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CA: a Cancer Journal For Clinicians 1994Major advances in the diagnosis, classification, and treatment of adult acute leukemias have resulted in significant increases in the number of complete remissions and... (Review)
Review
Major advances in the diagnosis, classification, and treatment of adult acute leukemias have resulted in significant increases in the number of complete remissions and long-term disease-free survivors. Despite these improvements, most adult patients with acute leukemias still eventually die from their disease or complications of its treatment. New experimental and clinical approaches used to diagnose, monitor, and treat these diseases hold promise for further increased cure rates in the future. This article reviews the classification, immunobiology, cytogenetics, diagnosis, and treatment of adult acute leukemias and describes new directions being taken toward their cure.
Topics: Acute Disease; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Humans; Leukemia
PubMed: 7953914
DOI: 10.3322/canjclin.44.6.326 -
Nature Reviews. Cancer Jul 2021In contrast to solid cancers, which often require genetic modifications and complex cellular reprogramming for effective metastatic dissemination, leukaemic cells... (Review)
Review
In contrast to solid cancers, which often require genetic modifications and complex cellular reprogramming for effective metastatic dissemination, leukaemic cells uniquely possess the innate ability for migration and invasion. Dedifferentiated, malignant leukocytes retain the benign leukocytes' capacity for cell motility and survival in the circulation, while acquiring the potential for rapid and uncontrolled cell division. For these reasons, leukaemias, although not traditionally considered as metastatic diseases, are in fact models of highly efficient metastatic spread. Accordingly, they are often aggressive and challenging diseases to treat. In this Perspective, we discuss the key molecular processes that facilitate metastasis in a variety of leukaemic subtypes, the clinical significance of leukaemic invasion into specific tissues and the current pipeline of treatments targeting leukaemia metastasis.
Topics: Animals; Cell Movement; Cellular Reprogramming; Humans; Leukemia; Neoplasm Invasiveness; Neoplasm Metastasis
PubMed: 33953370
DOI: 10.1038/s41568-021-00355-z -
Cancer Reports (Hoboken, N.J.) Apr 2019Carcinogenic transformation of white blood cells during hematopoiesis leads to the development of leukemia, a cancer characterized by incompetent immune cells and a... (Review)
Review
BACKGROUND
Carcinogenic transformation of white blood cells during hematopoiesis leads to the development of leukemia, a cancer characterized by incompetent immune cells and a disruption of normal bone marrow function. Leukemias are diverse in type, affected population, prognosis, and treatment regimen, yet a common theme in leukemia is the dysregulated metabolism of leukemic cells and leukemic stem cells with respect to their noncancerous counterparts.
RECENT FINDINGS
In this review, we highlight current findings that elucidate metabolic traits unique to the four major types of leukemia, which confer carcinogenic survival but can be potentially exploited for therapeutic intervention. These metabolic features can work in conjunction with or be independent of unique aspects of the bone marrow microenvironment that can also influence cell survival and proliferation, thus sustaining carcinogenesis.
CONCLUSION
Deepening our understanding of the interactions of leukemias with their niche environments in vivo will inform future treatments for leukemia, particularly for those that are refractive to tyrosine kinase inhibitors and other therapeutic mainstays.
Topics: Animals; Bone Marrow; Hematopoiesis; Humans; Leukemia; Metabolic Networks and Pathways; Stem Cell Niche; Tumor Microenvironment
PubMed: 32721091
DOI: 10.1002/cnr2.1139 -
Frontiers in Immunology 2022In recent years, there has been an emphasis on harnessing the immune system for therapeutic interventions. Adoptive cell therapies (ACT) have emerged as an effective... (Review)
Review
In recent years, there has been an emphasis on harnessing the immune system for therapeutic interventions. Adoptive cell therapies (ACT) have emerged as an effective option for B-cell derived hematological malignancies. Despite remarkable successes with ACT, immune dysregulation and the leukemia microenvironment can critically alter clinical responses. Therefore, preclinical modeling can contribute to the advancement of ACT for leukemias. Human xenografts, the current mainstay of ACT models, cannot evaluate the impact of the immunosuppressive leukemia microenvironment on adoptively transferred cells. Syngeneic mouse models utilize murine tumor models and implant them into immunocompetent mice. This provides an alternative model, reducing the need for complicated breeding strategies while maintaining a matched immune system, stromal compartment, and leukemia burden. Syngeneic models that evaluate ACT have analyzed the complexity of cytotoxic T lymphocytes, T cell receptor transgenics, and chimeric antigen receptors. This review examines the immunosuppressive features of the leukemia microenvironment, discusses how preclinical modeling helps predict ACT associated toxicities and dysfunction, and explores publications that have employed syngeneic modeling in ACT studies for the improvement of therapy for leukemias.
Topics: Animals; Humans; Immunosuppressive Agents; Immunotherapy, Adoptive; Leukemia; Mice; Receptors, Chimeric Antigen; T-Lymphocytes, Cytotoxic; Tumor Microenvironment
PubMed: 35401520
DOI: 10.3389/fimmu.2022.867103 -
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 -
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 -
Archives of Pathology & Laboratory... Jan 2011Timely and accurate diagnosis of hematologic malignancies is crucial to appropriate clinical management. Acute leukemias are a diverse group of malignancies with a range... (Review)
Review
CONTEXT
Timely and accurate diagnosis of hematologic malignancies is crucial to appropriate clinical management. Acute leukemias are a diverse group of malignancies with a range of clinical presentations, prognoses, and preferred treatment protocols. Historical classification systems relied predominantly on morphologic and cytochemical features, but currently, immunophenotypic, cytogenetic, and molecular data are incorporated to define clinically relevant diagnostic categories. Multiparameter flow cytometry provides rapid and detailed determination of antigen expression profiles in acute leukemias which, in conjunction with morphologic assessment, often suggests a definitive diagnosis or a narrow differential. Many recurrent molecular or cytogenetic aberrations are associated with distinct immunophenotypic features, and therefore flow cytometry is an important tool to direct further testing. In addition, detection of specific antigens may have prognostic or therapeutic implications even within a single acute leukemia subtype. After initial diagnosis, a leukemia's immunophenotypic fingerprint provides a useful reference to monitor response to therapy, minimal residual disease, and recurrence.
OBJECTIVE
To provide an overview of the application of flow cytometric immunophenotyping to the diagnosis and management of acute leukemias, including salient features of those entities described in the 2008 World Health Organization classification.
DATA SOURCES
Published articles pertaining to flow cytometry, acute leukemia classification, and experiences of a reference flow cytometry laboratory.
CONCLUSION
Immunophenotypic evaluation is essential to accurate diagnosis and classification of acute leukemia. Multiparameter flow cytometry provides a rapid and effective means to collect this information, as well as providing prognostic information and a modality for minimal residual disease evaluation.
Topics: Acute Disease; Disease Management; Flow Cytometry; Humans; Immunophenotyping; Leukemia; Leukemia, Myeloid, Acute; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 21204710
DOI: 10.5858/2010-0387-RAR.1 -
European Journal of Cancer (Oxford,... Mar 2022Despite improved outcomes achieved in the last decades for children with newly diagnosed leukaemia and lymphoma, treatment of patients with refractory/relapsed disease... (Review)
Review
Despite improved outcomes achieved in the last decades for children with newly diagnosed leukaemia and lymphoma, treatment of patients with refractory/relapsed disease remains a challenge. The cure rate is still unsatisfactory and often achieved at the cost of significant morbidity. Exploring treatment with novel agents should offer less toxic therapeutic options, without compromising efficacy. Bispecific and antibody-drug conjugates targeting CD19 and CD22 (blinatumomab and inotuzumab ozogamicin) play an important role in the treatment of relapsed and refractory B-cell precursor acute lymphoblastic leukaemia (BCP-ALL); antibodies targeting CD123 and CD38 are also under investigation for acute myeloid leukaemia (AML) and T-ALL, respectively. Targeted therapy with small molecules is of primary importance for specific genetic subtypes, such as BCR-ABL-positive ALL, FLT3-ITD AML and anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma. KMT2A-directed targeted therapy with menin inhibitors holds promise to be of relevance in KMT2A-rearranged leukaemias, known to have dismal prognosis. Target inhibition in cellular pathways such as BCL-2, RAS, MEK, Bruton's tyrosine kinase, JAK-STAT or CDK4/CDK6 inhibition may be suitable for different diseases with common mutated pathways. Nevertheless, development and approval of new agents for paediatric cancers lags behind adult therapeutic options. New regulations were implemented to accelerate drug development for children. Considering the number of oncology medicinal products available for adults and the rarity of paediatric cancers, prioritisation based on scientific evidence and medical need, as well as international collaboration, is critical. Herein, we review the current status of drug development for children with leukaemia and lymphoma, excluding cellular therapy despite its well-known significance.
Topics: Adult; Child; Humans; Immunotherapy; Inotuzumab Ozogamicin; Leukemia, Myeloid, Acute; Lymphoma, B-Cell; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 35121370
DOI: 10.1016/j.ejca.2021.12.029 -
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 -
Acta Biochimica Et Biophysica Sinica Jun 2023Leukaemia is the common name for a group of malignant diseases of the haematopoietic system with complex classifications and characteristics. Remarkable progress has... (Review)
Review
Leukaemia is the common name for a group of malignant diseases of the haematopoietic system with complex classifications and characteristics. Remarkable progress has been made in basic research and preclinical studies for acute leukaemia compared to that of the many other types/subtypes of leukaemia, especially the exploration of the biological basis and application of immunotherapy in acute myeloid leukaemia (AML) and B-cell acute lymphoblastic leukaemia (B-ALL). In this review, we summarize the basic approaches to immunotherapy for leukaemia and focus on the research progress made in immunotherapy development for AML and ALL. Importantly, despite the advances made to date, big challenges still exist in the effectiveness of leukaemia immunotherapy, especially in AML. Therefore, we use AML as an example and summarize the mechanisms of tumour cell immune evasion, describe recently reported data and known therapeutic targets, and discuss the obstacles in finding suitable treatment targets and the results obtained in recent clinical trials for several types of single and combination immunotherapies, such as bispecific antibodies, cell therapies (CAR-T-cell treatment), and checkpoint blockade. Finally, we summarize novel immunotherapy strategies for treating lymphocytic leukaemia and clinical trial results.
Topics: Immunotherapy; Humans; Bone Marrow Transplantation; Cancer Vaccines; Tumor Escape; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 37272727
DOI: 10.3724/abbs.2023101