scholarly journals FLT3 Gene Mutation in Acute Myeloid Leukemia: Correlation with Hematological, Immunophenotypic, and Cytogenetic Characteristics

2021 ◽  
Author(s):  
Sunitha Shankaralingappa ◽  
Hemangi D. Joshi ◽  
Jayendra B. Patel ◽  
Prabhudas Patel ◽  
Jyoti Sawhney
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Gene Mutation ◽  
Myeloid Leukemia ◽  
Leukocyte Count ◽  
Tumor Burden ◽  
Serum Lactate Dehydrogenase ◽  
High Tumor Burden ◽  
Flt3 Mutation ◽  
Acute Myeloid

Abstract Introduction In acute myeloid leukemia (AML), FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is a common driver mutation associated with high tumor burden and poor prognosis. This mutation is common in normal karyotype AML and such patients have high leukocyte count. The presence of this mutation can be predicted by certain hematological and immunophenotypic characteristics in day-to-day practice. Objective This study was undertaken to assess the strength of association between FLT3 gene mutation and hematological and immunophenotypic characteristics. Materials and Methods Morphological, hematological, immunophenotypic, and cytogenetic characteristics of FLT3 mutations recorded in 424 patients of AML in adults and children between 2016 and 2019 in a tertiary care cancer center in Western India. Blasts were classified according to French-American-British method. Tumor burden was assessed by serum lactate dehydrogenase (LDH) levels, leucocyte count, and peripheral smear blast percentage. Results Out of 424 cases, FLT3-ITD and FLT3-tyrosine kinase domain mutation were found in 72 and 25 AML patients, respectively. Patients with FLT3 mutation had high tumor burden, characterized by high leukocyte count (p < 0.001), peripheral blood (p = 0.01) and bone marrow (p = 0.03) blast percentage, and high serum LDH (mean 777.8 vs. 586; p = 0.10) compared with FLT3-negative patients. They also featured high platelet count (p < 0.001). Morphological, immunophenotypic, and cytogenetic characteristics also have been presented in the study. Conclusion Observations of the study suggest the presence of definitive hematological and immunophenotypic characteristics along with raised serum LDH levels serve as surrogate markers and indicators of FLT3 mutation in AML patients.

Addition of Cladribine to the Standard AML Treatment Improves Long-Term Outcome in High Tumor Burden and Older Than 40 Years Acute Myeloid Leukemia Patients. Five-Year Follow-Up of the Polish Adult Leukemia Group (PALG 1999 DAC vs. DA Study).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1795-1795
Author(s):  
Jerzy Holowiecki ◽  
Sebastian Grosicki ◽  
Tadeusz Robak ◽  
Slawomira Krzemien ◽  
Sebastian Giebel ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Tumor Burden ◽  
Consolidation Therapy ◽  
Term Outcome ◽  
Long Term Outcome ◽  
High Tumor Burden ◽  
Acute Myeloid

Abstract The goal of the study was to evaluate long-term outcome of acute myeloid leukemia (AML) patients treated within the PALG 1999 DAC vs, DA Study. Between 1999–2002, 445 patients, aged 18–60 years, were randomized to the induction DAC-7: daunorubicin 60 mg/m2/d iv 1–3; cytarabine 200 mg/m2/d ci 1–7; cladribine 5 mg/m2 2h inf. iv d 1–5 or standard DA-7 regimen (the same regimen without cladribine). Patients achieving CR received two courses of subsequent intensive consolidation: 1) HAM (HD AraC, mitoxantrone) 2) HD AraC with or without cladribine in the DAC-7 or DA-7 arm, respectively. In case of PR after the first induction course the same regimen was repeated, NR patients received CLAG (2-CDA, HD-AraC, G-CSF), regardless the randomization arm. Post-consolidation therapy was in both arms comparable. As previously reported, a single course of DAC-7 induction resulted in 17% higher CR rate compared to the DA-7 treatment. The difference was particularly pronounced in a population of patients >40 years and for those with initial WBC >100x109/L. In the latter subgroup also the overall CR rate (achieved after >=1 induction course) was higher in the DAC-7 arm (71% vs. 43%). [Leukemia. 2004 May;18(5):989–97] In the present report we analyzed long-term outcome (median follow-up 3.2 years) in the whole study group and in pre-defined subgroups taking into account initial tumor burden, age, cytogenetics, FAB subtype, and preceding myelodysplasia. At five years the overall survival (OS) rate equaled 31% for DAC-7 and 25% for DA-7 arm (p=0.42) and leukemia free survivall (LFS) 32% vs. 29% (p=0.38), respectively. The subgroup analysis revealed higher probability of the OS in patients with initial WBC ≥100 G/l assigned to DAC-7 compared to DA-7 arm (39% vs. 11%, p=0.02). The LFS rate and the probability of relapse equaled 50% and 32% (p=NS) and 36% and 68% (p=0.0497), respectively. In patients aged >40 years, the therapy containing cladribine was associated with improved LFS (30% for DAC-7 vs. 20% for DA-7, p=0.01), and a tendency to improved OS (28% vs. 18%, p=0.09). In this subgroup DAC-7 therapy resulted in reduced relapse incidence (60% vs. 69%, p=0.04).We conclude that addition of cladribine to induction/consolidation therapy of AML may improve long-term outcome in higher age ranges patients and in those with high tumor burden. The improvement results mainly from reduced risk of relapse, and, in patients with high initial WBC, from higher CR rate.

Effect of FMS-Like Tyrosine Kinase-3 Mutations on Prognosis in Acute Myeloid Leukemia: A Single Institution Experience between 2000 and 2007.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3489-3489
Author(s):  
Hady A. Ghanem ◽  
Dan Jones ◽  
Hagop M. Kantarjian ◽  
Stefan Faderl ◽  
Elihu H. Estey ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Negative Impact ◽  
Cancer Center ◽  
Molecular Abnormalities ◽  
Flt3 Mutation ◽  
Flt3 Mutations ◽  
Acute Myeloid

Abstract Mutations of the FMS-like tyrosine kinase-3 gene (FLT3), including internal tandem duplication (ITD) of the juxtamembrane domain or activating point mutations of the second tyrosine kinase domain involving codon 835 or 836 are among the most common molecular abnormalities in acute myeloid leukemia (AML). A clear negative impact of FLT3 mutation on survival has been demonstrated in AML patients younger than 60 years; however, this negative effect on prognosis or survival has not been confirmed in older patients. We evaluated 661 patients with AML treated at MD Anderson Cancer center between 2000 and 2007 for FLT3 mutations including 281 patients ≤ 60 years and 380 patients > 60 years. Median age for the entire group was 65 years (range, 17 to 86). A FLT3 mutation was present in 124 patients (18.7%). Patients with FLT3 mutations had a significantly higher WBC (median, 16.5 vs. 4.2, p<0.001) and a higher percentage of bone marrow blasts (median, 62% V/S 40%, p<0.001) at initial presentation. These differences were equally seen in both sexes. Patients with FLT3 mutations were younger than those without mutations (median age 58 vs. 64, p=0.005). Patients with FLT3 mutations were less likely to have an antecedent hematological disease compared to those without mutations (p<0.001). FLT3 mutations were less frequent in patients with core binding factor leukemia [t(8;21), inv(16)]. FLT3 mutations were more common in patients with acute promyelocytic leukemia (APL) than other FAB subgroups (p<0.001). Induction death and complete remission rates were not affected by FLT3 status. When favorable prognosis subgroups [APL, t(8;21), inv(16)] were excluded, patients with FLT3 mutations had a significantly shorter overall survival; this difference was seen in patients younger than 60 (p=0.019), as well as in patients over 60 (p=0.015). We have further confirmed a clear negative impact of FLT3 mutations on survival in patients ≤ 60 years and have demonstrated a negative impact on survival even in patients older than 60 years. FLT3 inhibitors should be considered as a component of therapy in older patients with non-favorable AML and FLT3 mutation.

Difference in FLT3 Mutational Status between Diagnosis and Relapsed/Refractory Acute Myeloid Leukemia: A Meta-Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 28-29
Author(s):  
Lais Teixeira Silva ◽  
Camilla C. Campos ◽  
Marco Aurelio Salvino
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Prognostic Value ◽  
Meta Analysis ◽  
Disease Course ◽  
Mutation Status ◽  
Flt3 Mutation ◽  
Mutational Status ◽  
Acute Myeloid

Introduction Research in recent years has shown that the class III receptor tyrosine kinase Fms-like tyrosine kinase 3 (FLT3) gene mutation was identified in 30% of Acute Myeloid Leukemia (AML) patients. The FLT3 internal tandem duplication (FLT3-ITD) is positive for 25% of AML cases, while FLT3 tyrosine kinase domain (FLT3-TKD) is present in 5% of cases. Some studies have showed that patients with AML with FLT3 mutation may maintain the alteration in the relapse/refractory (RR) disease, although this is not always the rule. This report is a review about the genetic change of FLT3 mutation in the RR AML scenario. Methods It is a retrospective meta-analysis research. A search in June/2020 was performed in PubMed to identify studies with the terms FLT3 (title/abstract) AND Acute Myeloid Leukemia without a restricted date. The papers were select based in title and abstract. Inclusion criteria were adult AML, language in English, Spanish or Portuguese. Exclusion criteria were studies in children and acute promyelocytic anemia. Data were collected from retrospective or prospective studies in which patients with RR AML had the data about FLT3-ITD or FLT-TKD in the diagnosis and relapse. Results and Discussion 1201 papers were found, in which 688 were excluded by reading the title, and 506 eliminated after the title and abstract revision. From these, 17 were eligible for full text reading. From eligible papers, 6 were rejected. All the studies used PCR as the method of evaluation of FLT3 mutational status. Six studies assessed FLT3 ITD and TKD mutations, four assessed only FLT3-ITD and one checked only FLT3-TKD mutation. Six articles described mutation status in both FLT3 alterations. The total of 272 patients with RR AML were analyzed in these studies. 74 (27%) were positive for FLT3-ITD at diagnosis and 15 (5%) for FLT3-TKD. In the relapse, 81 (29%) were FLT3-ITD positive and 11 (4%) FLT3-TKD positive. The change in mutation status occurred in 47 (17%) of patients, 3 patients of these change from FLT3-TKD to FLT3-ITD mutation. Three works had patients with acute promyelocytic leukemia, a total of 10 patients. In one work 42 children were included in the study, representing 15% of the total population. Mutational status change from negative to FLT3-ITD in 20 (7%) patients, FLT3-ITD to negative in 14 (5%). From those that were FLT3-ITD positive, 60 (22%) remained positive in the relapse. In patients with FLT3-TKD, change in mutation status from positive to negative occurred in 6 (2%) of the patients, 4 (1%) were negative and gained the mutation, 6 (2%) maintained positive in diagnosis and relapse. 159 (58%) were negative in all the disease course. When we analyzed only FLT3-ITD mutation, a total of 607 patients were studied at diagnosis and relapsed, 30% were FLT3-ITD positive in relapse. Change in mutational status occurred in 12%. Meanwhile, 392 patients had their mutational status available when considering only FLT3-TKD. 89% were negative in diagnosis and relapsed. 31 (8%) patients had their status changed. We described FLT3 mutations status in paired samples from diagnosis to relapsed/refractory AML. Our data demonstrate that 41% of patients were positive for FLT3 mutation in some point of the disease. One in six patients had their mutational status altered. Some patients may have had small clones with mutated cells that were below the limit of the detection by assay and proliferated after treatment. Another hypothesis is that ade novomutation was acquired during the disease course. From the population in the study, 7% were FLT3 positive/negative, which could represent the loss of the mutation post chemotherapy and a selection of a new clone originating from the relapsed disease. The information about FLT3 status is important due to a possible prognostic value in patients with relapse/refractory disease and because the patient can benefit from a novel therapeutic treatment with FLT3 inhibitors. Conclusion FLT3 mutation is an important mutation in AML at diagnosis and relapse/refractory scenario and the mutational status is variable during the disease. Since one in six patients had their mutational status altered in the study, reassessment should be mandatory in any case of relapse and refractoriness. More studies are needed to evaluate the prognostic value of those changes and the development of more sensitive methods could help to find small clones already present in AML at diagnosis. Disclosures No relevant conflicts of interest to declare.

scholarly journals Soluble P-selectin and correlation with Prothrombin Fragment 1 + 2 in myeloid malignancies in Cipto Mangunkusumo general hospital

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Lugyanti Sukrisman
Keyword(s):  
Acute Myeloid Leukemia ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Leukocyte Count ◽  
Endothelial Activation ◽  
Enzyme Linked Immunosorbent Assay ◽  
Newly Diagnosed ◽  
Prothrombin Fragment ◽  
Soluble P ◽  
Acute Myeloid

Abstract Background Myeloid cells express microparticles that could increase the expression of adhesion molecules including P-selectin. We aimed to evaluate the level of soluble P-selectin (sP-selectin) and prothrombin fragment 1 + 2 (F1 + 2), and to determine correlation of sP-selectin with leukocyte count and F1 + 2 levels in acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) patients. Methods Patients with newly diagnosed AML (n = 25), CML (n = 13), and controls (n = 17) were recruited in this study. The diagnosis of AML and CML is based on 2001 WHO and/or FAB criteria. Levels of sP-selectin and F1 + 2 were determined using enzyme-linked immunosorbent assay kits (Behring ELISA Processor-III® and Behring Enzygnost F1 + 2). Results sP-selectin was significantly elevated in CML patients compared to AML patients (p = 0.001). Levels of F1 + 2 in AML and CML patients were significantly increased in comparison to controls (p < 0.001 and p = 0.043). Levels of sP-selectin were significantly correlated to leukocyte count (r = 0.437; p = 0.029) and F1 + 2 (r = 0.436; p = 0.029) in AML patients. Conclusions AML and CML patients had an increased tendency to thrombosis. While CML patients had higher platelet and/or endothelial activation, hypercoagulable state are more pronounced in AML patients.

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