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International Journal of Molecular... Apr 2022Refractory disease and relapse remain the main causes of cancer therapy failure. Refined risk stratification, treatment regimens and improved early diagnosis and... (Review)
Review
Refractory disease and relapse remain the main causes of cancer therapy failure. Refined risk stratification, treatment regimens and improved early diagnosis and detection of minimal residual disease have increased cure rates in malignancies like childhood acute lymphoblastic leukaemia (ALL) to 90%. Nevertheless, overall survival in the context of drug resistance remains poor. The regulatory role of micro RNAs (miRNAs) in cell differentiation, homeostasis and tumorigenesis has been under extensive investigation in different cancers. There is accumulating data demonstrating the significance of miRNAs for therapy outcomes in lymphoid malignancies and some direct demonstrations of the interplay between these small molecules and drug response. Here, we summarise miRNAs' impact on chemotherapy resistance in adult and paediatric ALL and chronic lymphocytic leukaemia (CLL). The main focus of this review is on the modulation of particular signaling pathways like PI3K-AKT, transcription factors such as NF-κB, and apoptotic mediators, all of which are bona fide and pivotal elements orchestrating the survival of malignant lymphocytic cells. Finally, we discuss the attractive strategy of using mimics, antimiRs and other molecular approaches pointing at miRNAs as promising therapeutic targets. Such novel strategies to circumvent ALL and CLL resistance networks may potentially improve patients' responses and survival rates.
Topics: Adult; Child; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; MicroRNAs; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Signal Transduction
PubMed: 35563051
DOI: 10.3390/ijms23094657 -
Virchows Archiv : An International... Jan 2023The International Clinical Advisory Committee reviewed advances in our understanding of the clinicopathologic and biologic features of chronic lymphocytic... (Review)
Review
The International Clinical Advisory Committee reviewed advances in our understanding of the clinicopathologic and biologic features of chronic lymphocytic leukaemia/small lymphocytic lymphoma, B-cell prolymphocytic leukaemia, and mantle cell lymphoma since the revised 4th edition of the WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissues. Discussions amongst pathologists, clinicians, and molecular geneticists around these diseases focussed on incorporating new knowledge into the next classification system. In this manuscript, we review these disease entities and incorporate results of these deliberations, including advances in our understanding of early lesions and transformation.
Topics: Adult; Humans; Lymphoma, Mantle-Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell
PubMed: 36454275
DOI: 10.1007/s00428-022-03460-y -
The Journal of Clinical Investigation Jan 2019Targeted therapy with small molecules directed at essential survival pathways in leukemia represents a major advance, including the phosphatidylinositol-3'-kinase (PI3K)...
Targeted therapy with small molecules directed at essential survival pathways in leukemia represents a major advance, including the phosphatidylinositol-3'-kinase (PI3K) p110δ inhibitor idelalisib. Here, we found that genetic inactivation of p110δ (p110δD910A/D910A) in the Eμ-TCL1 murine chronic lymphocytic leukemia (CLL) model impaired B cell receptor signaling and B cell migration, and significantly delayed leukemia pathogenesis. Regardless of TCL1 expression, p110δ inactivation led to rectal prolapse in mice resembling autoimmune colitis in patients receiving idelalisib. Moreover, we showed that p110δ inactivation in the microenvironment protected against CLL and acute myeloid leukemia. After receiving higher numbers of TCL1 leukemia cells, half of p110δD910A/D910A mice spontaneously recovered from high disease burden and resisted leukemia rechallenge. Despite disease resistance, p110δD910A/D910A mice exhibited compromised CD4+ and CD8+ T cell response, and depletion of CD4+ or CD8+ T cells restored leukemia. Interestingly, p110δD910A/D910A mice showed significantly impaired Treg expansion that associated with disease clearance. Reconstitution of p110δD910A/D910A mice with p110δWT/WT Tregs reversed leukemia resistance. Our findings suggest that p110δ inhibitors may have direct antileukemic and indirect immune-activating effects, further supporting that p110δ blockade may have a broader immune-modulatory role in types of leukemia that are not sensitive to p110δ inhibition.
Topics: Amino Acid Substitution; Animals; CD8-Positive T-Lymphocytes; Class I Phosphatidylinositol 3-Kinases; Enzyme Activation; Immune Tolerance; Leukemia, Lymphoid; Mice; Mice, Transgenic; Mutation, Missense; Neoplasms, Experimental; T-Lymphocytes, Regulatory
PubMed: 30457982
DOI: 10.1172/JCI99386 -
Leukemia Feb 2016Acute leukemia (AL) and myelodysplastic syndrome (MDS) are uncommon in chronic lymphocytic leukemia (CLL). We retrospectively identified 95 patients with CLL, also...
Acute leukemia (AL) and myelodysplastic syndrome (MDS) are uncommon in chronic lymphocytic leukemia (CLL). We retrospectively identified 95 patients with CLL, also diagnosed with AL (n=38) or MDS (n=57), either concurrently (n=5) or subsequent (n=90) to CLL diagnosis and report their outcomes. Median number of CLL treatments prior to AL and MDS was 2 (0-9) and 1 (0-8), respectively; the most common regimen was purine analog combined with alkylating agent±CD20 monoclonal antibody. Twelve cases had no prior CLL treatment. Among 38 cases with AL, 33 had acute myelogenous leukemia (AML), 3 had acute lymphoid leukemia (ALL; 1 Philadelphia chromosome positive), 1 had biphenotypic and 1 had extramedullary (bladder) AML. Unfavorable AML karyotype was noted in 26, and intermediate risk in 7 patients. There was no association between survival from AL and number of prior CLL regimens or karyotype. Expression of CD7 on blasts was associated with shorter survival. Among MDS cases, all International Prognostic Scoring System (IPSS) were represented; karyotype was unfavorable in 36, intermediate in 6 and favorable in 12 patients; 10 experienced transformation to AML. Shorter survival from MDS correlated with higher risk IPSS, poor-risk karyotype and increased number of prior CLL treatments. Overall, outcomes for patients with CLL subsequently diagnosed with AL or MDS were very poor; AL/MDS occurred without prior CLL treatment. Effective therapies for these patients are desperately needed.
Topics: Aged; Female; Humans; Karyotype; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid, Acute; Male; Myelodysplastic Syndromes; Retrospective Studies
PubMed: 26290497
DOI: 10.1038/leu.2015.227 -
Canadian Medical Association Journal Jan 1981Acute lymphocytic leukemia is the most common cancer of childhood. A series of total therapy studies begun in 1962 at St. Jude Children's Research Hospital in Memphis,... (Clinical Trial)
Clinical Trial Review
Acute lymphocytic leukemia is the most common cancer of childhood. A series of total therapy studies begun in 1962 at St. Jude Children's Research Hospital in Memphis, Tennessee has had a dramatic impact on the survival of children with this disease. These studies have systematically examined various drug combinations and radiation therapy in an effort to cure acute lymphocytic leukemia. As a result, a once uniformly fatal condition is now curable in nearly one half of cases. In addition to improved control of the primary disease, refinements in drug treatment and in supportive care have diminished the frequency of severe infections, which may complicate aggressive therapy. Although the quality of life for the survivors so far appears generally good, treatment-induced toxic effects may impose subtle, though significant, handicaps in some cases. A combination of clinical and laboratory investigations begun in the mid-1970s is beginning to demonstrate a previously unknown heterogeneity among patients with acute lymphocytic leukemia. It is now possible to recognize a substantial minority of patients on the basis of these studies as being at "high risk" for treatment failure. For them, drastic modifications of present programs are being investigated in an attempt to improve their prognosis. For patients lacking high-risk features improvements are still needed, but changes in their treatment must be kept within the framework of what is presently successful and must address the hazard of long-term toxicity.
Topics: Adolescent; Antineoplastic Agents; Bone Marrow; Bone Marrow Transplantation; Child; Child, Preschool; Clinical Trials as Topic; Drug Resistance; Drug Therapy, Combination; Female; Humans; Infant; Leukemia, Lymphoid; Leukocyte Count; Male; Meningeal Neoplasms; Prognosis; Transplantation, Homologous
PubMed: 7006781
DOI: No ID Found -
CA: a Cancer Journal For Clinicians 1980At present, significant numbers of children with ALL enjoy prolonged survival without serious sequelae. All children should be given the benefit of treatment under the... (Review)
Review
At present, significant numbers of children with ALL enjoy prolonged survival without serious sequelae. All children should be given the benefit of treatment under the supervision of physicians experienced in childhood cancer. Risk factors should be properly assessed and children at high risk placed in innovative programs. Longterm follow-up of patients is essential to detect, as early as possible, potentially prohibitive toxicity.
Topics: Antineoplastic Agents; Bone Marrow Transplantation; Central Nervous System Diseases; Child; Humans; Leukemia, Lymphoid; Lymphocytes; Prognosis; Transplantation, Homologous
PubMed: 6769554
DOI: 10.3322/canjclin.30.3.158 -
Current Hematologic Malignancy Reports Feb 2016Chronic lymphocytic leukaemia (CLL) is well known to generate impaired immune responses in the host, with the malignant clone residing in well-vascularized tissues and... (Review)
Review
Chronic lymphocytic leukaemia (CLL) is well known to generate impaired immune responses in the host, with the malignant clone residing in well-vascularized tissues and circulating in peripheral blood but also in close proximity to effector cells that are capable, if activated appropriately, of eliciting a cytotoxic response. These, combined with the fact that this is frequently a condition affecting older patients with co-morbidities often unfit for many "traditional" cytotoxic agents with their significant associated toxicities, make CLL an ideal candidate for the development of immunotherapy. The impressive results seen with the addition of a monoclonal antibody, rituximab, to a chemotherapy backbone, for example, is testament to how effective harnessing an immune-mediated response in CLL can be. This review serves to outline the available arsenal of immunotherapies-past and present-demonstrated to have potential in CLL with some perspectives on how the landscape in this disease may evolve in the future.
Topics: Antibodies, Monoclonal; Antigens, CD20; Antigens, Neoplasm; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab; T-Lymphocytes
PubMed: 26857283
DOI: 10.1007/s11899-015-0295-9 -
Annals of Oncology : Official Journal... Mar 1995Chronic lymphocytic leukemia (CLL) is the form of leukemia which occurs most frequently in Western countries. Its etiology is unknown, and no relationship with viruses... (Review)
Review
Chronic lymphocytic leukemia (CLL) is the form of leukemia which occurs most frequently in Western countries. Its etiology is unknown, and no relationship with viruses or genes has been demonstrated. Epidemiological data suggest that genetic and ambiental factors might be of some significance. Clinical features of CLL are due to the accumulation of leukemic cells in bone marrow and lymphoid organs as well as the immune disturbances that accompany the disease. The prognosis of patients with CLL varies. Treatment is usually indicated by the risk of the individual patient, which is clearly reflected by the stage of the disease. In the early stage (Binet A, Rai O) it is reasonable to defer therapy until disease progression is observed. By contrast, because their median survival is less than five years, patients with more advanced stages require therapy. For almost 50 years, no major advances in the management of CLL, which has revolved around the use of alkylating agents, have been made. In recent years, the therapeutic approach in patients with CLL has changed as a result of the introduction of combination chemotherapy regimens and, in particular, purine analogues. The latter are already the treatment of choice for patients not responding to standard therapies, and their role as front-line therapy is being investigated. Bone marrow transplants are also being increasingly used. It is to be hoped that in years to come the outcome of patients with CLL will be improved by these advances.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Prognosis
PubMed: 7612488
DOI: 10.1093/oxfordjournals.annonc.a059151 -
British Journal of Haematology Feb 2011The WHO classification recognises three distinct disorders of large granular lymphocytes: T-cell large granular lymphocytic leukaemia (T-LGL), chronic... (Review)
Review
The WHO classification recognises three distinct disorders of large granular lymphocytes: T-cell large granular lymphocytic leukaemia (T-LGL), chronic lymphoproliferative disorders of NK-cells (CLPD-NK) and agressive NK-cell leukaemia. Despite the different cell of origin, there is considerable overlap between T-LGL and CLPD-NK in terms of clinical presentation and therapy. Many patients are asymptomatic and do not require treatment. Therapy, with immunosuppressant agents such as low dose methotrexate or ciclosporin, is usually indicated to correct cytopenias. In contrast, aggressive NK-cell leukaemia and the rare CD56(+) aggressive T-LGL leukaemia follow a fulminant clinical course, affect younger individuals and require more intensive combination chemotherapy followed by allogeneic stem cell transplant in eligible patients. The relative rarity of these disorders means that there have been few clinical trials to inform management. However, there is now considerable interest in the pathogenesis of the chronic LGL leukaemias and this has stimulated early trials to evaluate novel agents which target the dysregulated apoptotic pathways characteristic of this disease.
Topics: Antineoplastic Agents; Diagnosis, Differential; Humans; Immunophenotyping; Leukemia, Large Granular Lymphocytic
PubMed: 21158751
DOI: 10.1111/j.1365-2141.2010.08494.x -
Prilozi (Makedonska Akademija Na... 2014Chronic lymphocytic leukaemia (CLL) is a common lymphoid malignancy characterized by the expansion and progressive accumulation of mature autoreactive B lymphocytes. The... (Review)
Review
Chronic lymphocytic leukaemia (CLL) is a common lymphoid malignancy characterized by the expansion and progressive accumulation of mature autoreactive B lymphocytes. The disease is clinically heterogeneous and incurable by standard chemotherapy. A major feature of the disease is the marked dependence of the leukaemic cells on various microenvironmental stimuli, which promote leukaemia cell growth, survival, and drug-resistance. Recently, considerable progress has been made in the understanding of the molecular mechanisms that drive CLL. The identification of recurrent genetic lesions using next generation sequencing technology has provided new data on the pathophysiology of the disease and has improved its prognostication. The recognition of the critical role of the B cell receptor (BCR) in driving the disease has resulted in the development of BCR pathway inhibitors that have the potential to completely transform CLL treatment in the near future. Other novel therapeutic agents, such as BCL2 antagonists and chimeric antigen receptor (CAR)-modified T-cells, are also showing great promise in clinical trials. In this review, we summarize some of these recent advances, with a particular focus on the BCR and corresponding pathway inhibitors.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Receptors, Antigen, B-Cell
PubMed: 25725699
DOI: 10.1515/prilozi-2015-0015