The evolving molecular genetic landscape in acute myeloid leukaemia

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.

Download Full-text

The complex genetic landscape of acute myeloid leukaemia

The Lancet Haematology ◽

10.1016/s2352-3026(16)30063-1 ◽

2016 ◽

Vol 3 (7) ◽

pp. e301

Author(s):

The Lancet Haematology

Keyword(s):

Acute Myeloid Leukaemia ◽

Myeloid Leukaemia ◽

Genetic Landscape ◽

Acute Myeloid

Download Full-text

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

Hematology and Transfusiology ◽

10.35754/0234-5730-2020-65-4-444-459 ◽

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.

Download Full-text

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

Acta Haematologica ◽

10.1159/000496097 ◽

2019 ◽

Vol 141 (4) ◽

pp. 232-244 ◽

Cited By ~ 10

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.

Download Full-text

Clinical outcome of de novo acute myeloid leukaemia patients with normal cytogenetics is affected by molecular genetic alterations: a concise review

British Journal of Haematology ◽

10.1111/j.1365-2141.2007.06566.x ◽

2007 ◽

Vol 137 (5) ◽

pp. 387-400 ◽

Cited By ~ 72

Author(s):

Claudia D. Baldus ◽

Krzysztof Mrózek ◽

Guido Marcucci ◽

Clara D. Bloomfield

Keyword(s):

Clinical Outcome ◽

Acute Myeloid Leukaemia ◽

Myeloid Leukaemia ◽

De Novo ◽

Molecular Genetic ◽

Genetic Alterations ◽

Concise Review ◽

Normal Cytogenetics ◽

Acute Myeloid

Download Full-text

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 ◽

10.1182/blood.v124.21.5275.5275 ◽

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.

Download Full-text

Myelodysplastic syndromes

Oxford Textbook of Medicine ◽

10.1093/med/9780198746690.003.0514 ◽

2020 ◽

pp. 5197-5205

Author(s):

Charlotte K. Brierley ◽

David P. Steensma

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukaemia ◽

Myeloid Leukaemia ◽

Myelodysplastic Syndromes ◽

Peripheral Blood ◽

Lower Risk ◽

Molecular Genetic ◽

Diagnosis And Prognosis ◽

Chronic Anaemia ◽

Acute Myeloid

The myelodysplastic syndromes (MDS) are marrow failure syndromes characterized by cytopenias, blood cell dysmorphology, acquired clonal cytogenetic and molecular genetic mutations, and a risk of development of acute myeloid leukaemia. MDS may evolve in patients previously treated with cytotoxic chemotherapy or radiotherapy for a solid tumour, but most commonly arise de novo in patients over 60 years old. Most patients present with features of chronic anaemia or manifestations related to thrombocytopenia or infection. The diagnosis may be suggested by the presence of normocytic or macrocytic anaemia, with the peripheral blood smear showing dysplastic changes in red blood cells or neutrophils. Bone marrow aspirate and biopsy permits detailed cytogenetic study, which is critical for diagnostic classification and prognosis. Increasingly, molecular genetic assays (next-generation sequencing panels) aid in diagnosis and prognosis. The World Health Organization (WHO) classification recognizes various MDS subtypes based on the morphological appearance of the peripheral blood and bone marrow. These include MDS with excess blasts, MDS with deletion of the long arm of chromosome 5, and MDS with ring sideroblasts. Treatment is symptomatic in most cases. The only potentially curative treatment is allogeneic bone marrow transplantation, which is often precluded due to patients’ advanced age or comorbidity. Higher-risk patients may experience a survival benefit from treatment with the DNA hypomethylating agent azacitidine, and decitabine delays disease progression to acute myeloid leukaemia. Some patients with lower-risk disease may show a response to immunosuppression with antithymocyte globulin and ciclosporin. Patients with isolated chromosome 5q deletions and lower-risk disease may respond dramatically to lenalidomide, an immunomodulatory drug.

Download Full-text