scholarly journals Morphological and Immunophenotypic Clues to the WHO Categories of Acute Myeloid Leukaemia

2019 ◽  
Vol 141 (4) ◽  
pp. 232-244 ◽  
Author(s):  
Barbara J. Bain ◽  
Marie C. Béné
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Molecular Genetic ◽  
Npm1 Mutation ◽  
Transient Abnormal Myelopoiesis ◽  
Degree Of Certainty ◽  
Diagnosis And Classification ◽  
Provisional Identification ◽  
High Degree ◽  
Acute Myeloid

Diagnosis and classification of acute myeloid leukaemia (AML) require cytogenetic and molecular genetic investigation. However, while these evaluations are pending, morphology supplemented by immunophenotyping can provide clues to the diagnosis of specific cytogenetic/genetic categories of AML. Most importantly, acute promyelocytic leukaemia can be diagnosed with a high degree of certainty. However, provisional identification of cases associated with t(8; 21), inv(16), t(1; 22), and NPM1 mutation may also be possible. In addition, transient abnormal myelopoiesis of Down’s syndrome can generally be diagnosed morphologically.

scholarly journals A United Kingdom Population-Based Study of Survival in Patients Aged 19 to 60 with Acute Myeloid Leukaemia in the Era of Molecular Genetics

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5275-5275
Author(s):  
McGregor K Andrew ◽  
Deborah Moulton ◽  
Nick Bown ◽  
Gavin Cuthbert ◽  
Sue Matthew ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Conflicts Of Interest ◽  
Intensive Therapy ◽  
Molecular Genetic ◽  
Population Based ◽  
Npm1 Mutation ◽  
Poor Risk ◽  
Response To Chemotherapy ◽  
Acute Myeloid

Abstract Introduction Acute myeloid leukaemia is a heterogenous disease with variable response to chemotherapy. In order to prognosticate at an individual level numerous cytogenetic and molecular markers may have to be taken into account. Most publications in AML relate to clinical trials and outcomes in this context. We aimed to study outcome in a population-based cohort in the era of molecular genetic testing. Methods All patients, aged 19 and over, diagnosed with AML between 2007-2011, throughout the north east of England (population 3.1 million) were identified. This was done by searching weekly multidisciplinary team meeting minutes across the three haematology teams in the region and triangulating these data with cytogenetic and molecular genetic data. Only patients aged 19-60 years (inclusive) at diagnosis are reported. All biopsy specimens were subject to central pathology review. Results A total of 344 patients were identified and 150 were aged 19-60. Nineteen patients with acute promyelocytic leukaemia (APL) were excluded. Twelve patients were excluded due to missing data; thus 119 non-APL were analysed: 66 women and 53 men. All patients were considered suitable for intensive therapy and 58 (49%) were included in a national AML trial. Ninety eight out of 119 patients (82%) achieved a complete remission (CR); 79 patients entered CR post cycle 1. 21 patients (17%) did not enter a CR (four died before treatment could commence, nine died during induction, six were refractory and palliated and 2 became aplastic and died before remission status could be ascertained). Thirty-nine patients (40%) subsequently relapsed after achieving CR, 19 of these were successfully re-induced and all but one had an allograft in CR2. Eleven patients failed re-induction and were subsequently palliated and one received an allograft for refractory disease. With a median follow up of 1699 days, the median overall survival (OS) for the population was 603 days. Cytogenetics was a strong predictor of survival with median OS (days) being 225, 508 and not reached (NR) for poor (n=29), standard (n=75) and good (n=15) cytogenetic risk groups respectively (p<0.0006). Analysis by FLT3 ITD and NPM1 mutation status amongst normal karyotype patients demonstrated median OS (days) of 131, 437 and NR for the FLT3+/NPM1- (n=8), FLT3+/NPM1+ or FLT3-/NPM1- (n=36), FLT3-/NPM1+ (n=11) respectively (p=0.0067). Conclusions The incidence of AML in adults aged over 18 was 22 per million population per annum. In this population-based cohort of adults aged 19-60 for whom the intention was intensive curative therapy the induction death rate was 7.5 % and CR rate was 85% despite 24% having poor risk genetics. Within the standard risk arm FLT3 positivity conferred a poor risk unless associated with a mutated NPM1. In an unselected population-based cohort FLT3 and NPM1 status remains an important prognostic tool. Disclosures No relevant conflicts of interest to declare.

scholarly journals Investigating the Link Between Trisomy 21 and Acquired Mutations in the GATA1 Gene

The Physician ◽  
2019 ◽  
Vol 6 (1) ◽  
pp. c9
Author(s):  
Triya Chakravorty ◽  
Irene Roberts
Keyword(s):  
Down Syndrome ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Trisomy 21 ◽  
Children With Down Syndrome ◽  
Transient Abnormal Myelopoiesis ◽  
Increased Risk ◽  
Leukaemic Cells ◽  
Acute Myeloid

Children with Down syndrome (DS) due to trisomy 21 (T21) are at an increased risk of developing the neonatal preleukaemic disorder transient abnormal myelopoiesis (TAM), which may transform into childhood acute myeloid leukaemia (ML-DS). Leukaemic cells in TAM and ML-DS have acquired mutations in the GATA1 gene. Although it is clear that acquired mutations in GATA1 are necessary for the development of TAM and ML-DS, questions remain concerning the mechanisms of disease.

scholarly journals Clinico-Haematologic association and prognostic relevance of NPM1 and FLT3-ITD mutations in acute Myeloid Leukaemia

2019 ◽  
Vol 35 (1) ◽  
Author(s):  
Rafia Mahmood ◽  
Chaudhry Altaf ◽  
Hamid Saeed Malik ◽  
Saleem Ahmad Khan
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Disease Free Survival ◽  
Npm1 Mutation ◽  
Free Survival ◽  
Positive Group ◽  
Median Disease Free Survival ◽  
Prognostic Relevance ◽  
Disease Free ◽  
Acute Myeloid

Background & Objectives: Molecular genetic abnormalities have a significant role not only in diagnosis but also in determining the clinical course and prognosis. Nucleophosmin-1 (NPM-1) is associated with good prognosis while internal tandem duplication of the fms-like tyrosine kinase-3 gene (FLT3-ITD) confers a poor prognosis. Knowledge of the status of these mutations in AML patients not only guides treatment decisions but also helps in predicting response to frontline induction and consolidation chemotherapy as well as the risk of relapse and overall survival. Our objectives were to determine the prevalence, clinico-haematological features and immunophenotypic characteristics of AML patients with FLT3-ITD and NPM1 mutation and to evaluate the response to induction therapy (CR) and disease free survival (DFS) in this cohort of patients. Methods: Patients diagnosed as AML from March 2015 to March 2017 at Armed Forces Institute of Pathology Rawalpindi were included in the study. Clinico-haematologic and immunophenotypic parameters were noted and molecular analysis for FLT3-ITD and NPM1 mutation was performed. Any correlation with cytogenetics or other molecular markers was also studied. Response to standard induction chemotherapy and disease-free survival were assessed. Results: A total of 108 cases of AML were analyzed. Median age was 35 years and 64.8% were males. The median age of the study group was 35 years. Of these, 70 (64.8%) were males while 38 (35.2%) were females. Twenty-nine (26.9%) patients were NPM1 positive, twelve (11.1%) were FLT3-ITD positive while eight (7.4%) were positive for both mutations. Patients with NPM1 mutations were associated with female gender, higher haemoglobin level and platelet counts while those with FLT3-ITD mutations were predominantly seen in male patients and had significantly higher WBC counts, bone marrow blasts, biopsy cellularity and LDH levels. CR rates of NPM1 positive, FLT3-ITD positive and both mutation positive groups were 72%, 60% and 71%, respectively. The median disease-free survival was significantly lower in the FLT3-ITD positive group (7.1 months) as compared to the NPM1 positive group (16.1 months). The median disease-free survival was 12 months and 11.9 months in the NPM1 positive/FLT3-ITD positive and the NPM1 negative/FLT3-ITD negative groups, respectively. Conclusion: AML patients harbouring NPM1 and FLT3-ITD mutations have distinct clinical and haematological characteristics. NPM1 mutations have a better CR and DFS as compared to FLT3-ITD group. How to cite this:Mahmood R, Altaf C, Malik HS, Khan SA. Clinico-Haematologic association and prognostic relevance of NPM1 and FLT3-ITD mutations in acute Myeloid Leukaemia. Pak J Med Sci. 2019;35(1):---------. doi: https://doi.org/10.12669/pjms.35.1.285 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

scholarly journals Donor Cell-Derived Acute Myeloid Leukaemia with 3q26.2 Involvement/MECOM Rearrangement ‐ A Case Report and Literature Review

2020 ◽  
Vol 4 (4) ◽  
Author(s):  
Jun Gu ◽  
Wei Wang ◽  
Guilin Tang ◽  
Gokce A. Toruner ◽  
Ming Zhao ◽  
...  
Keyword(s):  
Risk Factors ◽  
Case Report ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Genetic Information ◽  
Molecular Genetic ◽  
Donor Cell ◽  
Hematopoietic Stem ◽  
Acute Myeloid ◽  
Uncommon Complication

Donor cell-derived leukaemia (DCL) is an uncommon complication of allogeneic hematopoietic stem cell transplantation (HSCT). DCL might represent up to 5% of the post-HSCT disease relapses, but case numbers reported in the literature might underestimate the frequency. The leukemogenesis of DCL is not well understood due to the limited numbers of cases reported and lack of detailed molecular genetic information from recipients and donors. Although many theories have been proposed for leukemogenesis of DCL, the underlying molecular genetic mechanism are likely heterogeneous. Here we report a case of donor cell-derived acute myeloid leukaemia with 3q26.2 involvement/MECOM rearrangement and chromosome 20q deletion. We also reviewed the literature of previously described DCL cases, and we discussed the risk factors that might be important to the onset of DCL.

scholarly journals A Mutation Pentad Defined Outcome of De Novo and Cytogenetically Normal Acute Myeloid Leukaemia in Young Adults

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1400-1400
Author(s):  
Sze Pui Tsui ◽  
Ip HW Alvin ◽  
Chunxiao Zhang ◽  
Tommy W.F. Tang ◽  
CH Lin ◽  
...  
Keyword(s):  
Young Adults ◽  
Hong Kong ◽  
Clinical Outcome ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Research Funding ◽  
De Novo ◽  
Gene Mutations ◽  
Npm1 Mutation ◽  
Acute Myeloid

Background. Cytogenetically normal acute myeloid leukaemia (CN-AML) occurs in 50% adult AML and is a group of diseases with diverse mutations and distinct clinical outcome. CEBPα, NPM1 and FLT3 mutations that are commonly seen in CN-AML have been incorporated into risk stratification. However, prognostic impacts of other gene mutations and their combinations in this AML subtype have remained unclear. In this study, we examined a cohort of young adults with de novo CN-AML who have received uniform treatment protocol in Hong Kong and identified a mutation pentad that might define their clinical outcome. Methodology. Young adults (18-60 years old) with de novo CN-AML, diagnosed from 1st August 2003 to 7th August 2018 in 8 regional hospitals in Hong Kong, were included. They received standard "7+3" induction (Daunorubicin 60-90 mg/m2 and Cytarabine 100 mg/m2) followed by up to 4 courses of high dose cytarabine consolidation (Cytarabine 3 gram/m2 for 4-6 doses). Decision on allogeneic haematopoietic stem cell transplantation (HSCT) was based on clinical grounds and gene mutations according to ELN recommendations. Next generation sequencing (NGS) was performed in diagnostic bone marrow (BM) in 362 patients for 36 recurrent mutated genes and analyzed by in-house bioinformatics pipelines. Relapse-free survival (RFS) was defined by the time from first complete remission (CR) to relapse or death and overall survival (OS) by the time from diagnosis to death. Patients were censored at last follow up. Survivals were evaluated by Kaplan-Meier analysis and compared by log-rank test. Multivariate analyses of clinical and genetic parameters were analyzed by Cox-regression. P-values of &lt;0.05 were considered statistically significant. Results. A total of 436 patients (Male=189; Female=247) were recruited. Their median age of onset was 49 years old (Range 18-60); median presenting white cell counts (WCC) was 21.85x109/L (range 0.25-411x109/L), median circulating blast % was 46% (range 1-99). 416 patients received induction of whom 90.1% achieved CR or CRi (N=375) after 1 (N=268), 2 (N=78) or ≥ 3 courses of induction (N=29). One hundred and sixty three patients received allogeneic HSCT at CR1 (N=102), CR2 (N=51), ≥ CR3 (N=2) and relapsed state (N=8). Eight mutations with ≥ 10% prevalence occurred in 79.8% patients (Figure 1). Univariate analyses showed that mutations of CEBPα, TET2, IDH2-R172K and RAS were not associated with treatment outcome and survival. Five genetic subgroups based on NPM1, FLT3 and DNMT3A mutations could be identified: NPM1 mutation only; NPM1 mutation and FLT3-ITD; All wildtype; FLT3-ITD only; DNMT3A irrespective of NPM1 and FLT3-ITD status. These subgroups showed distinct RFS and OS (Figure 2). Impacts of IDH1-R132 and IDH2-R140Q mutations were evaluated in these 5 subgroups. Interestingly, adverse impacts of IDH1-R132 on RFS and OS were only significant in the all wildtype subgroup and the adverse impact of IDH2-R140Q was only significant for RFS in the NPM1 mutation only subgroup. Conclusion. A mutation pentad comprising NPM1, FLT3, DNMT3A, IDH1-R132 and IDH2-R140Q seemed to define distinct prognostic subgroups in young adults with de novo CN-AML. A limited gene panel based on this pentad using conventional PCR may provide a practical and cost-effective means to guide post-remission therapy in these patients, especially in places where NGS may not be readily available. Acknowledgements: SK Yee Medical Foundation; Li Shu Fan Medical Foundation, LKS Faculty of Medicine, University of Hong Kong, Hong Kong Blood Cancer Foundation Disclosures Leung: Curegenix: Research Funding; Servier: Research Funding; Merck: Research Funding; Pfizer: Research Funding.

scholarly journals Next-generation sequencing-based molecular genetic profiling in adults with acute myeloid leukaemia

2020 ◽  
Vol 65 (4) ◽  
pp. 444-459
Author(s):  
A. I. Kashlakova ◽  
E. N. Parovichnikova ◽  
B. V. Biderman ◽  
Y. V. Sidorova ◽  
Y. A. Chabaeva ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Molecular Genetic ◽  
Driver Mutations ◽  
Next Generation ◽  
Old Patients ◽  
Generation Sequencing ◽  
Acute Myeloid

Introduction. Acute myeloid leukaemia (AML) is associated with multiple driver mutations, which prognostic value remains understudied.Aim. Assessment of the frequency of mutations in various genes and their impact on acute myeloid leukaemia outcome in adults.Materials and methods. The study included 90 adult patients with newly diagnosed AML; 76 were aged under 60, 14 were 60 and more years old. Patients under 60 had chemotherapy (CT) “7+3” as induction, the elder cohort had variant low-dose CT with hypomethylating agents. The molecular genetic status of patients was determined using next-generation sequencing; the in-house gene panel included ASXL1, BCOR, DNMT3, FLT3, IDH1, IDH2, PIGA, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53 and U2AF2.Results. Nucleotide substitutions were identified in genes DNMT3, TET2, TP53, SETBP1, BCOR, RUNX1, IDH2, IDH1, FLT3, U2AF2, SF3B1 in 57.8 % of the patients (n = 52), with 17.8 % (n = 16) having compound mutations in two or three genes. Treatment efficacy and long-term outcomes were assessed against age, ELN-2017 risk groups and mutations in genes TP53, RUNX1, IDH1, IDH2 and DNMT3. In the long term, a reliable variation was revealed in the overall survival (OS) rate with respect to mutations in genes TP53 and RUNX1. Patients with mutant TP53 had 30 % OS, those with the intact gene — 53.4 % (p = 0.0037). Similar results were obtained with RUNX1: mutations marked 20 % OS, intact patients had 54% OS (p = 0.0466).Conclusion. Mutations in genes FLT3-ITD, NPM1 and CEBPA are proxy to AML. However, a more accurate prognosis and optimal choice of therapy require detailed molecular profiling due to genetic heterogeneity of AML patients.

scholarly journals Molecular characterisation of NPM1 and FLT3-ITD mutations in a central South African adult de novo acute myeloid leukaemia cohort

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Jean F. Kloppers ◽  
André De Kock ◽  
Johané Cronjé ◽  
Anne-Cecilia Van Marle
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
De Novo ◽  
Molecular Characteristics ◽  
Allele Ratio ◽  
Npm1 Mutation ◽  
Poor Prognostic Factor ◽  
Molecular Abnormalities ◽  
Central South ◽  
Acute Myeloid

Background: Recognition of molecular abnormalities in acute myeloid leukaemia (AML) has improved our understanding of its biology. NPM1 and FLT3-ITD mutations are recurrent in AML and clinically significant. NPM1 mutations are associated with a favourable prognosis, while FLT3-ITD mutations are an independent poor prognostic factor in AML.Objective: This study described the prevalence and molecular characteristics of the NPM1 and FLT3-ITD mutations in a newly diagnosed AML patient cohort in central South Africa.Methods: The study included 40 de novo AML patients. An NPM1 and FLT3-ITD multiplex polymerase chain reaction assay was optimised to screen patients for the respective mutations and were confirmed using Sanger sequencing. The prevalence of the NPM1 and FLT3-ITD mutations were determined, and mutation-specific characteristics were described in relation to patients’ demographic information and AML classifications.Results: The patients’ median age was 38.5 years, with 77.5% (n = 31) of patients being self-proclaimed Black Africans. AML with recurrent genetic abnormalities was most prevalent (57.5%; n = 23), of which acute promyelocytic leukaemia (APL) was most common (40.0%; n = 16). None of the patients had the NPM1 mutation. FLT3-ITD was present in 37.5% (6/16) of APL patients and in one (20.0%) of five AML patients with a t(8;21) translocation. Most patients had an FLT3-ITD allele ratio of ≥ 50% and ITD lengths of 39 bp.Conclusion: FLT3-ITD mutations were mainly found in APL cases at a similar prevalence as reported in the literature. High FLT3-ITD allele ratios and long ITD lengths predominated. No NPM1 mutations were detected.

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