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Seminars in Cancer Biology Feb 2020The development of a myeloid neoplasm is a step-wise process that originates from leukemic stem cells (LSC) and includes pre-leukemic stages, overt leukemia and a... (Review)
Review
The development of a myeloid neoplasm is a step-wise process that originates from leukemic stem cells (LSC) and includes pre-leukemic stages, overt leukemia and a drug-resistant terminal phase. Organ-invasion may occur in any stage, but is usually associated with advanced disease and a poor prognosis. Sometimes, extra-medullary organ invasion shows a metastasis-like or even sarcoma-like destructive growth of neoplastic cells in local tissue sites. Examples are myeloid sarcoma, mast cell sarcoma and localized blast phase of chronic myeloid leukemia. So far, little is known about mechanisms underlying re-distribution and extramedullary dissemination of LSC in myeloid neoplasms. In this article, we discuss mechanisms through which LSC can mobilize out of the bone marrow niche, can transmigrate from the blood stream into extramedullary organs, can invade local tissue sites and can potentially create or support the formation of local stem cell niches. In addition, we discuss strategies to interfere with LSC expansion and organ invasion by targeted drug therapies.
Topics: Animals; Biomarkers; Bone Marrow; Cell Communication; Cell Movement; Humans; Immunophenotyping; Leukemia, Myeloid; Neoplasm Staging; Neoplastic Stem Cells; Phenotype; Recurrence; Transendothelial and Transepithelial Migration; Tumor Microenvironment
PubMed: 31408723
DOI: 10.1016/j.semcancer.2019.07.025 -
British Journal of Haematology Aug 2019Despite significant advances in the treatment of myeloid malignancies, many patients become resistant to therapy and ultimately succumb to their disease. Accumulating... (Review)
Review
Despite significant advances in the treatment of myeloid malignancies, many patients become resistant to therapy and ultimately succumb to their disease. Accumulating evidence over the past several years has suggested that the inadequacy of many leukaemia therapies results from their failure to target the leukaemic stem cell (LSC). For this reason, the LSC population currently represents the most critical target in the treatment of myeloid malignancies. However, while LSCs are ideal targets in the treatment of these diseases, they are also the most difficult population to target. This is due to both their heterogeneity within the LSC population, and also their phenotypic similarities with normal haematopoietic stem cells. This review will highlight the current landscape surrounding LSC biology in myeloid malignancies, with a focus on altered energy metabolism, and how that knowledge is being translated into clinical advances for the treatment of chronic and acute myeloid leukaemia and myelodysplastic syndromes.
Topics: Antineoplastic Agents; Biomarkers, Tumor; Clinical Trials as Topic; Drug Resistance, Neoplasm; Energy Metabolism; Hematopoiesis; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid; Myelodysplastic Syndromes; Neoplastic Stem Cells; Signal Transduction; Treatment Outcome
PubMed: 31236939
DOI: 10.1111/bjh.16074 -
Current Opinion in Hematology Mar 2021In the past decade, numerous studies analysing the genome and transcriptome of large cohorts of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) patients... (Review)
Review
PURPOSE OF REVIEW
In the past decade, numerous studies analysing the genome and transcriptome of large cohorts of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) patients have substantially improved our knowledge of the genetic landscape of these diseases with the identification of heterogeneous constellations of germline and somatic mutations with prognostic and therapeutic relevance. However, inclusion of integrated genetic data into classification schema is still far from a reality. The purpose of this review is to summarize recent insights into the prevalence, pathogenic role, clonal architecture, prognostic impact and therapeutic management of genetic alterations across the spectrum of myeloid malignancies.
RECENT FINDINGS
Recent multiomic-studies, including analysis of genetic alterations at the single-cell resolution, have revealed a high heterogeneity of lesions in over 200 recurrently mutated genes affecting disease initiation, clonal evolution and clinical outcome. Artificial intelligence and specifically machine learning approaches have been applied to large cohorts of AML and MDS patients to define in an unbiased manner clinically meaningful disease patterns including, disease classification, prognostication and therapeutic vulnerability, paving the way for future use in clinical practice.
SUMMARY
Integration of genomic, transcriptomic, epigenomic and clinical data coupled to conventional and machine learning approaches will allow refined leukaemia classification and risk prognostication and will identify novel therapeutic targets for these still high-risk leukaemia subtypes.
Topics: Clinical Decision-Making; Clonal Evolution; Disease Management; Epigenomics; Genetic Association Studies; Genetic Predisposition to Disease; Genomics; Humans; Leukemia, Myeloid, Acute; Mutation; Myelodysplastic Syndromes; Prognosis; Single-Cell Analysis; Treatment Outcome
PubMed: 33427759
DOI: 10.1097/MOH.0000000000000629 -
European Journal of Immunology Jan 2022Acute myeloid leukemia (AML) is a highly aggressive disease with high relapse and mortality rates. Recent years have shown a surge in novel therapeutic development for... (Review)
Review
Acute myeloid leukemia (AML) is a highly aggressive disease with high relapse and mortality rates. Recent years have shown a surge in novel therapeutic development for AML, both in clinical and preclinical stages. These developments include targeted therapies based on AML-specific molecular signatures as well as more general immune modulation and vaccination studies. In this review, we will explore the evolving arena of AML therapy and suggest some intriguing connections between immune system modulation and targeted therapy. Improved understanding of the immune system involvement in various stages of the disease and the crosstalk between immune effectors, targeted therapy, and AML cells can provide a better framework for designing the next generation of AML therapies.
Topics: Humans; Leukemia, Myeloid, Acute; Molecular Targeted Therapy
PubMed: 34648664
DOI: 10.1002/eji.202048945 -
Current Oncology Reports Oct 2020Acute myeloid leukemia (AML) is a costly disease, and its impact is greater in developing countries (DC). We will review the current concept of what are DC, compare the... (Review)
Review
PURPOSE OF REVIEW
Acute myeloid leukemia (AML) is a costly disease, and its impact is greater in developing countries (DC). We will review the current concept of what are DC, compare the differences in the epidemiology and economic burden of this disease between developed and DC, and finally, analyze the barriers and possible solutions that DC should implement to achieve better results.
RECENT FINDINGS
DC is a frequently misunderstood name. The way we use to measure human development is changing, and multidimension metrics better define what are DC. With this in mind, we show the differences in the AML epidemiology and the impact of economic burden in DC. We analyze the barriers to access therapy from a clinician point of view, to show that most DC shared similar challenges but with a diverse healthcare structure. Finally, we provide several possible solutions for a more integrated and timely treatment that allows better results not only in terms of survival but with a better quality of life. The economic burden of AML treatment in DC is high, and the results are poor. It is crucial to face this challenge and propose new treatment approaches to achieve better results.
Topics: Cost of Illness; Developing Countries; Health Services Accessibility; Humans; Leukemia, Myeloid, Acute; Quality of Life
PubMed: 33025161
DOI: 10.1007/s11912-020-00987-8 -
Acute myelogenous leukemia - current recommendations and approaches in molecular-genetic assessment.Romanian Journal of Internal Medicine =... Jun 2022Acute myelogenous leukemia is a multi-step hematological malignancy, affecting function, growth, proliferation and cell cycle of myeloid precursors. Overall assessment... (Review)
Review
Acute myelogenous leukemia is a multi-step hematological malignancy, affecting function, growth, proliferation and cell cycle of myeloid precursors. Overall assessment of patients with the disease requires among everything else, a comprehensive investigation of the genetic basis through various methods such as cytogenetic and molecular-genetic ones. This clarification provides diagnostic refinement and carries prognostic and predictive value in respect of essential therapeutic choices.With this review of the literature, we focus on summarizing the latest recommendations and preferred genetic methods, as well as on emphasizing on their general benefits and limitations. Since none of these methods is actually totipotent, we also aim to shed light over the often-difficult choice of appropriate genetic analyses.
Topics: Humans; Leukemia, Myeloid, Acute; Prognosis
PubMed: 35182066
DOI: 10.2478/rjim-2022-0004 -
Hematology. American Society of... Nov 2018Given the recent approvals of new agents for acute myeloid leukemia (AML), a clinical trial pipeline stocked with novel therapies, and the rapid integration of... (Review)
Review
Given the recent approvals of new agents for acute myeloid leukemia (AML), a clinical trial pipeline stocked with novel therapies, and the rapid integration of imaginative approaches in diseases like acute lymphocytic leukemia and chronic lymphocytic leukemia, it is reasonable to ask whether treatment of AML might finally depart from the classical cytotoxic induction therapy that has been employed since the 1970s. However, for better or worse, in 2018, cytotoxic induction regimens remain the standard of care for most patients. Indeed, the future likely lies in combinations of therapies that act with a spectrum of mechanisms. Using a case-based format, this review will outline current treatment expectations for patients according to karyotypic risk and familiarize readers with the basis for common induction choices. Relapsed/refractory disease may be especially amenable to interventions with novel agents or clinical trials; however, there are still some patients who most benefit from intensive chemotherapy. This review will outline risk systems that help the practitioner identify those with the best chances for response and survival. Finally, clinical tools, including geriatric assessments and comorbidity calculators, may help clinicians recognize patients for whom disease risk and comorbidity tip the balance against classical chemotherapy, a frequent challenge for those who treat this devastating disease.
Topics: Antineoplastic Agents; Cytotoxins; Disease-Free Survival; Humans; Leukemia, Myeloid, Acute; Survival Rate
PubMed: 30504291
DOI: 10.1182/asheducation-2018.1.51 -
Haematologica Dec 2022Considerable progress has been made in the past several years in the scientific understanding of, and available treatments for, acute myeloid leukemia (AML). Achievement... (Review)
Review
Considerable progress has been made in the past several years in the scientific understanding of, and available treatments for, acute myeloid leukemia (AML). Achievement of a conventional remission, evaluated cytomorphologically via small bone marrow samples, is a necessary but not sufficient step toward cure. It is increasingly appreciated that molecular or immunophenotypic methods to identify and quantify measurable residual disease (MRD) - populations of leukemia cells below the cytomorphological detection limit - provide refined information on the quality of response to treatment and prediction of the risk of AML recurrence and leukemia-related deaths. The principles and practices surrounding MRD remain incompletely determined however and the genetic and immunophenotypic heterogeneity of AML may prevent a one-sizefits- all approach. Here, we review the current approaches to MRD testing in AML, discuss strengths and limitations, highlight recent technological advances that may improve such testing, and summarize ongoing initiatives to generate the clinical evidence needed to advance the use of MRD testing in patients with AML.
Topics: Humans; Neoplasm, Residual; Leukemia, Myeloid, Acute; Immunophenotyping
PubMed: 36453518
DOI: 10.3324/haematol.2022.282034 -
Nature Reviews. Clinical Oncology May 2016Acute myeloid leukaemia (AML) is a heterogeneous disease that is, in general, associated with a very poor prognosis. Multiple cytogenetic and molecular abnormalities... (Review)
Review
Acute myeloid leukaemia (AML) is a heterogeneous disease that is, in general, associated with a very poor prognosis. Multiple cytogenetic and molecular abnormalities that characterize different forms of AML have been used to better prognosticate patients and inform treatment decisions. Indeed, risk status in patients with this disease has classically been based on cytogenetic findings; however, additional molecular characteristics have been shown to inform risk assessment, including FLT3, NPM1, KIT, and CEBPA mutation status. Advances in sequencing technology have led to the discovery of novel somatic mutations in tissue samples from patients with AML, providing deeper insight into the mutational landscape of the disease. The majority of patients with AML (>97%) are found to have a clonal somatic abnormality on mutational profiling. Nevertheless, our understanding of the utility of mutation profiling in clinical practice remains incomplete and is continually evolving, and evidence-based approaches to application of these data are needed. In this Review, we discuss the evidence-base for integrating mutational data into treatment decisions for patients with AML, and propose novel therapeutic algorithms in the era of molecular medicine.
Topics: Acute Disease; Drug Therapy; Genetic Predisposition to Disease; Humans; Leukemia, Myeloid; Models, Genetic; Molecular Targeted Therapy; Mutation; Nucleophosmin; Prognosis; Risk Factors
PubMed: 26620272
DOI: 10.1038/nrclinonc.2015.210 -
The FEBS Journal Aug 2022It is essential to relate the biology of acute leukaemia to normal blood cell development. In this review, we discuss how modern models of haematopoiesis might inform... (Review)
Review
It is essential to relate the biology of acute leukaemia to normal blood cell development. In this review, we discuss how modern models of haematopoiesis might inform approaches to diagnosis and management of immature leukaemias, with a specific focus on T-lymphoid and myeloid cases. In particular, we consider whether next-generation analytical tools could provide new perspectives that could improve our understanding of immature blood cancer biology.
Topics: Acute Disease; Hematopoiesis; Humans; Leukemia, Myeloid, Acute
PubMed: 34028982
DOI: 10.1111/febs.16030