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a Detection of FLT3/ITD mutations by Genomic PCR: Lane 1–3 shows FLT3/ITD mutations, while Lane 4–7 shows normal wildtype FLT3. b Detection of FLT3/D835 mutation: Lane 5 shows detection of FLT3/D835 mutation
Source publication
Acute myeloid leukemia (AML) with normal karyotype represents a clinically and molecularly heterogeneous disease. Molecular markers with prognostic significance have been examined to improve risk profile characterization of this group. Activating mutations on FLT3 receptor are one of the most common genetic alterations reported. However, the preval...
Citations
... No remarkable differences between the control and the NaOCl could be found. The group treated with the bromelain enzyme displayed the maximum bond strength [8]. ...
... AML is more common in males than in women, with a male to female ratio of roughly 2:1. The current investigation's observation of a male majority (58.5% of patients) was consistent with other researches (16,17) . ...
... Activating mutations in FLT3, especially ITD, leads to proliferative signals and is commonly associated with high white blood cell counts, increased chances of central nervous system disease, short DOR, and poor survival outcomes in AML [16,[23][24][25][26]. The oncogenic impact of FLT3 ITD is also dependent on the mutated to wild-type allelic ratio, the mutation length and its interaction with cytogenetics, and co-occurring mutations [15,18,[27][28][29]. ...
Opinion statement
Treatment options in acute myeloid leukemia (AML) have improved significantly over the last decade with better understanding of disease biology and availability of a multitude of targeted therapies. The use of FLT3 inhibitors (FLT3i) in FLT3-mutated (FLT3mut) AML is one such development; however, the clinical decisions that govern their use and dictate the choice of the FLT3i are evolving. Midostaurin and gilteritinib are FDA-approved in specific situations; however, available data from clinical trials also shed light on the utility of sorafenib maintenance post-allogeneic stem cell transplantation (allo-SCT) and quizartinib as part of combination therapy in FLT3mut AML. The knowledge of the patient’s concurrent myeloid mutations, type of FLT3 mutation, prior FLT3i use, and eligibility for allo-SCT helps to refine the choice of FLT3i. Data from ongoing studies will further precisely define their use and help in making more informed choices. Despite improvements in FLT3i therapy, the definitive aim is to enable the eligible patient with FLT3mut AML (esp. ITD) to proceed to allo-SCT with regimens containing FLT3i incorporated prior to SCT and as maintenance after SCT.
... Therefore, it was concluded that rapid identification of specific translocations at diagnosis is important for prognostic purposes and their detection should be incorporated into routine assessment. In India, Chauhan et al 14 showed FLT3-ITD mutation to be present in 23% with association to young age less than 15 years and high WBC count. However, no significant difference was reported in the response rates to conventional chemotherapy in patients with or without FLT3/ITD mutation. ...
Background:
FLT-3 mutation is a valuable prognostic marker in patients of AML being related with bad prognosis and poor clinical response to conventional chemotherapeutic agents. Frequency of FLT-3 mutation in AML varies from 25% to 35%. The objective of this study was to determine prevalence of FLT-3 mutation in patients with Acute Myeloid Leukaemia.
Methods:
This observational cross-sectional Study was conducted in Department of Oncology, Jinnah Hospital Lahore from 1st October 2018 to 31st March 2019. Patients with acute myeloid leukaemia, aged 15-60 years, of both genders were included. After taking consent, demographic data was noted. Three ml of sample of blood was obtained from each patient and sent for detection of FLT-3 mutation. Data was analysed using SPSS version 20.0. Chi square test was applied, pvalue <0.05 significant.
Results:
A total of 180 patients were enrolled in this study. The mean±SD age of patients was 34.72±14.3 years, among which 38.3% were female and 61.7% male. The mean±SD duration of disease was 3.39±2.8 months. The mean±SD haemoglobin level, TLC and platelet counts were 7.2±2.3 g/dl, 30,913±63,573 per cm and 58.6±52.3×103 per cm. The blast cell (%) count was 69.6±19.8. FLT-3 mutation was present in 18.9%.
Conclusions:
We conclude that FLT-3 mutation to be present in only a minority of patients with Acute Myeloid Leukaemia having no significant association with age, sex, haemoglobin, WBCs and blast counts.
... The myeloblastic populations included Table 1. Clinical and biological characteristics of patient populations according to FLT3-ITD and NPM1 mutational sta- The selection of specific antigens for quantitative analysis was based on an initial antigen expression screening (using qualitative flow cytometry data obtained from patient diagnostic reports, Supplementary data methods section, Supplementary Table 2), and on previously published reports regarding antigen expression in FLT3-ITD and/ or NPM1-MUT AML [7][8][9]11,15,[19][20][21][22][23]. The geometric mean fluorescence intensities (MFIs) of CD4, CD7, CD9, CD13, CD14, CD33, CD34, CD56, CD64, CD71, CD117, and CD123 were determined for the blasts populations and normalized to the MFIs of negative lymphocyte populations for the respective markers, as previously described (Supplementary Figure 1(D,E)) [9]. ...
... CD117 negtive populations were observed in the FLT3-WT/NPM1-MUT group (Fischer's exact test ¼ 7.747, p¼0.023). Based on these results and a review of the literature [7][8][9]11,15,[19][20][21][22][23], as described above, the following markers were selected for MFI analyses: CD4, CD7, CD9, CD13, CD14, CD33, CD34, CD56, CD64, CD71, CD117, and CD123. Antigen expression levels according to only the FLT3-ITD and Antigen expression patterns and levels according to FLT3-ITD and NPM1 mutation combinations ...
The most frequent mutations in acute myeloid leukemia (AML) – FLT3-ITD and NPM1 – are associated with a specific immunophenotype. We evaluated the levels of surface antigens in an uninvestigated AML patient population according to the combination of FLT3-ITD/NPM1 mutations. Antigen levels were calculated as the geometric mean fluorescence index (MFI) ratio between myeloblasts or monoblasts/monocytes and a negative population for the specific antigen. In myeloblastic populations, FLT3-ITD cases presented CD7high MFI values (p < .001), while NPM1-MUT cases presented CD33high (p < .001), and CD34low (p < .001) MFI values. Within the monoblastic/monocytic populations, CD56high expression was observed only in the FLT3-WT/NPM1-MUT population (p=.003). The single common antigen expression between myeloblasts and monoblasts/monocytes was CD123high expression only within the FLT3-ITD/NPM1-MUT subgroup. Our results present a subtle influence of FLT3-ITD/NPM1 mutations upon antigen expression profiles in myeloblasts vs monoblasts/monocytes, and we described a novel correlation between the presence of NPM1 and CD56high values within bulk leukemic monoblasts/monocytes.
... Several individual markers have been studied for their association with prognosis, but reports on a possible association vary widely between studies. Expression of CD7, normally found on thymocytes and mature T-cells, on AML blasts has been associated with FLT3/ITD mutations (7,8) and double mutated CEBPa (9,10), while reports on the impact on prognosis vary (11)(12)(13)(14)(15)(16)(17). CD11b (MAC-1), a protein subunit that binds to ICAM1 and is involved in leukocyte adhesion and migration (18), has been related to presence of a monosomal karyotype (MK) (19) and poor prognosis (19)(20)(21), but this is disputed by others (22). ...
Background:
In acute myeloid leukemia controversy exists about the role of immunophenotyping of the blasts at diagnosis as a potential prognostic factor.
Methods:
We retrospectively analyzed immunophenotypic marker expression on blasts in relation to genetic aberrancies and survival data of 684 patients. All patients were included in different studies from the HOVON/SAKK Consortium.
Results:
Markers CD2, CD7, CD11b, CD19, CD22, and CD56 all appeared to be associated with one or more established prognostic genetic aberrancies. In the overall population, differences in univariate survival analyses were observed for CD2, CD11b, and CD22. After correcting these survival differences for currently used risk profile data, only CD11b expression remained of prognostic value for poor overall survival (OS) and event-free survival (EFS). CD11b expression turned out to be an independent factor for poor OS and EFS in the subgroup of patients who lacked cytogenetic and molecular aberrancies.
Conclusions:
In this study, we demonstrate that associations between immunophenotypic markers and genetic aberrancies interfere with the prognostic properties of immunophenotypic markers. Such may account for most of the previously reported prognostic impact of these markers. Only CD11b expression remained as an independent prognostic marker. © 2017 International Clinical Cytometry Society.
... (9) Surprisingly, the mean age of the patients in our study is 42 years, which is in concurrence to published reports from Pakistan (10,11) AML is slightly more common in men, with a male to female ratio of 2:1. (12) However, in our study female patients were slight dominant which may be coincidence. However, one of the study recently conducted in Iranian population showed same prevalence of male versus female which was seen in our patients. ...
Background:
Acute myeloid leukemia (AML) is a malignant disease of the bone marrow in which karyotypic analysis is the most important diagnostic and prognostic tool for predicting remission rate, relapse and overall survival. This study was carried out to determine the frequency and type of cytogenetic aberrations in de novo acute myeloid leukemia in adults at a tertiary care hospital.
Materials and methods:
This descriptive cross-sectional study was carried out in the Hematology Department, Liaquat National Hospital from November 2014 to April 2016.A total of 51cases were diagnosed with AML during the study period. Cytogenetic analysis was carried out by banding technique on bone marrow aspirate samples.
Results:
The mean age of the study subject was 42.03±17.70 years. Frequency of karyotyping abnormalities was observed in 47% of cases, in which most frequently occurring cytogenetic abnormalities were those of good cytogenetics including t(15;17) and t(8;21), seen in 23.5% and 9.8% of cases respectively. Intermediate risk cytogenetics including Del 9q was seen in 1.96% of cases. However, poor risk cytogenetics including complex cytogenetics, t(11;q23) and del (13) were seen in 7.8%, 1.96% and 1.96% of cases respectively. Normal cytogenetics was seen in 27 (52.9%) patients.
Conclusion:
Karyotyping is one of the most important diagnostic and prognostic tools and a maximum benefit could be attained through cytogenetic analysis. Cytogenetic aberrations in our series are more or less similar as reported at national level with preponderance of good risk cytogenetics in our setting.
... AML is slightly more common in men, with a male to female ratio of ~2:1. In the present study male preponderance was observed and it was consistent with other studies (Harani et al., 2005;Chauhan et al., 2011). ...
Background:
Acute myeloid leukemia (AML) is an acquired clonal frequent malignant disorder of myeloid progenitor cells. Our aim was to study demographical and clinicopathological features of adult Pakistani AML patients at presentation.
Materials and methods:
In this single centre study extending from January 2010 to December 2014, data were retrieved from the patient records with a predetermined performa and analyzed with SPSS version 22.
Results:
Overall 125 patients were diagnosed at our institution with de novo AML during the study period. There were 76 males and 49 females (ratio 1.5:1), with an age range between 15 and 85 years and a mean age of 38.8±20.1 years. The major complaints were fever (72.8%), generalized weakness (60%), bleeding (37.6%) and dyspnea (12%). Physical examination revealed pallor in 56.8%, splenomegaly and hepatomegaly in 16% and 12.8%, respectively, and lymphodenopathy in 10.4%. The mean hemoglobin was 8.19±2.12g/dl with a mean MCV of 86.0±9.83 fl, a mean total leukocyte count of 43.1±68.5x109/l, an ANC of 3.09±6.66x109/l and a mean platelet count of 62.3±78.6x109/l.
Conclusions:
AML in Pakistani patients is seen in a relatively very young population with male preponderance, compared with the west. However, clinico-pathological features appear comparable to published data.
... Overexpression of the FLT3 receptor takes place in about 70%-100% of acute myeloid leukemia (AML) as well as the majority of acute lymphoblastic leukemia (ALL) cases. [9][10][11][12] The FLT3 receptor gene mutations are the most frequent genetic defects observed in AML patients, and among them ITD mutations and point mutation at location of ASP835 (D835) are the most known. [13][14][15][16] in 1996 by Nakao et al, occur in the juxtamembrane domain (JM). ...
FLT3 ITD and D835 mutations occur in high frequency in AML and to a lower rate in ALL patients with poor prognosis.
ITD and D835 mutations were studied in 100 diagnosed acute leukemia patients including 27 AML and 73 ALL with various FAB classifications by PCR and PCR-RFLP, respectively. Subsequently, PCR products of positive samples were confirmed by sequencing analyses.
ITD mutations occurred in 10% of all pediatric acute leukemia, including AML and ALL. 25.9% of AML patients harbor a mutation in the ITD in various subtypes. The frequency of ITD mutations was 4% in ALL. Various insertions of nucleotides in ITD were observed, similar to those described in the literature previously.
These preliminary data suggest that flt3-ITD mutations may play an important role in leukemogenesis in a proportion of children, particularly in the case of AML.
... The FLT3-ITD occurs in approximately 23% of adult AML patients and is associated with poor prognosis (72,73). FLT3-ITD mutated AML is associated with a variable CD34 expression and high expression of the myeloid antigens HLA-DR, CD13, CD33, and MPO (74,75). In addition, expression of CD36, CD11b (75), and CD7 (74) were frequently observed in FLT3-ITD cases (Table 6). ...
Detection of minimal residual disease is recognized as an important post-therapy risk factor in acute myeloid leukemia patients. Two most commonly used methods for residual disease monitoring are real-time quantitative polymerase chain reaction and multiparameter flow cytometry. The results so far are very promising, whereby it is likely that minimal residual disease results will enable to guide future post-remission treatment strategies. However, the leukemic clone may change between diagnosis and relapse due to the instability of the tumor cells. This instability may already be evident at diagnosis if different subpopulations of tumor cells coexist. Such tumor heterogeneity, which may be reflected by immunophenotypic, molecular, and/or cytogenetic changes, can have important consequences for minimal residual disease detection, since false-negative results can be expected to be the result of losses of aberrancies used as minimal residual disease markers. In this review the role of such changes in minimal residual disease monitoring is explored. Furthermore, possible causes of tumor instability are discussed, whereby the concept of clonal selection and expansion of a chemotherapy-resistant subpopulation is highlighted. Accordingly, detailed knowledge of the process of clonal evolution is required to improve both minimal residual disease risk stratification and patient outcome. © 2013 International Clinical Cytometry Society.
