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Blood Sep 2022The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for...
The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic, and genetic aspects of these disorders, developed the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias. Using a multiparameter approach, the main objective of the consensus process was the definition of real disease entities, including the introduction of new entities and refined criteria for existing diagnostic categories, based on accumulated data. The ICC is aimed at facilitating diagnosis and prognostication of these neoplasms, improving treatment of affected patients, and allowing the design of innovative clinical trials.
Topics: Acute Disease; Consensus; Genomics; Hematologic Neoplasms; Humans; Leukemia; Myeloproliferative Disorders; World Health Organization
PubMed: 35767897
DOI: 10.1182/blood.2022015850 -
Rhode Island Medical Journal (2013) Apr 2020Acute myeloid leukemia (AML) is a malignancy of the stem cell precursors of the myeloid lineage (red blood cells, platelets, and white blood cells other than B and T... (Review)
Review
Acute myeloid leukemia (AML) is a malignancy of the stem cell precursors of the myeloid lineage (red blood cells, platelets, and white blood cells other than B and T cells). Like other malignancies, it is due to genetic variations that lead to neoplastic changes and clonal proliferation. AML remains a rare malignancy, accounting for only 1.2% of all new cancer diagnoses in the United States per year, but it accounts for close to one third of all leukemias diagnosed.* For much of the 20th and early 21st century treatment paradigms were unchanged with survival curves remaining stagnant for many decades. Recent changes in our understanding of the genetic variations in the disease have led to some promising new therapies with hopes for improved outcomes in the future. Below we review the definitions, diagnosis and classification of AML and how this affects the evolving treatment paradigm of AML.
Topics: Antineoplastic Agents; Forecasting; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Recurrence; Treatment Outcome
PubMed: 32236160
DOI: No ID Found -
Lancet (London, England) Aug 2018For several decades, few substantial therapeutic advances have been made for patients with acute myeloid leukaemia. However, since 2017 unprecedented growth has been... (Review)
Review
For several decades, few substantial therapeutic advances have been made for patients with acute myeloid leukaemia. However, since 2017 unprecedented growth has been seen in the number of drugs available for the treatment of acute myeloid leukaemia, with several new drugs receiving regulatory approval. In addition to advancing our therapeutic armamentarium, an increased understanding of the biology and genomic architecture of acute myeloid leukaemia has led to refined risk assessment of this disease, with consensus risk stratification guidelines now incorporating a growing number of recurrent molecular aberrations that aid in the selection of risk-adapted management strategies. Despite this promising recent progress, the outcomes of patients with acute myeloid leukaemia remain unsatisfactory, with more than half of patients ultimately dying from their disease. Enrolment of patients into clinical trials that evaluate novel drugs and rational combination therapies is imperative to continuing this progress and further improving the outcomes of patients with acute myeloid leukaemia.
Topics: Aminoglycosides; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Consolidation Chemotherapy; Cytarabine; Gemtuzumab; Genomics; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Patient Selection; Recurrence; Remission Induction; Risk Assessment; Risk Factors; Staurosporine
PubMed: 30078459
DOI: 10.1016/S0140-6736(18)31041-9 -
Blood Apr 2017RUNX1 is a member of the core-binding factor family of transcription factors and is indispensable for the establishment of definitive hematopoiesis in vertebrates. is... (Review)
Review
RUNX1 is a member of the core-binding factor family of transcription factors and is indispensable for the establishment of definitive hematopoiesis in vertebrates. is one of the most frequently mutated genes in a variety of hematological malignancies. Germ line mutations in cause familial platelet disorder with associated myeloid malignancies. Somatic mutations and chromosomal rearrangements involving are frequently observed in myelodysplastic syndrome and leukemias of myeloid and lymphoid lineages, that is, acute myeloid leukemia, acute lymphoblastic leukemia, and chronic myelomonocytic leukemia. More recent studies suggest that the wild-type is required for growth and survival of certain types of leukemia cells. The purpose of this review is to discuss the current status of our understanding about the role of RUNX1 in hematological malignancies.
Topics: Acute Disease; Animals; Chromosome Aberrations; Chronic Disease; Core Binding Factor Alpha 2 Subunit; Hematologic Neoplasms; Humans; Leukemia; Myelodysplastic Syndromes; Neoplasm Proteins
PubMed: 28179279
DOI: 10.1182/blood-2016-10-687830 -
Nature Reviews. Cancer Feb 2021Although much work has focused on the elucidation of somatic alterations that drive the development of acute leukaemias and other haematopoietic diseases, it has become... (Review)
Review
Although much work has focused on the elucidation of somatic alterations that drive the development of acute leukaemias and other haematopoietic diseases, it has become increasingly recognized that germline mutations are common in many of these neoplasms. In this Review, we highlight the different genetic pathways impacted by germline mutations that can ultimately lead to the development of familial and sporadic haematological malignancies, including acute lymphoblastic leukaemia, acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). Many of the genes disrupted by somatic mutations in these diseases (for example, TP53, RUNX1, IKZF1 and ETV6) are the same as those that harbour germline mutations in children and adolescents who develop these malignancies. Moreover, the presumption that familial leukaemias only present in childhood is no longer true, in large part due to the numerous studies demonstrating germline DDX41 mutations in adults with MDS and AML. Lastly, we highlight how different cooperating events can influence the ultimate phenotype in these different familial leukaemia syndromes.
Topics: Disease Progression; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Phenotype; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 33328584
DOI: 10.1038/s41568-020-00315-z -
Nature Mar 2023Targeting critical epigenetic regulators reverses aberrant transcription in cancer, thereby restoring normal tissue function. The interaction of menin with lysine...
Targeting critical epigenetic regulators reverses aberrant transcription in cancer, thereby restoring normal tissue function. The interaction of menin with lysine methyltransferase 2A (KMT2A), an epigenetic regulator, is a dependence in acute leukaemia caused by either rearrangement of KMT2A or mutation of the nucleophosmin 1 gene (NPM1). KMT2A rearrangements occur in up to 10% of acute leukaemias and have an adverse prognosis, whereas NPM1 mutations occur in up to 30%, forming the most common genetic alteration in acute myeloid leukaemia. Here, we describe the results of the first-in-human phase 1 clinical trial investigating revumenib (SNDX-5613), a potent and selective oral inhibitor of the menin-KMT2A interaction, in patients with relapsed or refractory acute leukaemia (ClinicalTrials.gov, NCT04065399). We show that therapy with revumenib was associated with a low frequency of grade 3 or higher treatment-related adverse events and a 30% rate of complete remission or complete remission with partial haematologic recovery (CR/CRh) in the efficacy analysis population. Asymptomatic prolongation of the QT interval on electrocardiography was identified as the only dose-limiting toxicity. Remissions occurred in leukaemias refractory to multiple previous lines of therapy. We demonstrate clearance of residual disease using sensitive clinical assays and identify hallmarks of differentiation into normal haematopoietic cells, including differentiation syndrome. These data establish menin inhibition as a therapeutic strategy for susceptible acute leukaemia subtypes.
Topics: Humans; Antineoplastic Agents; Histone-Lysine N-Methyltransferase; Leukemia, Myeloid, Acute; Neoplasm, Residual; Nucleophosmin; Prognosis; Protein Binding; Proto-Oncogene Proteins; Remission Induction
PubMed: 36922593
DOI: 10.1038/s41586-023-05812-3 -
British Journal of Haematology Jul 2018Neonatal leukaemia is defined as occurring within the first 28 days of life and most, if not all, cases are congenital. With the exception of Down syndrome-associated... (Review)
Review
Neonatal leukaemia is defined as occurring within the first 28 days of life and most, if not all, cases are congenital. With the exception of Down syndrome-associated transient abnormal myelopoiesis, which is not considered here, neonatal leukaemias are rare. In two-thirds of patients the disease manifests as an acute myeloid leukaemia, frequently with monocytic/monoblastic characteristics. Most other cases are acute lymphoblastic leukaemia, particularly B lineage, but some are mixed phenotype or blastic plasmacytoid dendritic cell neoplasms. The most frequently observed cytogenetic/molecular abnormality is t(4;11)(q21.3;q23.3)/KMT2A-AFF1 followed by t(1;22)(p13.3;q13.1)/RBM15-MKL1 and t(8;16)(p11.2;p13.3)/KAT6A-CREBBP. Common clinical features include prominent hepatosplenomegaly and a high incidence of skin involvement, sometimes in the absence of bone marrow disease. A distinctive feature is the occurrence of spontaneous remission in some cases, particularly in association with t(8;16). In this review, we summarise current knowledge of the clinical, cytogenetic and molecular features of neonatal leukaemia and discuss clinical management of these cases.
Topics: Antineoplastic Agents; Dendritic Cells; Diagnosis, Differential; Exanthema; Gene Order; Histone-Lysine N-Methyltransferase; Humans; Infant, Newborn; Leukemia; Myeloid-Lymphoid Leukemia Protein; Remission, Spontaneous; Treatment Outcome
PubMed: 29806701
DOI: 10.1111/bjh.15246 -
Blood Jan 2023Despite recent progress in identifying the genetic drivers of acute lymphoblastic leukemia (ALL), prognosis remains poor for those individuals who experience disease... (Review)
Review
Despite recent progress in identifying the genetic drivers of acute lymphoblastic leukemia (ALL), prognosis remains poor for those individuals who experience disease recurrence. Moreover, acute leukemias of ambiguous lineage lack a biologically informed framework to guide classification and therapy. These needs have driven the adoption of multiple complementary single-cell sequencing approaches to explore key issues in the biology of these leukemias, including cell of origin, developmental hierarchy and ontogeny, and the molecular heterogeneity driving pathogenesis, progression, and therapeutic responsiveness. There are multiple single-cell techniques for profiling a specific modality, including RNA, DNA, chromatin accessibility and methylation; and an expanding range of approaches for simultaneous analysis of multiple modalities. Single-cell sequencing approaches have also enabled characterization of cell-intrinsic and -extrinsic features of ALL biology. In this review we describe these approaches and highlight the extensive heterogeneity that underpins ALL gene expression, cellular differentiation, and clonal architecture throughout disease pathogenesis and treatment resistance. In addition, we discuss the importance of the dynamic interactions that occur between leukemia cells and the nonleukemia microenvironment. We discuss potential opportunities and limitations of single-cell sequencing for the study of ALL biology and treatment responsiveness.
Topics: Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Lymphocytes; Acute Disease; Prognosis; Single-Cell Analysis; Tumor Microenvironment
PubMed: 35926109
DOI: 10.1182/blood.2022016954 -
Current Treatment Options in Oncology May 2023Although safe and effective immune therapies have been developed in several cancers, this has not been so in acute myeloid leukaemia (AML). Studies of antibodies to... (Review)
Review
Although safe and effective immune therapies have been developed in several cancers, this has not been so in acute myeloid leukaemia (AML). Studies of antibodies to CD33, CD123 and CLL-1 report with unconvincing efficacy and substantial adverse events. Lacking AML-specific target antigens, these approaches using non-specific antigen targets often cause unacceptable bone marrow toxicity and off-target adverse events. Studies of AML incidence in persons with immune deficiency indicate little if any immune surveillance against AML. In contrast, data studies of recipients of haematopoietic cell transplants support an effective allogeneic anti-AML effect associated with graft-versus-host disease (GvHD) and possibly a specific graft-versus-leukaemia (GvL) effect. A special problem in the immune therapy of AML is few neo-antigens compared with solid cancers because of a relatively low mutation frequency. Studies of CAR-T-, CAR-NK-adaptor CAR-T- and allogeneic NK-cells are progressing as are approaches using synthetic biology. Presently, there are no convincing data of efficacy of immune therapy in AML.
Topics: Humans; Receptors, Chimeric Antigen; Leukemia, Myeloid, Acute; Immunotherapy; Immunotherapy, Adoptive
PubMed: 36949279
DOI: 10.1007/s11864-023-01066-3 -
Acta Haematologica 2019Diagnosis and classification of acute myeloid leukaemia (AML) require cytogenetic and molecular genetic investigation. However, while these evaluations are pending,... (Review)
Review
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.
Topics: Chromosome Inversion; Chromosomes, Human; Down Syndrome; Humans; Leukemia, Promyelocytic, Acute; Myelopoiesis; Neoplasm Proteins; Nuclear Proteins; Nucleophosmin; Translocation, Genetic; World Health Organization
PubMed: 30965338
DOI: 10.1159/000496097