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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 -
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 -
International Journal of Molecular... Jan 2019Acute myeloid leukaemia (AML) is a rare but severe form of human cancer that results from a limited number of functionally cooperating genetic abnormalities leading to... (Review)
Review
Acute myeloid leukaemia (AML) is a rare but severe form of human cancer that results from a limited number of functionally cooperating genetic abnormalities leading to uncontrolled proliferation and impaired differentiation of hematopoietic stem and progenitor cells. Before the identification of genetic driver lesions, chemically, irradiation or viral infection-induced mouse leukaemia models provided platforms to test novel chemotherapeutics. Later, transgenic mouse models were established to test the in vivo transforming potential of newly cloned fusion genes and genetic aberrations detected in patients' genomes. Hereby researchers constitutively or conditionally expressed the respective gene in the germline of the mouse or reconstituted the hematopoietic system of lethally irradiated mice with bone marrow virally expressing the mutation of interest. More recently, immune deficient mice have been explored to study patient-derived human AML cells in vivo. Unfortunately, although complementary to each other, none of the currently available strategies faithfully model the initiation and progression of the human disease. Nevertheless, fast advances in the fields of next generation sequencing, molecular technology and bioengineering are continuously contributing to the generation of better mouse models. Here we review the most important AML mouse models of each category, briefly describe their advantages and limitations and show how they have contributed to our understanding of the biology and to the development of novel therapies.
Topics: Animals; Bone Marrow Transplantation; Carcinogens; Cell Transformation, Viral; Disease Models, Animal; Gene Editing; Heterografts; Humans; Immunocompromised Host; Leukemia, Myeloid, Acute; Mice; Mice, Transgenic; Radiation, Ionizing
PubMed: 30669675
DOI: 10.3390/ijms20020453 -
Haematologica Sep 2023Although outcomes of children and adolescents with newly diagnosed acute myeloid leukemia (AML) have improved significantly over the past two decades, more than... (Review)
Review
Although outcomes of children and adolescents with newly diagnosed acute myeloid leukemia (AML) have improved significantly over the past two decades, more than one-third of patients continue to relapse and experience suboptimal long-term outcomes. Given the small numbers of patients with relapsed AML and historical logistical barriers to international collaboration including poor trial funding and drug availability, the management of AML relapse has varied among pediatric oncology cooperative groups with several salvage regimens utilized and a lack of universally defined response criteria. The landscape of relapsed pediatric AML treatment is changing rapidly, however, as the international AML community harnesses collective knowledge and resources to characterize the genetic and immunophenotypic heterogeneity of relapsed disease, identify biological targets of interest within specific AML subtypes, develop new precision medicine approaches for collaborative investigation in early-phase clinical trials, and tackle challenges of universal drug access across the globe. This review provides a comprehensive overview of progress achieved to date in the treatment of pediatric patients with relapsed AML and highlights modern, state-of-the-art therapeutic approaches under active and emerging clinical investigation that have been facilitated by international collaboration among academic pediatric oncologists, laboratory scientists, regulatory agencies, pharmaceutical partners, cancer research sponsors, and patient advocates.
Topics: Adolescent; Humans; Child; Treatment Outcome; Leukemia, Myeloid, Acute; Recurrence
PubMed: 36861399
DOI: 10.3324/haematol.2022.281106 -
British Journal of Haematology Jan 2020The field of acute myeloid leukaemia (AML) diagnostics, initially based solely on morphological assessment, has integrated more and more disciplines. Today,... (Review)
Review
The field of acute myeloid leukaemia (AML) diagnostics, initially based solely on morphological assessment, has integrated more and more disciplines. Today, state-of-the-art AML diagnostics relies on cytomorphology, cytochemistry, immunophenotyping, cytogenetics and molecular genetics. Only the integration of all of these methods allows for a comprehensive and complementary characterisation of each case, which is prerequisite for optimal AML diagnosis and management. Here, we will review why multidisciplinary diagnostics is mandatory today and will gain even more importance in the future, especially in the context of precision medicine. We will discuss ideas and strategies that are likely to shape and improve multidisciplinary diagnostics in AML and may even overcome some of today's gold standards. This includes recent technical advances that provide genome-wide molecular insights. The enormous amount of data obtained by these latter techniques represents a great challenge, but also a unique chance. We will reflect on how this increase in knowledge can be incorporated into the routine to pave the way for personalised medicine in AML.
Topics: Cytogenetic Analysis; Genome-Wide Association Study; Humans; Immunophenotyping; Leukemia, Myeloid, Acute; Precision Medicine
PubMed: 31808952
DOI: 10.1111/bjh.16360 -
Leukemia Jan 2022While the understanding of the genomic aberrations that underpin chronic and acute myeloid leukaemia (CML and AML) has allowed the development of therapies for these... (Review)
Review
While the understanding of the genomic aberrations that underpin chronic and acute myeloid leukaemia (CML and AML) has allowed the development of therapies for these diseases, limitations remain. These become apparent when looking at the frequency of treatment resistance leading to disease relapse in leukaemia patients. Key questions regarding the fundamental biology of the leukaemic cells, such as their metabolic dependencies, are still unresolved. Even though a majority of leukaemic cells are killed during initial treatment, persistent leukaemic stem cells (LSCs) and therapy-resistant cells are still not eradicated with current treatments, due to various mechanisms that may contribute to therapy resistance, including cellular metabolic adaptations. In fact, recent studies have shown that LSCs and treatment-resistant cells are dependent on mitochondrial metabolism, hence rendering them sensitive to inhibition of mitochondrial oxidative phosphorylation (OXPHOS). As a result, rewired energy metabolism in leukaemic cells is now considered an attractive therapeutic target and the significance of this process is increasingly being recognised in various haematological malignancies. Therefore, identifying and targeting aberrant metabolism in drug-resistant leukaemic cells is an imperative and a relevant strategy for the development of new therapeutic options in leukaemia. In this review, we present a detailed overview of the most recent studies that present experimental evidence on how leukaemic cells can metabolically rewire, more specifically the importance of OXPHOS in LSCs and treatment-resistant cells, and the current drugs available to target this process. We highlight that uncovering specific energy metabolism dependencies will guide the identification of new and more targeted therapeutic strategies for myeloid leukaemia.
Topics: Animals; Antineoplastic Agents; Energy Metabolism; Humans; Leukemia, Myeloid, Acute; Mitochondria; Neoplastic Stem Cells; Oxidative Phosphorylation
PubMed: 34561557
DOI: 10.1038/s41375-021-01416-w -
Nature Reviews. Cancer Mar 2020For two decades, leukaemia stem cells (LSCs) in chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML) have been advanced paradigms for the cancer stem cell... (Review)
Review
For two decades, leukaemia stem cells (LSCs) in chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML) have been advanced paradigms for the cancer stem cell field. In CML, the acquisition of the fusion tyrosine kinase BCR-ABL1 in a haematopoietic stem cell drives its transformation to become a LSC. In AML, LSCs can arise from multiple cell types through the activity of a number of oncogenic drivers and pre-leukaemic events, adding further layers of context and genetic and cellular heterogeneity to AML LSCs not observed in most cases of CML. Furthermore, LSCs from both AML and CML can be refractory to standard-of-care therapies and persist in patients, diversify clonally and serve as reservoirs to drive relapse, recurrence or progression to more aggressive forms. Despite these complexities, LSCs in both diseases share biological features, making them distinct from other CML or AML progenitor cells and from normal haematopoietic stem cells. These features may represent Achilles' heels against which novel therapies can be developed. Here, we review many of the similarities and differences that exist between LSCs in CML and AML and examine the therapeutic strategies that could be used to eradicate them.
Topics: Animals; Biomarkers, Tumor; Cell Transformation, Neoplastic; Disease Management; Disease Susceptibility; Drug Development; History, 20th Century; History, 21st Century; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Molecular Targeted Therapy; Neoplastic Stem Cells; Research
PubMed: 31907378
DOI: 10.1038/s41568-019-0230-9 -
Annals of Oncology : Official Journal... Jun 2020
Topics: Adult; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute
PubMed: 32171751
DOI: 10.1016/j.annonc.2020.02.018 -
International Journal of Molecular... Jun 2022Acute myeloid leukaemia (AML) is defined as a malignant disorder of the bone marrow (BM) that is characterised by the clonal expansion and differentiation arrest of...
Acute myeloid leukaemia (AML) is defined as a malignant disorder of the bone marrow (BM) that is characterised by the clonal expansion and differentiation arrest of myeloid progenitor cells [...].
Topics: Bone Marrow; Bone Marrow Cells; Humans; Leukemia, Myeloid, Acute
PubMed: 35682932
DOI: 10.3390/ijms23116251 -
Tidsskrift For Den Norske Laegeforening... Oct 2023It is uncertain what the best treatment is for older patients with acute myeloid leukaemia who are not candidates for allogeneic stem cell transplantation. The purpose... (Review)
Review
BACKGROUND
It is uncertain what the best treatment is for older patients with acute myeloid leukaemia who are not candidates for allogeneic stem cell transplantation. The purpose of the study was to examine the treatment practices for this patient group at Akershus University Hospital, as well as survival according to treatment choices and the genetic risk of a tumour.
MATERIAL AND METHOD
The study is based on a review of the medical records of patients aged 65 and older with recently diagnosed acute myeloid leukaemia treated without allogeneic stem cell transplantation at Akershus University Hospital from 1 January 2006 to 1 January 2021.
RESULTS
We included 151 out of 156 identified patients. The median age was 76 years, 42 patients (28 %) received intensive chemotherapy, 38 (25 %) received low-intensity chemotherapy and 71 (47 %) received supportive care only. Supportive care was mainly given in the early part of the period. From 2014 onwards, low-intensity chemotherapy made up a significant part of the treatment. Tumour genetic analyses were available for 88 patients, of which 17, 47 and 24 had a favourable, intermediate and unfavourable genetic risk of a tumour respectively. None of the patients with an unfavourable genetic risk of a tumour survived for 2 years. There were no statistically significant differences in survival between low-intensity and intensive chemotherapy. In the group with a favourable genetic risk of a tumour, the median survival was 573 days with intensive chemotherapy (n=12) and 101 days with low-intensity chemotherapy (n=4) (p=0.09). Patients treated with intensive chemotherapy were in hospital the longest.
INTERPRETATION
The results suggest that knowledge of the genetic risk of a tumour is useful when choosing treatment for older patients with acute myeloid leukaemia.
Topics: Aged; Humans; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols; Leukemia, Myeloid, Acute; Hematopoietic Stem Cell Transplantation; Hospitals
PubMed: 37874067
DOI: 10.4045/tidsskr.22.0490