>Acute myeloid leukemia (AML) is a genetically heterogeneous disease at both the cytogenetic and molecular levels. In AML cells many chromosomal aberrations are observed, some of them being characteristic of a particular subtype of patients, and others being less significant. Besides chromosomal abnormalities, the leukemic cells can have a variety of mutations involving individual genes. The aim of this work was to investigate the frequencies of molecular alterations with the ...[more]

PMID: 26925127

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Project description:ObjectiveWe aimed to retrospectively discern the heterogeneity of outcomes from clinicopathological characteristics and next-generation sequencing (NGS) data in adult patients with NPM1-mutated (NPM1mut ) acute myeloid leukemia (AML) induced with standard-dose (SD, 100-200 mg/m2 ) and intermediate-dose (ID, 1000-2000 mg/m2 ) cytarabine arabinose (Ara-C).MethodsIn the entire cohort and FLT3-ITD subgroups, multivariate Logistic and Cox regression analyses were used to analyze the comprehensive complete remission (cCR) rate after one or two induction cycles, event-free survival (EFS), and overall survival (OS).ResultsAmong a total of 203 NPM1mut patients evaluable for clinical outcome, 144 (70.9%) received a first SD-Ara-C induction and 59 (29.1%) received ID-Ara-C induction. Early death was recorded in seven (3.4%) after one or two cycles of induction. Focusing analysis on the NPM1mut /FLT3-ITD(-) subgroup, independent factors showing inferior outcome were presence of TET2 mutation [cCR rate, OR = 12.82 (95%CI 1.93-85.28), p = 0.008; EFS, HR = 2.92 (95%CI 1.46-5.86), p = 0.003], increasing age [EFS, HR = 1.49 (95%CI 1.10-2.02), p = 0.012 by every 10-years elevation], white blood cell count ≥60 × 109 /L [EFS, HR = 3.30 (95%CI 1.63-6.70), p = 0.001], and ≥4 mutated genes at initial diagnosis [OS, HR = 5.54 (95%CI 1.77-17.33), p = 0.003]. In contrast, when focusing on the NPM1mut /FLT3-ITD(+) subgroup, factors showing superior outcome were ID-Ara-C induction [cCR rate, OR = 0.20 (95%CI 0.05-0.81), p = 0.025; EFS, HR = 0.27 (95%CI 0.13-0.60), p = 0.001] and allo-transplantation [OS, HR = 0.45 (95%CI 0.21-0.94), p = 0.033]. Factors showing inferior outcome included CD34(+) [cCR rate, OR = 6.22 (95%CI 1.86-20.77), p = 0.003; EFS, HR = 2.01 (95%CI 1.12-3.61), p = 0.020] and ≥5 mutated genes [OS, HR = 2.85 (95%CI 1.33-6.10), p = 0.007].ConclusionWe conclude that TET2(+) , age, and white blood cell count convey an outcome risk modulation for AML with NPM1mut /FLT3-ITD(-) , as does CD34 and ID-Ara-C induction for NPM1mut /FLT3-ITD(+) . The findings permit re-stratification of NPM1mut AML into distinct prognostic subsets to guide risk-adapted individualized treatment.

Project description:ObjectiveAmong 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.Methods100 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.ResultsFLT3-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.ConclusionPatients 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.

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Examination of the FLT3 and NPM1 mutational status in patients with acute myeloid leukemia from southeastern Poland.

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Examination of the FLT3 and NPM1 mutational status in patients with acute myeloid leukemia from southeastern Poland.

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