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Best Practice & Research. Clinical... Sep 2023
Topics: Humans; Leukemia, Myeloid, Acute; Acute Disease
PubMed: 37611998
DOI: 10.1016/j.beha.2023.101499 -
Genes Jul 2023As our understanding of the biologic basis of acute myeloid leukemia evolves, so do the classification systems used to describe this group of cancers. Early... (Review)
Review
As our understanding of the biologic basis of acute myeloid leukemia evolves, so do the classification systems used to describe this group of cancers. Early classification systems focused on the morphologic features of blasts and other cell populations; however, the explosion in genomic technologies has led to rapid growth in our understanding of these diseases and thus the refinement of classification systems. Recently, two new systems, the International Consensus Classification system and the 5th edition of the World Health Organization classification of tumors of hematopoietic and lymphoid tissues, were published to incorporate the latest genomic advances in blood cancer. This article reviews the major updates in acute myeloid leukemia in both systems and highlights the biologic insights that have driven these changes.
Topics: Humans; Leukemia, Myeloid, Acute; Leukocytes; Genomics; Biological Products
PubMed: 37510328
DOI: 10.3390/genes14071424 -
British Journal of Haematology Apr 2024Venetoclax, an oral BCL-2 inhibitor, has been widely incorporated in the treatment of acute myeloid leukaemia. The combination of hypomethylating agents and venetoclax... (Review)
Review
Venetoclax, an oral BCL-2 inhibitor, has been widely incorporated in the treatment of acute myeloid leukaemia. The combination of hypomethylating agents and venetoclax is the current standard of care for elderly and patient's ineligible for aggressive therapies. However, venetoclax is being increasingly used with aggressive chemotherapy regimens both in the front line and in the relapse setting. Our growing experience and intensive research demonstrate that certain genetic abnormalities are associated with venetoclax sensitivity, while others with resistance, and that resistance can emerge during treatment leading to disease relapse. In the current review, we provide a summary of the known mechanisms of venetoclax cytotoxicity, both regarding the inhibition of BCL-2-mediated apoptosis and its effect on cell metabolism. We describe how these pathways are linked to venetoclax resistance and are associated with specific mutations. Finally, we provide the rationale for novel drug combinations in current and future clinical trials.
Topics: Humans; Aged; Neoplasm Recurrence, Local; Leukemia, Myeloid, Acute; Proto-Oncogene Proteins c-bcl-2; Bridged Bicyclo Compounds, Heterocyclic; Recurrence; Antineoplastic Combined Chemotherapy Protocols; Sulfonamides
PubMed: 38296617
DOI: 10.1111/bjh.19314 -
Acta Haematologica 2024Acute myeloid leukemia (AML) is a heterogenous disease that affects mostly older adults with varying baseline health and functional status. Treatment options have... (Review)
Review
BACKGROUND
Acute myeloid leukemia (AML) is a heterogenous disease that affects mostly older adults with varying baseline health and functional status. Treatment options have expanded for older adults, ranging from less intensive chronic therapies to intensive induction strategies with curative intent. Despite this, outcomes remain poor with advancing age due to underlying disease biology and variability in treatment tolerance. Reliance on chronological age alone, however, increases risks of both over- and under-treatment. Strategies to better characterize fitness in the context of therapy are needed to optimize decision-making and enhance clinical trial design.
SUMMARY
Geriatric assessment (GA) is a series of validated tools that evaluate multiple health and functional domains of an older adult including physical function, comorbidities, cognition, nutrition, psychological health, and social support. While studies of GA in AML remain limited, current evidence shows that it is feasible to perform GA among older adults starting therapy for AML. GA measures including those assessing physical function, cognition, and mood are associated with mortality and toxicity in both intensive and less intensive treatment settings.
KEY MESSAGES
In this review, we discuss the existing evidence to support use of GA in AML and highlight implications for clinical practice and future research.
Topics: Humans; Aged; Geriatric Assessment; Comorbidity; Leukemia, Myeloid, Acute
PubMed: 38035561
DOI: 10.1159/000535500 -
Annals of Hematology Aug 2023Ferroptosis is a form of cell death that is regulated by iron and characterized by the buildup of lipid peroxides (LPO) and subsequent rupture of the cell membrane. The... (Review)
Review
Ferroptosis is a form of cell death that is regulated by iron and characterized by the buildup of lipid peroxides (LPO) and subsequent rupture of the cell membrane. The molecular mechanisms of ferroptosis involve metabolic pathways related to iron, lipids, and amino acids, which contribute to the production of lipid reactive oxygen species (ROS). In recent years, there has been increasing attention on the occurrence of ferroptosis in various diseases. Ferroptosis has been found to play a crucial role in cardiovascular diseases, digestive diseases, respiratory and immunological diseases, and particularly in malignancies. However, there is still a lack of studies on ferroptosis in acute myeloid leukemia (AML). This paper provides a comprehensive review of the mechanism of ferroptosis and its regulatory molecules and therapeutic agents in AML. It also evaluates the relationship between ferroptosis-related genes (FRGs), non-coding RNAs (ncRNAs), and prognosis to develop prognostic molecular models in AML. The study also explores the association between ferroptosis and immune infiltration in AML, to identify novel potential target regimens for AML.
Topics: Humans; Ferroptosis; Leukemia, Myeloid, Acute; Cardiovascular Diseases; Iron; Lipid Peroxides
PubMed: 37314462
DOI: 10.1007/s00277-023-05293-4 -
Blood Reviews Nov 2023Core binding factor acute myeloid leukemia (CBF AML), defined by t(8;21) or inv(16), is a subset of favorable risk AML. Despite its association with a high complete... (Review)
Review
Core binding factor acute myeloid leukemia (CBF AML), defined by t(8;21) or inv(16), is a subset of favorable risk AML. Despite its association with a high complete remission rate after induction and relatively good prognosis overall compared with other subtypes of AML, relapse risk after induction chemotherapy remains high. Optimizing treatment planning to promote recurrence free survival and increase the likelihood of survival after relapse is imperative to improving outcomes. Recent areas of research have included evaluation of the role of gemtuzumab in induction and consolidation, the relative benefit of increased cycles of high dose cytarabine in consolidation, the utility of hypomethylating agents and kinase inhibitors, and the most appropriate timing of stem cell transplant. Surveillance with measurable residual disease testing is increasingly being utilized for monitoring disease in remission, and ongoing investigation seeks to determine how to use this tool for early identification of patients who would benefit from proceeding to transplant. In this review, we outline the current therapeutic approach from diagnosis to relapse while highlighting the active areas of investigation in each stage of treatment.
Topics: Humans; Leukemia, Myeloid, Acute; Prognosis; Cytarabine; Core Binding Factors; Recurrence
PubMed: 37524647
DOI: 10.1016/j.blre.2023.101117 -
Current Oncology Reports Apr 2024This review seeks to identify and describe novel genetic and protein targets and their associated therapeutics currently being used or studied in the treatment of acute... (Review)
Review
PURPOSE OF REVIEW
This review seeks to identify and describe novel genetic and protein targets and their associated therapeutics currently being used or studied in the treatment of acute myeloid leukemia (AML).
RECENT FINDINGS
Over the course of the last 5-6 years, several targeted therapies have been approved by the FDA, for the treatment of both newly diagnosed as well as relapsed/refractory AML. These novel therapeutics, as well as several others currently under investigation, have demonstrated activity in AML and have improved outcomes for many patients. Patient outcomes in AML have slowly improved over time, though for many patients, particularly elderly patients or those with relapsed/refractory disease, mortality remains very high. With the identification of several molecular/genetic drivers and protein targets and development of therapeutics which leverage those mechanisms to target leukemic cells, outcomes for patients with AML have improved and continue to improve significantly.
Topics: Humans; Aged; Leukemia, Myeloid, Acute
PubMed: 38502417
DOI: 10.1007/s11912-024-01503-y -
Pathobiology : Journal of... 2024TP53-mutated myeloid neoplasms including acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDS) are notoriously treatment resistant with uniformly poor... (Review)
Review
TP53-mutated myeloid neoplasms including acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDS) are notoriously treatment resistant with uniformly poor outcomes. TP53 status is an important prognostic indicator and early knowledge of the TP53 mutation/allelic state may assist in appropriate management including clinical trial enrollment for eligible patients. Thus far, no therapy has shown to demonstrate durable response or incremental survival benefit in TP53-mutated AML or MDS. Therefore, there is an urgent need for innovative therapies to improve the outcomes in this notoriously recalcitrant genomic subset. In this review, we dissect the biology, classification, prognosis, current treatment landscape, and the early phase evaluation of investigational agents in TP53-mutated AML and MDS.
Topics: Humans; Mutation; Myelodysplastic Syndromes; Myeloproliferative Disorders; Leukemia, Myeloid, Acute; Tumor Suppressor Protein p53
PubMed: 37839402
DOI: 10.1159/000534566 -
Free Radical Biology & Medicine Mar 2024Short-chain fatty acids (SCFAs), particularly propionate and butyrate, have been reported in many cancers. However, the relationship between propionate and acute myeloid...
Short-chain fatty acids (SCFAs), particularly propionate and butyrate, have been reported in many cancers. However, the relationship between propionate and acute myeloid leukemia (AML) remains unclear. Additionally, Acyl-CoA synthetase long chain family member 4 (ACSL4) has been reported to regulate immunity in solid tumors, but there are still many gaps to be filled in AML. Here, we discovered the underlying mechanism of propionate and ACSL4-mediated ferroptosis for immunotherapy. Our results showed that the level of propionate in the AML patients' feces was decreased, which was correlated to gut microbiota dysbiosis. Moreover, we demonstrated that propionate suppressed AML progression both in vivo and in vitro. In mechanism, propionate induced AML cells apoptosis and ferroptosis. The imbalance of reactive oxygen species (ROS) and redox homeostasis induced by propionate caused mitochondrial fission and mitophagy, which enhanced ferroptosis and apoptosis. Furthermore, ACSL4-mediated ferroptosis caused by propionate increased the immunogenicity of AML cells, induced the release of damage-associated molecular patterns (DAMPs), and promoted the maturation of dendritic cells (DCs). The increased level of immunogenicity due to ferroptosis enable propionate-based whole-cell vaccines to activate immunity, thus further facilitating effective killing of AML cells. Collectively, our study uncovers a crucial role for propionate suppresses AML progression by inducing ferroptosis and the potential mechanisms of ACSL4-mediated ferroptosis in the regulation of AML immunity.
Topics: Humans; Propionates; Mitophagy; Ferroptosis; Apoptosis; Leukemia, Myeloid, Acute
PubMed: 38215892
DOI: 10.1016/j.freeradbiomed.2024.01.005 -
Cell Stem Cell Nov 2023Engineered hematopoietic stem cells can be shielded from targeted immunotherapy. Recently published in Nature, Casirati et al. utilized single-base editing of epitopes...
Engineered hematopoietic stem cells can be shielded from targeted immunotherapy. Recently published in Nature, Casirati et al. utilized single-base editing of epitopes implicated in acute myeloid leukemia and healthy hematopoiesis to alter their antibody and chimeric antigen receptor (CAR) T recognition while preserving their ligand binding and enzymatic function.
Topics: Humans; T-Lymphocytes; Gene Editing; Receptors, Chimeric Antigen; Immunotherapy; Leukemia, Myeloid, Acute; Hematopoietic Stem Cells; Immunotherapy, Adoptive
PubMed: 37922877
DOI: 10.1016/j.stem.2023.09.009