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Frontiers in Cell and Developmental... 2021Involvement of the Central Nervous System (CNS) in acute leukemia confers poor prognosis and lower overall survival. Existing CNS-directed therapies are associated with... (Review)
Review
Involvement of the Central Nervous System (CNS) in acute leukemia confers poor prognosis and lower overall survival. Existing CNS-directed therapies are associated with a significant risk of short- or long-term toxicities. Leukemic cells can metabolically adapt and survive in the microenvironment of the CNS. The supporting role of the CNS microenvironment in leukemia progression and dissemination has not received sufficient attention. Understanding the mechanism by which leukemic cells survive in the nutrient-poor and oxygen-deprived CNS microenvironment will lead to the development of more specific and less toxic therapies. Here, we review the current literature regarding the roles of metabolic reprogramming in leukemic cell adhesion and survival in the CNS.
PubMed: 34957100
DOI: 10.3389/fcell.2021.767510 -
Scientific Reports Dec 2021Central nervous system (CNS) relapse is a significant cause of treatment failure among patients with acute lymphoblastic leukemia. In prior work we found that the...
Central nervous system (CNS) relapse is a significant cause of treatment failure among patients with acute lymphoblastic leukemia. In prior work we found that the meninges, the thin layer of tissue that covers the brain and spinal cord, harbor leukemia cells in the CNS. Importantly, direct interactions between leukemia and meningeal cells enabled leukemia chemoresistance. Herein, we show that an antibody targeting CD99, a transmembrane protein expressed on meningeal cells and many leukemia cells, disrupts adhesion between leukemia and meningeal cells and restores sensitivity of the leukemia cells to chemotherapy. This work identifies a mechanism regulating critical intercellular interactions within the CNS leukemia niche and may lead to novel therapeutic approaches for overcoming niche-mediated chemoresistance.
Topics: 12E7 Antigen; Antibodies, Monoclonal; Drug Resistance, Neoplasm; Humans; Meningeal Neoplasms; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Tumor Cells, Cultured
PubMed: 34934147
DOI: 10.1038/s41598-021-03929-x -
Molecular Cell Jun 2021Riedel et al. (2021) show that expression of MN1 is capable of blocking myeloid differentiation and initiating leukemia through mechanisms that require Brg1-containing...
Riedel et al. (2021) show that expression of MN1 is capable of blocking myeloid differentiation and initiating leukemia through mechanisms that require Brg1-containing chromatin remodeling complexes. Intriguingly, this process depends on an unstructured polyglutamine repeat region within MN1.
Topics: Humans; Leukemia, Myeloid, Acute; Meningeal Neoplasms; Meningioma; Trans-Activators; Tumor Suppressor Proteins
PubMed: 34087176
DOI: 10.1016/j.molcel.2021.05.001 -
Cancers Feb 2021Cytarabine is a pyrimidine nucleoside analog, commonly used in multiagent chemotherapy regimens for the treatment of leukemia and lymphoma, as well as for neoplastic... (Review)
Review
Cytarabine is a pyrimidine nucleoside analog, commonly used in multiagent chemotherapy regimens for the treatment of leukemia and lymphoma, as well as for neoplastic meningitis. Ara-C-based chemotherapy regimens can induce a suboptimal clinical outcome in a fraction of patients. Several studies suggest that the individual variability in clinical response to Leukemia & Lymphoma treatments among patients, underlying either Ara-C mechanism resistance or toxicity, appears to be associated with the intracellular accumulation and retention of Ara-CTP due to genetic variants related to metabolic enzymes. Herein, we reported (a) the latest Pharmacogenomics biomarkers associated with the response to cytarabine and (b) the new drug formulations with optimized pharmacokinetics. The purpose of this review is to provide readers with detailed and comprehensive information on the effects of Ara-C-based therapies, from biological to clinical practice, maintaining high the interest of both researcher and clinical hematologist. This review could help clinicians in predicting the response to cytarabine-based treatments.
PubMed: 33669053
DOI: 10.3390/cancers13050966 -
Frontiers in Neurology 2023Chimeric antigen receptor (CAR) T-cell systemic immunotherapy has revolutionized how clinicians treat several refractory and relapsed hematologic malignancies. Due to... (Review)
Review
Chimeric antigen receptor (CAR) T-cell systemic immunotherapy has revolutionized how clinicians treat several refractory and relapsed hematologic malignancies. Due to its peculiar mechanism of action, CAR T-cell-based therapy has enlarged the spectrum of neurological toxicities. CAR T-cell-associated neurotoxicity-initially defined as CAR T-cell-related encephalopathy syndrome (CRES) and currently coined within the acronym ICANS (immune effector cell-associated neurotoxicity syndrome)-is perhaps the most concerning toxicity of CAR T-cell therapy. Importantly, hematologic malignancies (especially lymphoid malignancies) may originate in or spread to the central nervous system (CNS) in the form of parenchymal and/or meningeal disease. Due to the emergence of deadly and neurological adverse events, such as fatal brain edema in some patients included in early CAR T-cell trials, safety concerns for those with CNS primary or secondary infiltration arose and contributed to the routine exclusion of individuals with pre-existing or active CNS involvement from pivotal trials. However, based primarily on the lack of evidence, it remains unknown whether CNS involvement increases the risk and/or severity of CAR T-cell-related neurotoxicity. Given the limited treatment options available for patients once they relapse with CNS involvement, it is of high interest to explore the role of novel clinical strategies including CAR T cells to treat leukemias/lymphomas and myeloma with CNS involvement. The purpose of this review was to summarize currently available neurological safety data of CAR T-cell-based immunotherapy from the clinical trials and real-world experiences in adult patients with CNS disease due to lymphoma, leukemia, or myeloma. Increasing evidence supports that CNS involvement in hematologic disease should no longer be considered as an absolute contraindication to CAR T-cell-based therapy. While the incidence may be high, severity does not appear to be impacted significantly by pre-existing CNS status. Close monitoring by trained neurologists is recommended.
PubMed: 37090983
DOI: 10.3389/fneur.2023.1144414 -
British Journal of Haematology May 2023The effective prophylaxis and treatment of central nervous system (CNS) involvement in acute lymphoblastic leukaemia (ALL) remains a significant clinical challenge....
The effective prophylaxis and treatment of central nervous system (CNS) involvement in acute lymphoblastic leukaemia (ALL) remains a significant clinical challenge. Developing novel and more effective CNS-directed therapies has been hampered, in part, by our limited understanding of the leukaemia niche in the CNS relative to the bone marrow. Accordingly, defining the molecular and cellular components critical for the establishment and maintenance of the CNS leukaemia niche may lead to new therapeutic opportunities. In prior work we showed that direct intercellular interactions between leukaemia and meningeal cells enhance leukaemia chemoresistance in the CNS. Herein, we show that the CXCR4/CXCL12 chemokine axis contributes to leukaemia-meningeal cell adhesion. Importantly, clinically tested CXCR4 antagonists, which are likely to cross the blood-brain and blood-cerebral spinal fluid barriers and penetrate the CNS, effectively disrupted leukaemia-meningeal cell adhesion. Moreover, by disrupting these intercellular interactions, CXCR4 antagonists attenuated leukaemia chemoresistance in leukaemia-meningeal cell co-culture experiments and enhanced the efficacy of cytarabine in targeting leukaemia cells in the meninges in vivo. This work identifies the CXCR4/CXCL12 axis as an important regulator of intercellular interactions within the CNS leukaemia niche and supports further testing of the therapeutic efficacy of CXCR4 antagonists in overcoming CNS niche-mediated chemoresistance.
Topics: Humans; Cell Adhesion; Drug Resistance, Neoplasm; Leukemia; Signal Transduction; Receptors, CXCR4; Chemokine CXCL12; Meninges
PubMed: 36535585
DOI: 10.1111/bjh.18607 -
Haematologica Aug 2020Protection from acute lymphoblastic leukemia relapse in the central nervous system (CNS) is crucial to survival and quality of life for leukemia patients. Current...
Protection from acute lymphoblastic leukemia relapse in the central nervous system (CNS) is crucial to survival and quality of life for leukemia patients. Current CNS-directed therapies cause significant toxicities and are only partially effective. Moreover, the impact of the CNS microenvironment on leukemia biology is poorly understood. In this study we showed that leukemia cells associated with the meninges of xenotransplanted mice, or co-cultured with meningeal cells, exhibit enhanced chemoresistance due to effects on both apoptosis balance and quiescence. From a mechanistic standpoint, we found that leukemia chemoresistance is primarily mediated by direct leukemia-meningeal cell interactions and overcome by detaching the leukemia cells from the meninges. Next, we used a co-culture adhesion assay to identify drugs that disrupted leukemia-meningeal adhesion. In addition to identifying several drugs that inhibit canonical cell adhesion targets we found that Me6TREN (Tris[2-(dimethylamino)ethyl]amine), a novel hematopoietic stem cell-mobilizing compound, also disrupted leukemia-meningeal adhesion and enhanced the efficacy of cytarabine in treating CNS leukemia in xenotransplanted mice. This work demonstrates that the meninges exert a critical influence on leukemia chemoresistance, elucidates mechanisms of relapse beyond the well-described role of the blood-brain barrier, and identifies novel therapeutic approaches for overcoming chemoresistance.
Topics: Animals; Central Nervous System; Cytarabine; Drug Resistance, Neoplasm; Humans; Leukemia; Mice; Quality of Life; Tumor Microenvironment
PubMed: 31624109
DOI: 10.3324/haematol.2019.230334 -
Neurotherapeutics : the Journal of the... Jan 2013Alemtuzumab is a humanized monoclonal antibody that is administered daily for 5 days, and then no further therapy is required for 12 months. It causes rapid and... (Review)
Review
Alemtuzumab is a humanized monoclonal antibody that is administered daily for 5 days, and then no further therapy is required for 12 months. It causes rapid and prolonged lymphocyte depletion; the consequent homeostatic reconstitution leads to a radically reformed lymphocyte pool with a relative increase in regulatory T cells and expansion of autoreactive T cells. Although previously licensed for the treatment of B-cell chronic lymphocytic leukemia, it is now been considered for licensing in the treatment of multiple sclerosis (MS). From a disappointing experience with alemtuzumab in progressive MS, Alastair Compston and I argued that immunotherapies should be given early in the course of the disease. In a unique program of drug development in MS, alemtuzumab has been compared in 1 phase 2 trial and 2 phase 3 trials with the active comparator interferon beta-1a. In all trials, alemtuzumab was more effective in suppressing relapses than interferon beta-1a. In one phase 2 and one phase 3 trial, alemtuzumab also reduced the risk of accumulating disability compared with interferon beta-1a. Indeed, alemtuzumab treatment led to an improvement in disability and a reduction in cerebral atrophy. The safety issues are infusion-associated reactions largely controlled by methylprednisolone, antihistamines, and antipyretics; mild-to-moderate infections (with 3 opportunistic infections from the open-label experience: 1 case each of spirochaetal gingivitis, pyogenic granuloma, and Listeria meningitis); and autoimmunity. Usually autoimmunity is directed against the thyroid gland, but causes (1 %) immune thrombocytopenia, and in a few cases antiglomerular basement membrane syndrome. Alemtuzumab is an effective therapy for early relapsing-remitting MS, offering disability improvement at least to 5 years after treatment. Its use requires careful monitoring so that potentially serious side effects can be treated early and effectively.
Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Clinical Trials as Topic; Humans; Immunologic Factors; Multiple Sclerosis
PubMed: 23184314
DOI: 10.1007/s13311-012-0159-0 -
Archives of Disease in Childhood Aug 1967
Topics: Child; Female; Humans; Injections, Spinal; Leukemia; Male; Meningeal Neoplasms; Methotrexate; Prognosis; Recurrence
PubMed: 4951644
DOI: 10.1136/adc.42.224.441 -
Cancers Jun 2019The central nervous system (CNS) may be considered as a sanctuary site, protected from systemic chemotherapy by the meninges, the cerebrospinal fluid (CSF) and the... (Review)
Review
The central nervous system (CNS) may be considered as a sanctuary site, protected from systemic chemotherapy by the meninges, the cerebrospinal fluid (CSF) and the blood-brain barrier (BBB). Consequently, parenchymal and CSF exposure of most antineoplastic agents following intravenous (IV) administration is lower than systemic exposure. In this review, we describe the different strategies developed to improve delivery of antineoplastic agents into the brain in primary and metastatic CNS tumors. We observed that several methods, such as BBB disruption (BBBD), intra-arterial (IA) and intracavitary chemotherapy, are not routinely used because of their invasiveness and potentially serious adverse effects. Conversely, intrathecal (IT) chemotherapy has been safely and widely practiced in the treatment of pediatric primary and metastatic tumors, replacing the neurotoxic cranial irradiation for the treatment of childhood lymphoma and acute lymphoblastic leukemia (ALL). IT chemotherapy may be achieved through lumbar puncture (LP) or across the Ommaya intraventricular reservoir, which are both described in this review. Additionally, we overviewed pharmacokinetics and toxic aspects of the main IT antineoplastic drugs employed for primary or metastatic childhood CNS tumors (such as methotrexate, cytosine arabinoside, hydrocortisone), with a concise focus on new and less used IT antineoplastic agents.
PubMed: 31200562
DOI: 10.3390/cancers11060824