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Best Practice & Research. Clinical... Dec 2023The goal of a disease classification system is (or should be) to provide a tool for researchers and clinicians to study and treat the disease. The last decade has seen a... (Review)
Review
The goal of a disease classification system is (or should be) to provide a tool for researchers and clinicians to study and treat the disease. The last decade has seen a markedly improved understanding of the pathophysiology of acute myeloid leukemia (AML), the development of new methods to measure the disease, and approval by the Food and Drug Administration (FDA) of at least ten new therapies targeted to its treatment. In response, in 2022 one updated and one new AML classification system were published. In the same year, the European LeukemiaNet updated their recommendations about how to incorporate the advances in diagnosis and treatment into the risk stratification of AML and its treatment. The following discussion summarizes the highlights of these changes and offers an opinion of how well these changes meet the goal of aiding researchers and clinicians in the study and treatment of AML.
Topics: United States; Humans; Leukemia, Myeloid, Acute; World Health Organization
PubMed: 38092471
DOI: 10.1016/j.beha.2023.101518 -
Critical Reviews in Oncology/hematology Jun 2024Disease classification of complex and heterogenous diseases, such as acute myeloid leukaemia (AML), is continuously updated to define diagnoses, appropriate treatments,... (Review)
Review
Disease classification of complex and heterogenous diseases, such as acute myeloid leukaemia (AML), is continuously updated to define diagnoses, appropriate treatments, and assist research and education. Recent availability of molecular profiling techniques further benefits the classification of AML. The World Health Organization (WHO) classification of haematolymphoid tumours and the International Consensus Classification of myeloid neoplasms and acute leukaemia from 2022 are two updated versions of the WHO 2016 classification. As a consequence, the European LeukemiaNet 2022 recommendations on the diagnosis and management of AML in adults have been also updated. The current review provides a practical interpretation of these guidelines to facilitate the diagnosis of AML and discusses genetic testing, disease genetic heterogeneity, and FLT3 mutations. We propose a practical algorithm for the speedy diagnosis of AML. Future classifications may need to incorporate gene mutation combinations to enable personalised treatment regimens in the management of patients with AML.
Topics: Humans; Leukemia, Myeloid, Acute; Algorithms; Mutation; World Health Organization; fms-Like Tyrosine Kinase 3
PubMed: 38615870
DOI: 10.1016/j.critrevonc.2024.104358 -
Leukemia & Lymphoma Sep 2023The year 2023 marks the semi-centennial of the introduction of classic '7 + 3' chemotherapy for acute myeloid leukemia (AML) in 1973. It also marks the decennial of... (Review)
Review
The year 2023 marks the semi-centennial of the introduction of classic '7 + 3' chemotherapy for acute myeloid leukemia (AML) in 1973. It also marks the decennial of the first comprehensive sequencing efforts from The Cancer Genome Atlas (TCGA), which revealed that dozens of unique genes are recurrently mutated in AML genomes. Although more than 30 distinct genes have been implicated in AML pathogenesis, the current therapeutic armamentarium that is commercially available only targets and mutations, with olutasidenib as the most recent addition. This focused review spotlights management approaches that exploit the exquisite molecular dependencies of specific subsets of AML, with an emphasis on emerging therapies in the pipeline, including agents targeting -mutant cells. We summarize precision and strategic targeting of AML based on leveraging functional dependencies and explore how mechanisms involving critical gene products can inform rational therapeutic design in 2024.
Topics: Humans; Nucleophosmin; Leukemia, Myeloid, Acute; Mutation
PubMed: 37328939
DOI: 10.1080/10428194.2023.2224473 -
Clinical and Experimental Medicine Dec 2023Circular RNAs (circRNAs) have been recently identified as important regulators of various diseases, especially cancer. However, the roles of circRNAs in hematologic...
Circular RNAs (circRNAs) have been recently identified as important regulators of various diseases, especially cancer. However, the roles of circRNAs in hematologic malignancies have been rarely reported. This study aimed to identify a specific circRNA expression profile in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), and to evaluate the biological roles of circRNA in MDS and AML for understanding their clinical significance. Reverse transcription-quantitative PCR was performed to validate the expression of circZBTB46. Kruskal-Wallis test, Kaplan-Meier curves, and the Cox regression model were employed to analyze the clinical significance of circZBTB46. Two specific shRNAs as well as an expression lentiviral vector of circZBTB46 were constructed to identify the biological function of circZBTB46. The impact of circZBTB46 on leukemia cell proliferation, cell cycle distribution, and apoptosis was confirmed using cell viability assay and flow cytometry analysis. The expression of circZBTB46 gradually increased in patients with higher-risk MDS and AML, as compared to controls. CircZBTB46 expression was significantly correlated with important clinical parameters of MDS, including WHO classification, absolute neutrophil count (ANC), marrow blast, IPSS karyotype, IPSS/IPSS-R risk groups, and AML transformation. CircZBTB46 expression was also associated with ANC, marrow blast, cytogenetic risk groups, FLT3-ITD mutation, and treatment response in AML patients. Furthermore, circZBTB46 overexpression was significantly correlated with shorter overall survival (OS, P = 0.0342, median survival time 18.5 vs. 45.4 months) and leukemia-free survival (LFS, P = 0.0421) in MDS, also with the shorter OS in AML (P = 0.0293, median survival time 11.6 vs. 16.9 months). Functional studies revealed that silencing circZBTB46 expression significantly inhibited proliferation and induced apoptosis in SKM-1, THP-1, and K562 cell lines, while rescue experiments alleviated the siRNA-mediated growth inhibition and apoptosis in these leukemic cells. The present data suggested the essential oncogenic role of circZBTB46, as a progression and survival indicator in both MDS and AML.
Topics: Humans; RNA, Circular; Prognosis; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Disease Progression
PubMed: 37930606
DOI: 10.1007/s10238-023-01243-6 -
Leukemia & Lymphoma 2023We conducted a retrospective analysis of mutated acute myeloid leukemia (AML) patients who underwent allogeneic stem cell transplant. Thirty-seven patients with mutated...
We conducted a retrospective analysis of mutated acute myeloid leukemia (AML) patients who underwent allogeneic stem cell transplant. Thirty-seven patients with mutated AML were identified. Primary induction failure (40%) and early relapse rate (18%) after idarubicin/cytarabine (7 + 3) chemotherapy were observed. All patients with induction failure subsequently achieved CR with additional chemotherapy. There was no significant difference between outcomes after myeloablative vs. reduced intensity (Fludarabine/Melphalan [Flu/Mel]) conditioning regimens. RFS but not OS was significantly better in patients who received FLAG-IDA prior to transplant and/or a fludarabine-containing conditioning. In an independent study, -mutated AML samples exhibited greater sensitivity to fludarabine ( = 0.026) and melphalan ( = 0.0005) than non-mutated AML samples while there was no difference between sensitivity to cytarabine. Our data favor using a fludarabine-based induction for AML with mutation instead of 7 + 3. Fludarabine conditioning regimens for alloHCT showed better RFS but not OS.
Topics: Humans; Melphalan; Retrospective Studies; Antineoplastic Combined Chemotherapy Protocols; Leukemia, Myeloid, Acute; Idarubicin; Cytarabine; WT1 Proteins
PubMed: 37533373
DOI: 10.1080/10428194.2023.2241096 -
International Journal of Molecular... Feb 2024Minimal residual disease (MRD) is of major importance in onco-hematology, particularly in acute myeloid leukemia (AML). MRD measures the amount of leukemia cells... (Review)
Review
Minimal residual disease (MRD) is of major importance in onco-hematology, particularly in acute myeloid leukemia (AML). MRD measures the amount of leukemia cells remaining in a patient after treatment, and is an essential tool for disease monitoring, relapse prognosis, and guiding treatment decisions. Patients with a negative MRD tend to have superior disease-free and overall survival rates. Considerable effort has been made to standardize MRD practices. A variety of techniques, including flow cytometry and molecular methods, are used to assess MRD, each with distinct strengths and weaknesses. MRD is recognized not only as a predictive biomarker, but also as a prognostic tool and marker of treatment efficacy. Expected advances in MRD assessment encompass molecular techniques such as NGS and digital PCR, as well as optimization strategies such as unsupervised flow cytometry analysis and leukemic stem cell monitoring. At present, there is no perfect method for measuring MRD, and significant advances are expected in the future to fully integrate MRD assessment into the management of AML patients.
Topics: Humans; Neoplasm, Residual; Leukemia, Myeloid, Acute; Hematopoietic Stem Cell Transplantation; Recurrence; Flow Cytometry
PubMed: 38396825
DOI: 10.3390/ijms25042150 -
Cytopathology : Official Journal of the... Nov 2023Precise subclassification of myeloid malignancies per the World Health Organization (WHO) classification system and the International Consensus Classification of Myeloid... (Review)
Review
Precise subclassification of myeloid malignancies per the World Health Organization (WHO) classification system and the International Consensus Classification of Myeloid Neoplasms and Acute Leukaemias (ICC) requires investigation and documentation of the presence of cytogenetic and/or molecular genetic changes. These ancillary studies not only help in diagnosis, but also the prognosis of disease; however, they take time to be completed. In contrast, morphological evaluation of material from the blood and bone marrow specimens of cases where myeloid malignancies are suspected is usually completed quickly. Cytomorphological assessment may predict genetic changes and can be helpful in triaging acuity. This is especially true in haematological emergencies such as acute promyelocytic leukaemia (APL), where prompt APL-specific therapy can be life changing. Similarly, some morphological clues may help identify core binding factor leukaemias where a diagnosis of acute myeloid leukaemia (AML) could be rendered without reaching the 20% blast cutoff with immediate treatment-decision implications, or even a subset of cases of AML with FLT3 ITD/NPM1 mutation(s) which show characteristic features. Even though FISH/cytogenetics and/or PCR are still required for establishing the final diagnosis, evaluation for the presence of specific cytomorphological features that help predict genetic changes can be a useful tool to help guide early therapy.
Topics: Humans; Nucleophosmin; Leukemia, Myeloid, Acute; Cytogenetic Analysis; Mutation
PubMed: 37522274
DOI: 10.1111/cyt.13280 -
Acta Haematologica 2024In the past decade, there have been significant breakthroughs in immunotherapies for B-cell lymphoid malignancies and multiple myeloma, but progress has been much less... (Review)
Review
BACKGROUND
In the past decade, there have been significant breakthroughs in immunotherapies for B-cell lymphoid malignancies and multiple myeloma, but progress has been much less for acute myeloid leukemia (AML). Nevertheless, challenge begets innovation and several therapeutic strategies are under investigation.
SUMMARY
In this review, we review the state of the art in AML immunotherapy including CD33- and CD123-targeted agents, immune checkpoint inhibition, and adoptive cell therapy strategies. We also share conceptual frameworks for approaching the growing catalog of investigational AML immunotherapies and propose future directions for the field.
KEY MESSAGES
Immunotherapies for AML face significant challenges but novel strategies are in development.
Topics: Humans; Immunotherapy; Antineoplastic Agents; Molecular Targeted Therapy; Leukemia, Myeloid, Acute; Immunotherapy, Adoptive
PubMed: 37673048
DOI: 10.1159/000533990 -
Hematology (Amsterdam, Netherlands) Dec 2023Myeloid sarcoma (MS) is a very rare hematologic disorder. This study analyzes the early treatment options for patients with different types of MS and explores the...
BACKGROUND
Myeloid sarcoma (MS) is a very rare hematologic disorder. This study analyzes the early treatment options for patients with different types of MS and explores the prognostic factors of MS.
METHODS
Patients aged 15 years and older with MS in the SEER database (diagnosed from 2000 to 2018) were selected, excluding those with an unknown first course of treatment, an unknown location of disease, and less than 1 month of follow-up. Statistical methods used a chi-square test to compare clinical characteristics; Kaplan-Meier analysis to compare survival differences; and Cox proportional risk models to identify prognostic factors affecting overall survival (OS).
RESULTS
Data were collected from 472 patients: 244 patients with isolated myeloid sarcoma (IMS) and 228 patients with non-isolated myeloid sarcoma (non-IMS). IMS patients mostly chose local treatment, while non-IMS patients mostly chose chemotherapy. There was a significant difference in OS between IMS patients treated with combined treatment and those without treatment. For non-IMS, treated patients had longer OS than untreated, but the difference was not statistically significant. Among adult patients, those younger than 60 years had a better prognosis. Patients with the urinary system, digestive system, reproductive system and chest and abdomen as the initial site had a better prognosis.
CONCLUSIONS
Early combination therapy in IMS patients had a longer OS, and chemotherapy combined with radiotherapy/surgery should be the treatment of choice. For non-IMS patients, early combination therapy did not show a significant advantage. Age and location of first presentation were independent factors affecting MS patients' long-term prognosis.
Topics: Adult; Humans; Sarcoma, Myeloid; Prognosis; Combined Modality Therapy; Databases, Factual; Kaplan-Meier Estimate
PubMed: 37594298
DOI: 10.1080/16078454.2023.2247898 -
BioRxiv : the Preprint Server For... Nov 2023Myeloid cells, including neutrophils, monocytes and macrophages, accumulate quickly after ischemic injury in the heart where they play integral roles in the regulation...
Myeloid cells, including neutrophils, monocytes and macrophages, accumulate quickly after ischemic injury in the heart where they play integral roles in the regulation of inflammation and repair. We previously reported that deletion of β2-adrenergic receptor (β2AR) in all cells of hematopoietic origin resulted in generalized disruption of immune cell responsiveness to injury, but with unknown impact on myeloid cells specifically. To investigate this, we crossed floxed β2AR (F/F) mice with myeloid cell-expressing Cre (LysM-Cre) mice to generate myeloid cell-specific β2AR knockout mice (LB2) and subjected them to myocardial infarction (MI). Via echocardiography and immunohistochemical analyses, LB2 mice displayed better cardiac function and less fibrotic remodeling after MI than the control lines. Despite similar accumulation of myeloid cell subsets in the heart at 1-day post-MI, LB2 mice displayed reduced numbers of Nu by 4 days post-MI, suggesting LB2 hearts have enhanced capacity for Nu efferocytosis. Indeed, bone marrow-derived macrophage (BMDM)-mediated efferocytosis of Nu was enhanced in LB2-versus F/F-derived cells in vitro. Mechanistically, several pro-efferocytosis-related genes were increased in LB2 myeloid cells, with annexin A1 ( ) in particular elevated in several myeloid cell types following MI. Accordingly, shRNA-mediated knockdown of in LB2 bone marrow prior to transplantation into irradiated LB2 mice reduced Mac-induced Nu efferocytosis in vitro and prevented the ameliorative effects of myeloid cell-specific β2AR deletion on cardiac function and fibrosis following MI in vivo. Altogether, our data reveal a previously unrecognized role for β2AR in the regulation of myeloid cell-dependent efferocytosis in the heart following injury.
PubMed: 38076917
DOI: 10.1101/2023.11.27.568873