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Dartigeas C, Quinquenel A, Ysebaert L, Dilhuydy MS, Anglaret B, Slama B, Le Du K, Tardy S, Tchernonog E, Orfeuvre H, Voillat L, Guidez S, Malfuson JV, Dupuis S, Deslandes M, Feugier P, Leblond V. Final results on effectiveness and safety of Ibrutinib in patients with chronic lymphocytic leukemia from the non-interventional FIRE study. Ann Hematol 2025; 104:1079-1093. [PMID: 38443660 PMCID: PMC11971162 DOI: 10.1007/s00277-024-05666-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Accepted: 02/15/2024] [Indexed: 03/07/2024]
Abstract
We conducted an observational study (FIRE) to understand the effectiveness and safety outcomes of ibrutinib in patients with chronic lymphocytic leukemia (CLL) in France, after a maximum follow-up of five years. Patients were included according to the French marketing authorization in 2016 (i.e. patients with relapsed or refractory CLL or to previously untreated CLL patients with deletion 17p and/or tumor protein p53 mutations unsuitable for chemoimmunotherapy) and could have initiated ibrutinib more than 30 days prior their enrolment in the study (i.e. retrospective patients) or between 30 days before and 14 days after their enrolment (i.e. prospective patients). The results showed that in the effectiveness population (N = 388), the median progression-free survival (PFS) was 53.1 (95% CI: 44.5-60.5) months for retrospective patients and 52.9 (95% CI: 40.3-60.6) months for prospective patients and no difference was shown between the PFS of patients who had at least one dose reduction versus the PFS of patients without dose reduction (p = 0.7971 for retrospective and p = 0.3163 for prospective patients). For both retrospective and prospective patients, the median overall survival was not reached. The most frequent treatment-emergent adverse event of interest was infections (57.6% retrospective; 71.4% prospective). A total of 14.6% of the retrospective patients and 22.4% of the prospective patients had an adverse event leading to death. Our findings on effectiveness were consistent with other studies and the fact that patients with dose reductions had similar PFS than patients without dose reduction is reassuring. No additional safety concerns than those already mentioned in previous studies could be noticed.Trial registration ClinicalTrials.gov, NCT03425591. Registered 1 February 2018 - Retrospectively registered.
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MESH Headings
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
- Leukemia, Lymphocytic, Chronic, B-Cell/mortality
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Adenine/analogs & derivatives
- Adenine/adverse effects
- Male
- Female
- Aged
- Piperidines/adverse effects
- Middle Aged
- Aged, 80 and over
- Retrospective Studies
- Follow-Up Studies
- Adult
- France/epidemiology
- Pyrazoles/adverse effects
- Pyrazoles/administration & dosage
- Pyrazoles/therapeutic use
- Prospective Studies
- Treatment Outcome
- Progression-Free Survival
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Affiliation(s)
- Caroline Dartigeas
- Hématologie et Thérapie Cellulaire, CHRU Hôpitaux de Tours, 2 Boulevard Tonnellé, 37044, Tours Cedex 9, France.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Véronique Leblond
- AP-HP Hôpital de La Pitié-Salpêtrière, Paris La Sorbonne, Paris, France
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Reigler O, Ben Ishai M, Oliphant H. Lacrimal Sac CLL: A Review of Clinical Features, Investigations, and Management. Ophthalmic Plast Reconstr Surg 2025:00002341-990000000-00575. [PMID: 39840744 DOI: 10.1097/iop.0000000000002907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2025]
Abstract
PURPOSE This study reviews all reported cases of lacrimal gland chronic lymphocytic leukemia (CLL) to identify patterns in clinical presentation, diagnosis, and management to aid in early recognition and treatment of this uncommon occurrence. METHODS A comprehensive search of medical literature databases was performed to identify studies reporting lacrimal sac involvement in CLL from 1970 to 2024. Data were extracted regarding demographics, symptoms, diagnostic methods, treatment, and outcomes. RESULTS Thirty-three cases of CLL lacrimal sac infiltration were identified. The median age was 71, with a slight female predominance of 54.5%. The most common symptoms were epiphora (63.6%) and pseudo-dacryocystitis or symptoms of dacryocystitis (48.5%). A significant proportion of patients (87.9%) had a known history of CLL at presentation. Chemotherapy combined with surgery was the most frequent treatment, 48.4%, with a positive response in 93.3% of patients. Local recurrence occurred in 10.3% of cases, predominantly in those treated with chemotherapy and surgery, or surgery alone. CONCLUSIONS Lacrimal sac CLL, though rare, should be considered in patients with nasolacrimal duct obstruction, especially those with a prior CLL diagnosis. Early diagnosis can be aided by imaging and histopathological evaluation, and treatment typically results in favorable outcomes with low recurrence rates. Tailoring treatment based on individual patient factors is essential for optimal management.
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Affiliation(s)
- Oliver Reigler
- Brighton and Sussex Medical School, University of Sussex, Brighton, United Kingdom
- Department of Ophthalmology, Sussex Eye Hospital, Brighton, United Kingdom
| | - Meydan Ben Ishai
- Brighton and Sussex Medical School, University of Sussex, Brighton, United Kingdom
- Department of Ophthalmology, Sussex Eye Hospital, Brighton, United Kingdom
| | - Huw Oliphant
- Brighton and Sussex Medical School, University of Sussex, Brighton, United Kingdom
- Department of Ophthalmology, Sussex Eye Hospital, Brighton, United Kingdom
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3
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Long BY, Wang Y, Hao SH, Shi G. Molecular significance of circRNAs in malignant lymphoproliferative disorders: pathogenesis and novel biomarkers or therapeutic targets. Am J Cancer Res 2024; 14:4633-4651. [PMID: 39417189 PMCID: PMC11477815 DOI: 10.62347/kmwb5164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Accepted: 09/22/2024] [Indexed: 10/19/2024] Open
Abstract
Recent studies have shown that circular RNAs (CircRNAs) have the novel functions and molecular mechanisms in the pathogenesis of malignant diseases. CircRNAs have been found to be associated with the occurrence and development of lymphoproliferative diseases, impacting on lymphocyte proliferation. This article provides a review of the pathogenesis of circRNAs in malignant lymphoproliferative disorders, focusing on conditions such as acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), and lymphoma. Additionally, it discusses the potential value of circRNAs as novel biomarkers or therapeutic targets in these disorders.
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Affiliation(s)
- Bo-Yang Long
- Department of Oncology and Hematology, The Second Hospital of Jilin UniversityChangchun, Jilin, China
| | - Yan Wang
- Department of Hematology, The Affiliated Yantai Yuhuangding Hospital of Qingdao UniversityYantai, Shandong, China
| | - Shu-Hong Hao
- Department of Oncology and Hematology, The Second Hospital of Jilin UniversityChangchun, Jilin, China
| | - Guang Shi
- Department of Oncology and Hematology, The Second Hospital of Jilin UniversityChangchun, Jilin, China
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Abohassan M, Khaleel AQ, Pallathadka H, Kumar A, Allela OQB, Hjazi A, Pramanik A, Mustafa YF, Hamzah HF, Mohammed BA. Circular RNA as a Biomarker for Diagnosis, Prognosis and Therapeutic Target in Acute and Chronic Lymphoid Leukemia. Cell Biochem Biophys 2024; 82:1979-1991. [PMID: 39136839 DOI: 10.1007/s12013-024-01404-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/03/2024] [Indexed: 10/02/2024]
Abstract
Circular RNAs (circRNAs) are single-stranded RNAs that have received much attention in recent years. CircRNAs lack a 5' head and a 3' poly-A tail. The structure of this type of RNAs make them resistant to digestion by exonucleases. CircRNAs are expressed in different cells and have various functions. The function of circRNAs is done by sponging miRNAs, changing gene expression, and protein production. The expression of circRNAs changes in different types of cancers, which causes changes in cell growth, proliferation, differentiation, and apoptosis. Changes in the expression of circRNAs can cause the invasion and progression of tumors. Studies have shown that changes in the expression of circRNAs can be seen in acute lymphoid leukemia (ALL) and chronic lymphoid leukemia (CLL). The conducted studies aim to identify circRNAs whose expression has changed in these leukemias and their more precise function so that these circRNAs can be identified as biomarkers, prediction of patient prognosis, and treatment targets for ALL and CLL patients. In this study, we review the studies conducted on the role and function of circRNAs in ALL and CLL patients. The results of the studies show that there is a possibility of using circRNAs as biomarkers in the identification and treatment of patients in the future.
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MESH Headings
- Humans
- RNA, Circular/genetics
- RNA, Circular/metabolism
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/metabolism
- Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
- Prognosis
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy
- RNA/metabolism
- RNA/genetics
- MicroRNAs/genetics
- MicroRNAs/metabolism
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Affiliation(s)
- Mohammad Abohassan
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Abdulrahman Qais Khaleel
- Department of Medical Instruments Engineering, Al-Maarif University College, Al Anbar, 31001, Iraq.
| | | | - Ashwani Kumar
- Department of Life Sciences, School of Sciences, Jain (Deemed-to-be) University, Bengaluru, Karnataka, 560069, India
- Department of Pharmacy, Vivekananda Global University, Jaipur, Rajasthan, 303012, India
| | | | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj, 11942, Saudi Arabia
| | - Atreyi Pramanik
- School of Applied and Life Sciences, Ivison of Research and Innovation Uttaranchal University, Dehradun, India
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Hamza Fadhel Hamzah
- Department of Medical Laboratories Technology, AL-Nisour University College, Baghdad, Iraq
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Mavridou D, Psatha K, Aivaliotis M. Integrative Analysis of Multi-Omics Data to Identify Deregulated Molecular Pathways and Druggable Targets in Chronic Lymphocytic Leukemia. J Pers Med 2024; 14:831. [PMID: 39202022 PMCID: PMC11355716 DOI: 10.3390/jpm14080831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 07/25/2024] [Accepted: 07/27/2024] [Indexed: 09/03/2024] Open
Abstract
Chronic Lymphocytic Leukemia (CLL) is the most common B-cell malignancy in the Western world, characterized by frequent relapses despite temporary remissions. Our study integrated publicly available proteomic, transcriptomic, and patient survival datasets to identify key differences between healthy and CLL samples. We exposed approximately 1000 proteins that differentiate healthy from cancerous cells, with 608 upregulated and 415 downregulated in CLL cases. Notable upregulated proteins include YEATS2 (an epigenetic regulator), PIGR (Polymeric immunoglobulin receptor), and SNRPA (a splicing factor), which may serve as prognostic biomarkers for this disease. Key pathways implicated in CLL progression involve RNA processing, stress resistance, and immune response deficits. Furthermore, we identified three existing drugs-Bosutinib, Vorinostat, and Panobinostat-for potential further investigation in drug repurposing in CLL. We also found limited correlation between transcriptomic and proteomic data, emphasizing the importance of proteomics in understanding gene expression regulation mechanisms. This generally known disparity highlights once again that mRNA levels do not accurately predict protein abundance due to many regulatory factors, such as protein degradation, post-transcriptional modifications, and differing rates of translation. These results demonstrate the value of integrating omics data to uncover deregulated proteins and pathways in cancer and suggest new therapeutic avenues for CLL.
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Affiliation(s)
- Dimitra Mavridou
- Laboratory of Biological Chemistry, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece;
- Functional Proteomics and Systems Biology (FunPATh), Center for Interdisciplinary Research and Innovation (CIRI-AUTH), GR-57001 Thessaloniki, Greece;
- Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece
| | - Konstantina Psatha
- Functional Proteomics and Systems Biology (FunPATh), Center for Interdisciplinary Research and Innovation (CIRI-AUTH), GR-57001 Thessaloniki, Greece;
- Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece
- Laboratory of Medical Biology—Genetics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece
| | - Michalis Aivaliotis
- Laboratory of Biological Chemistry, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece;
- Functional Proteomics and Systems Biology (FunPATh), Center for Interdisciplinary Research and Innovation (CIRI-AUTH), GR-57001 Thessaloniki, Greece;
- Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece
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Manivannan MS, Yang X, Patel N, Peters A, Johnston JB, Gibson SB. Lysosome-Disrupting Agents in Combination with Venetoclax Increase Apoptotic Response in Primary Chronic Lymphocytic Leukemia (CLL) Cells Mediated by Lysosomal Cathepsin D Release and Inhibition of Autophagy. Cells 2024; 13:1041. [PMID: 38920669 PMCID: PMC11202145 DOI: 10.3390/cells13121041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 06/10/2024] [Accepted: 06/13/2024] [Indexed: 06/27/2024] Open
Abstract
Venetoclax and obinutuzumab are becoming frontline therapies for chronic lymphocytic leukemia (CLL) patients. Unfortunately, drug resistance still occurs, and the combination could be immunosuppressive. Lysosomes have previously been identified as a target for obinutuzumab cytotoxicity in CLL cells, but the mechanism remains unclear. In addition, studies have shown that lysosomotropic agents can cause synergistic cell death in vitro when combined with the BTK inhibitor, ibrutinib, in primary CLL cells. This indicates that targeting lysosomes could be a treatment strategy for CLL. In this study, we have shown that obinutuzumab induces lysosome membrane permeabilization (LMP) and cathepsin D release in CLL cells. Inhibition of cathepsins reduced obinutuzumab-induced cell death in CLL cells. We further determined that the lysosomotropic agent siramesine in combination with venetoclax increased cell death in primary CLL cells through an increase in reactive oxygen species (ROS) and cathepsin release. Siramesine treatment also induced synergistic cytotoxicity when combined with venetoclax. Microenvironmental factors IL4 and CD40L or incubation with HS-5 stromal cells failed to significantly protect CLL cells from siramesine- and venetoclax-induced apoptosis. We also found that siramesine treatment inhibited autophagy through reduced autolysosomes. Finally, the autophagy inhibitor chloroquine failed to further increase siramesine-induced cell death. Taken together, lysosome-targeting drugs could be an effective strategy in combination with venetoclax to overcome drug resistance in CLL.
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MESH Headings
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- Leukemia, Lymphocytic, Chronic, B-Cell/metabolism
- Bridged Bicyclo Compounds, Heterocyclic/pharmacology
- Sulfonamides/pharmacology
- Lysosomes/metabolism
- Lysosomes/drug effects
- Apoptosis/drug effects
- Autophagy/drug effects
- Cathepsin D/metabolism
- Reactive Oxygen Species/metabolism
- Drug Synergism
- Cell Line, Tumor
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Affiliation(s)
- Madhumita S. Manivannan
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada; (M.S.M.); (X.Y.); (N.P.); (A.P.)
| | - Xiaoyan Yang
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada; (M.S.M.); (X.Y.); (N.P.); (A.P.)
| | - Nirav Patel
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada; (M.S.M.); (X.Y.); (N.P.); (A.P.)
| | - Anthea Peters
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada; (M.S.M.); (X.Y.); (N.P.); (A.P.)
- Cross Cancer Institute, Alberta Health Services, Edmonton, AB T5J 3E4, Canada
| | - James B. Johnston
- CancerCare Manitoba Research Institute, Hematologist/Oncologist, CancerCare Manitoba, Winnipeg, MB R3E 0V9, Canada;
| | - Spencer B. Gibson
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada; (M.S.M.); (X.Y.); (N.P.); (A.P.)
- Department of Internal Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
- Department of Biochemistry and Medical Genetics, Faculty of Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, USA
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Cui Y, Yan Y. The global burden of childhood and adolescent leukaemia and attributable risk factors: An analysis of the Global Burden of Disease Study 2019. J Glob Health 2024; 14:04045. [PMID: 38426852 PMCID: PMC10906348 DOI: 10.7189/jogh.14.04045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/02/2024] Open
Abstract
Background Aim of this study is to estimate the burden of leukaemia in children and adolescents, as well as the socio-demographic index (SDI), for 21 regions around the world from 1990 to 2019. Methods We also conducted an analysis of the Joinpoint model to estimate the time trend of childhood and adolescent leukaemia incidence, death, and disability-adjusted life years (DALYs) rate and age-standardised rates (ASR) of leukaemia. Results According to our analysis, the middle SDI experienced the highest decrease in incidence rate between 1990 and 2019, with an average annual percent change (AAPC) of -2.8 (95% confidence interval (CI) = -3.0, -2.6, P < 0.05). We showed that DALYs of children leukaemia is 155.98 (95% uncertainty interval (UI) = 127.18, 182.64) for global male, however, global female leukaemia DALYs is 117.65 (95% UI = 102.07, 132.70). Conclusions Despite the observed decline in the incidence, mortality, and DALYs of leukaemia over the last three decades, the burden of childhood and adolescent leukaemia remains high, particularly in areas with lower SDI.
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Ullah MA, Garcillán B, Whitlock E, Figgett WA, Infantino S, Eslami M, Yang S, Rahman MA, Sheng YH, Weber N, Schneider P, Tam CS, Mackay F. An unappreciated cell survival-independent role for BAFF initiating chronic lymphocytic leukemia. Front Immunol 2024; 15:1345515. [PMID: 38469292 PMCID: PMC10927009 DOI: 10.3389/fimmu.2024.1345515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 01/25/2024] [Indexed: 03/13/2024] Open
Abstract
Background Chronic Lymphocytic Leukemia (CLL) is characterized by the expansion of CD19+ CD5+ B cells but its origin remains debated. Mutated CLL may originate from post-germinal center B cells and unmutated CLL from CD5+ mature B cell precursors. Irrespective of precursor types, events initiating CLL remain unknown. The cytokines BAFF and APRIL each play a significant role in CLL cell survival and accumulation, but their involvement in disease initiation remains unclear. Methods We generated novel CLL models lacking BAFF or APRIL. In vivo experiments were conducted to explore the impact of BAFF or APRIL loss on leukemia initiation, progression, and dissemination. Additionally, RNA-seq and quantitative real-time PCR were performed to unveil the transcriptomic signature influenced by BAFF in CLL. The direct role of BAFF in controlling the expression of tumor-promoting genes was further assessed in patient-derived primary CLL cells ex-vivo. Results Our findings demonstrate a crucial role for BAFF, but not APRIL, in the initiation and dissemination of CLL cells. In the absence of BAFF or its receptor BAFF-R, the TCL1 transgene only increases CLL cell numbers in the peritoneal cavity, without dissemination into the periphery. While BAFF binding to BAFF-R is dispensable for peritoneal CLL cell survival, it is necessary to activate a tumor-promoting gene program, potentially linked to CLL initiation and progression. This direct role of BAFF in controlling the expression of tumor-promoting genes was confirmed in patient-derived primary CLL cells ex-vivo. Conclusions Our study, involving both mouse and human CLL cells, suggests that BAFF might initiate CLL through mechanisms independent of cell survival. Combining current CLL therapies with BAFF inhibition could offer a dual benefit by reducing peripheral tumor burden and suppressing transformed CLL cell output.
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Affiliation(s)
- Md Ashik Ullah
- Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute, Cancer Program, Herston, QLD, Australia
| | - Beatriz Garcillán
- The Department of Microbiology and Immunology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia
| | - Eden Whitlock
- Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute, Cancer Program, Herston, QLD, Australia
| | - William A. Figgett
- The Department of Microbiology and Immunology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia
- Garvan Institute of Medical Research, Kinghorn Centre for Clinical Genomics, Darlinghurst, NSW, Australia
| | - Simona Infantino
- The Department of Microbiology and Immunology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia
| | - Mahya Eslami
- Department of Immunobiology, University of Lausanne, Epalinges, Switzerland
- Department of Oncology and Children’s Research Centre, University Children’s Hospital Zürich, Zürich, Switzerland
| | - SiLing Yang
- Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute, Cancer Program, Herston, QLD, Australia
| | - M. Arifur Rahman
- Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute, Cancer Program, Herston, QLD, Australia
| | - Yong H. Sheng
- Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute, Cancer Program, Herston, QLD, Australia
| | - Nicholas Weber
- Cancer Care Services, Royal Brisbane and Women’s Hospital, Herston, QLD, Australia
| | - Pascal Schneider
- Department of Immunobiology, University of Lausanne, Epalinges, Switzerland
| | - Constantine S. Tam
- Department of Haematology, Alfred Hospital, Melbourne, VIC, Australia
- Department of Haematology, Monash University, Melbourne, VIC, Australia
| | - Fabienne Mackay
- Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute, Cancer Program, Herston, QLD, Australia
- The Department of Microbiology and Immunology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia
- The Department of Immunology and Pathology, Monash University, VIC, Australia
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
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Lee CH, Wu YY, Huang TC, Lin C, Zou YF, Cheng JC, Chen PH, Jhou HJ, Ho CL. Maintenance therapy for chronic lymphocytic leukaemia. Cochrane Database Syst Rev 2024; 1:CD013474. [PMID: 38174814 PMCID: PMC10765471 DOI: 10.1002/14651858.cd013474.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
BACKGROUND Chronic lymphocytic leukaemia (CLL) is the most common lymphoproliferative disease in adults and currently remains incurable. As the progression-free period shortens after each successive treatment, strategies such as maintenance therapy are needed to improve the degree and duration of response to previous therapies. Monoclonal antibodies, immunomodulatory agents, and targeted therapies are among the available options for maintenance therapy. People with CLL who achieve remission after previous therapy may choose to undergo medical observation or maintenance therapy to deepen the response. Even though there is widespread use of therapeutic maintenance agents, the benefits and harms of these treatments are still uncertain. OBJECTIVES To assess the effects and safety of maintenance therapy, including anti-CD20 monoclonal antibody, immunomodulatory drug therapy, anti-CD52 monoclonal antibody, Bruton tyrosine kinase inhibitor, and B-cell lymphoma-2 tyrosine kinase inhibitor, for individuals with CLL. SEARCH METHODS We conducted a comprehensive literature search for randomised controlled trials (RCTs) with no language or publication status restrictions. We searched CENTRAL, MEDLINE, Embase, and three trials registers in January 2022 together with reference checking, citation searching, and contact with study authors to identify additional studies. SELECTION CRITERIA We included RCTs with prospective identification of participants. We excluded cluster-randomised trials, cross-over trial designs, and non-randomised studies. We included studies comparing maintenance therapies with placebo/observation or head-to-head comparisons. DATA COLLECTION AND ANALYSIS We used standard Cochrane methodological procedures. We assessed risk of bias in the included studies using Cochrane's RoB 1 tool for RCTs. We rated the certainty of evidence for the following outcomes using the GRADE approach: overall survival (OS), health-related quality of life (HRQoL), grade 3 and 4 adverse events (AEs), progression-free survival (PFS), treatment-related mortality (TRM), treatment discontinuation (TD), and all adverse events (AEs). MAIN RESULTS We identified 11 RCTs (2393 participants) that met the inclusion criteria, including seven trials comparing anti-CD20 monoclonal antibodies (mAbs) (rituximab or ofatumumab) with observation in 1679 participants; three trials comparing immunomodulatory drug (lenalidomide) with placebo/observation in 693 participants; and one trial comparing anti-CD 52 mAbs (alemtuzumab) with observation in 21 participants. No comparisons of novel small molecular inhibitors were found. The median age of participants was 54.1 to 71.7 years; 59.5% were males. The type of previous induction treatment, severity of disease, and baseline stage varied among the studies. Five trials included early-stage symptomatic patients, and three trials included advanced-stage patients (Rai stage III/IV or Binet stage B/C). Six trials reported a frequent occurrence of cytogenic aberrations at baseline (69.7% to 80.1%). The median follow-up duration was 12.4 to 73 months. The risk of selection bias in the included studies was unclear. We assessed overall risk of performance bias and detection bias as low risk for objective outcomes and high risk for subjective outcomes. Overall risk of attrition bias, reporting bias, and other bias was low. Anti-CD20 monoclonal antibodies (mAbs): rituximab or ofatumumab maintenance versus observation Anti-CD20 mAbs maintenance likely results in little to no difference in OS (hazard ratio (HR) 0.94, 95% confidence interval (CI) 0.73 to 1.20; 1152 participants; 3 studies; moderate-certainty evidence) and likely increases PFS significantly (HR 0.61, 95% CI 0.50 to 0.73; 1255 participants; 5 studies; moderate-certainty evidence) compared to observation alone. Anti-CD20 mAbs may result in: an increase in grade 3/4 AEs (rate ratio 1.34, 95% CI 1.06 to 1.71; 1284 participants; 5 studies; low-certainty evidence); little to no difference in TRM (risk ratio 0.82, 95% CI 0.39 to 1.71; 1189 participants; 4 studies; low-certainty evidence); a slight reduction to no difference in TD (risk ratio 0.93, 95% CI 0.72 to 1.20; 1321 participants; 6 studies; low-certainty evidence); and an increase in all AEs (rate ratio 1.23, 95% CI 1.03 to 1.47; 1321 participants; 6 studies; low-certainty evidence) compared to the observation group. One RCT reported that there may be no difference in HRQoL between the anti-CD20 mAbs (ofatumumab) maintenance and the observation group (mean difference -1.70, 95% CI -8.59 to 5.19; 480 participants; 1 study; low-certainty evidence). Immunomodulatory drug (IMiD): lenalidomide maintenance versus placebo/observation IMiD maintenance therapy likely results in little to no difference in OS (HR 0.91, 95% CI 0.61 to 1.35; 461 participants; 3 studies; moderate-certainty evidence) and likely results in a large increase in PFS (HR 0.37, 95% CI 0.19 to 0.73; 461 participants; 3 studies; moderate-certainty evidence) compared to placebo/observation. Regarding harms, IMiD maintenance therapy may result in an increase in grade 3/4 AEs (rate ratio 1.82, 95% CI 1.38 to 2.38; 400 participants; 2 studies; low-certainty evidence) and may result in a slight increase in TRM (risk ratio 1.22, 95% CI 0.35 to 4.29; 458 participants; 3 studies; low-certainty evidence) compared to placebo/observation. The evidence for the effect on TD compared to placebo is very uncertain (risk ratio 0.71, 95% CI 0.47 to 1.05; 400 participants; 2 studies; very low-certainty evidence). IMiD maintenance therapy probably increases all AEs slightly (rate ratio 1.41, 95% CI 1.28 to 1.54; 458 participants; 3 studies; moderate-certainty evidence) compared to placebo/observation. No studies assessed HRQoL. Anti-CD52 monoclonal antibodies (mAbs): alemtuzumab maintenance versus observation Maintenance with alemtuzumab may have little to no effect on PFS, but the evidence is very uncertain (HR 0.55, 95% CI 0.32 to 0.95; 21 participants; 1 study; very low-certainty evidence). We did not identify any study reporting the outcomes OS, HRQoL, grade 3/4 AEs, TRM, TD, or all AEs. AUTHORS' CONCLUSIONS There is currently moderate- to very low-certainty evidence available regarding the benefits and harms of maintenance therapy in people with CLL. Anti-CD20 mAbs maintenance improved PFS, but also increased grade 3/4 AEs and all AEs. IMiD maintenance had a large effect on PFS, but also increased grade 3/4 AEs. However, none of the above-mentioned maintenance interventions show differences in OS between the maintenance and control groups. The effects of alemtuzumab maintenance are uncertain, coupled with a warning for drug-related infectious toxicity. We found no studies evaluating other novel maintenance interventions, such as B-cell receptor inhibitors, B-cell leukaemia-2/lymphoma-2 inhibitors, or obinutuzumab.
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Affiliation(s)
- Cho-Hao Lee
- Division of Hematology and Oncology Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Yi-Ying Wu
- Division of Hematology and Oncology Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Tzu-Chuan Huang
- Division of Hematology and Oncology Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chin Lin
- School of Public Health, National Defense Medical Center, Taipei, Taiwan
| | - Yi-Fen Zou
- Department of Pharmacy, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Ju-Chun Cheng
- Department of Pharmacy, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Po-Huang Chen
- Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Hong-Jie Jhou
- Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan
| | - Ching-Liang Ho
- Division of Hematology and Oncology Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
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10
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Huntington SF, de Nigris E, Puckett JT, Kamal‐Bahl S, Farooqui M, Ryland K, Sarpong EM, Leng S, Yang X, Doshi JA. Real-world analysis of adverse event rates after initiation of ibrutinib among Medicare beneficiaries with chronic lymphocytic leukemia. Cancer Med 2024; 13:e6953. [PMID: 38348963 PMCID: PMC10832339 DOI: 10.1002/cam4.6953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 12/11/2023] [Accepted: 01/10/2024] [Indexed: 02/15/2024] Open
Abstract
BACKGROUND The first-generation BTK inhibitor ibrutinib is a standard-of-care therapy in the treatment of chronic lymphocytic leukemia (CLL) despite potential side effects that often lead to discontinuation. METHODS This study used 2013-2019 claims data to describe the incidence rate of adverse events (AEs) among elderly Medicare beneficiaries newly initiating ibrutinib for CLL. RESULTS The final sample contained 11,870 Medicare beneficiaries with CLL (mean age 77.2) newly initiating ibrutinib, of whom 65.2% discontinued over mean follow-up of 2.3 years. The overall incidence rate of AEs was 62.5 per 1000 patient-months for all discontinuers and 32.9 per 1000 patient-months for non-discontinuers. Discontinuers had a higher incidence rate of AEs per 1000 patient-months compared with non-discontinuers for all AEs examined, including infection (22.8 vs. 14.5), atrial fibrillation (15.1 vs. 7.0), anemia (21.9 vs. 14.5), and arthralgia/myalgia (19.5 vs. 13.6). CONCLUSION In this first real-world study of a national sample of elderly US patients treated with ibrutinib, we found a clear unmet need for improved management of ibrutinib-related AEs and/or new treatments to improve real-world outcomes in patients with CLL.
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Affiliation(s)
- Scott F. Huntington
- Department of Internal Medicine, Section of HematologyYale University School of MedicineNew HavenConnecticutUSA
| | | | | | | | | | | | | | | | | | - Jalpa A. Doshi
- Division of General Internal Medicine, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
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11
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Mezger NCS, Hämmerl L, Griesel M, Seraphin TP, Joko-Fru YW, Feuchtner J, Zietsman A, Péko JF, Tadesse F, Buziba NG, Wabinga H, Nyanchama M, Chokunonga E, Kéita M, N’da G, Lorenzoni CF, Akele-Akpo MT, Mezger JM, Binder M, Liu B, Bauer M, Henke O, Jemal A, Kantelhardt EJ. Guideline Concordance of Treatment and Outcomes Among Adult Non-Hodgkin Lymphoma Patients in Sub-Saharan Africa: A Multinational, Population-Based Cohort. Oncologist 2023; 28:e1017-e1030. [PMID: 37368350 PMCID: PMC10628567 DOI: 10.1093/oncolo/oyad157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 04/24/2023] [Indexed: 06/28/2023] Open
Abstract
BACKGROUND Although non-Hodgkin lymphoma (NHL) is the 6th most common malignancy in Sub-Saharan Africa (SSA), little is known about its management and outcome. Herein, we examined treatment patterns and survival among NHL patients. METHODS We obtained a random sample of adult patients diagnosed between 2011 and 2015 from 11 population-based cancer registries in 10 SSA countries. Descriptive statistics for lymphoma-directed therapy (LDT) and degree of concordance with National Comprehensive Cancer Network (NCCN) guidelines were calculated, and survival rates were estimated. FINDINGS Of 516 patients included in the study, sub-classification was available for 42.1% (121 high-grade and 64 low-grade B-cell lymphoma, 15 T-cell lymphoma and 17 otherwise sub-classified NHL), whilst the remaining 57.9% were unclassified. Any LDT was identified for 195 of all patients (37.8%). NCCN guideline-recommended treatment was initiated in 21 patients. This corresponds to 4.1% of all 516 patients, and to 11.7% of 180 patients with sub-classified B-cell lymphoma and NCCN guidelines available. Deviations from guideline-recommended treatment were initiated in another 49 (9.5% of 516, 27.2% of 180). By registry, the proportion of all patients receiving guideline-concordant LDT ranged from 30.8% in Namibia to 0% in Maputo and Bamako. Concordance with treatment recommendations was not assessable in 75.1% of patients (records not traced (43.2%), traced but no sub-classification identified (27.8%), traced but no guidelines available (4.1%)). By registry, diagnostic work-up was in part importantly limited, thus impeding guideline evaluation significantly. Overall 1-year survival was 61.2% (95%CI 55.3%-67.1%). Poor ECOG performance status, advanced stage, less than 5 cycles and absence of chemo (immuno-) therapy were associated with unfavorable survival, while HIV status, age, and gender did not impact survival. In diffuse large B-cell lymphoma, initiation of guideline-concordant treatment was associated with favorable survival. INTERPRETATION This study shows that a majority of NHL patients in SSA are untreated or undertreated, resulting in unfavorable survival. Investments in enhanced diagnostic services, provision of chemo(immuno-)therapy and supportive care will likely improve outcomes in the region.
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Affiliation(s)
- Nikolaus Christian Simon Mezger
- Global Health Working Group, Institute of Medical Epidemiology, Biometrics and Informatics, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Lucia Hämmerl
- Global Health Working Group, Institute of Medical Epidemiology, Biometrics and Informatics, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Mirko Griesel
- Global Health Working Group, Institute of Medical Epidemiology, Biometrics and Informatics, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Tobias Paul Seraphin
- Global Health Working Group, Institute of Medical Epidemiology, Biometrics and Informatics, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Yvonne Walburga Joko-Fru
- African Cancer Registry Network, Oxford, UK
- Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Jana Feuchtner
- Global Health Working Group, Institute of Medical Epidemiology, Biometrics and Informatics, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Annelle Zietsman
- African Cancer Registry Network, Oxford, UK
- Dr AB May Cancer Care Centre, Windhoek, Namibia
| | - Jean-Félix Péko
- African Cancer Registry Network, Oxford, UK
- Registre des cancers de Brazzaville, Brazzaville, Republic of the Congo
| | - Fisihatsion Tadesse
- African Cancer Registry Network, Oxford, UK
- Division of Hematology, Department of Internal Medicine, University and Black Lion Hospital, Addis Ababa, Ethiopia
| | - Nathan Gyabi Buziba
- African Cancer Registry Network, Oxford, UK
- Eldoret Cancer Registry, School of Medicine, Moi University, Eldoret, Kenya
| | - Henry Wabinga
- African Cancer Registry Network, Oxford, UK
- Kampala Cancer Registry, Makerere University School of Medicine, Kampala, Uganda
| | - Mary Nyanchama
- African Cancer Registry Network, Oxford, UK
- National Cancer Registry, Kenya Medical Research Institute, Nairobi, Kenya
| | - Eric Chokunonga
- African Cancer Registry Network, Oxford, UK
- Zimbabwe National Cancer Registry, Harare, Zimbabwe
| | - Mamadou Kéita
- African Cancer Registry Network, Oxford, UK
- Service du Laboratoire d’Anatomie et Cytologie Pathologique, Bamako, Mali
- CHU du point G , Bamako, Mali
| | - Guy N’da
- African Cancer Registry Network, Oxford, UK
- Registre des cancers d’Abidjan, Abidjan, Côte d’Ivoire
| | - Cesaltina Ferreira Lorenzoni
- African Cancer Registry Network, Oxford, UK
- Departamento de Patologia, Faculdade de Medicina, Universidade Eduardo Mondlane, Hospital Central de Maputo, Mozambique
- Registo de Cancro, Ministério da Saúde, Maputo, Mozambique
| | - Marie-Thérèse Akele-Akpo
- African Cancer Registry Network, Oxford, UK
- Département d’anatomo-pathologie, Faculté des Sciences de la Santé, Cotonou, Benin
| | | | - Mascha Binder
- Department of Internal Medicine IV, Oncology/Hematology, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Biying Liu
- African Cancer Registry Network, Oxford, UK
| | - Marcus Bauer
- Institute of Pathology, Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Oliver Henke
- Section Global Health, Institute for Public Health and Hygiene, University Hospital Bonn, Germany
| | - Ahmedin Jemal
- Surveillance and Health Equity Science, American Cancer Society, Atlanta, USA
| | - Eva Johanna Kantelhardt
- Global Health Working Group, Institute of Medical Epidemiology, Biometrics and Informatics, Martin-Luther-University Halle-Wittenberg, Halle, Germany
- Department of Gynaecology, Martin-Luther-University Halle-Wittenberg, Halle, Germany
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12
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Bos S, Pradère P, Beeckmans H, Zajacova A, Vanaudenaerde BM, Fisher AJ, Vos R. Lymphocyte Depleting and Modulating Therapies for Chronic Lung Allograft Dysfunction. Pharmacol Rev 2023; 75:1200-1217. [PMID: 37295951 PMCID: PMC10595020 DOI: 10.1124/pharmrev.123.000834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 04/27/2023] [Accepted: 06/05/2023] [Indexed: 06/12/2023] Open
Abstract
Chronic lung rejection, also called chronic lung allograft dysfunction (CLAD), remains the major hurdle limiting long-term survival after lung transplantation, and limited therapeutic options are available to slow the progressive decline in lung function. Most interventions are only temporarily effective in stabilizing the loss of or modestly improving lung function, with disease progression resuming over time in the majority of patients. Therefore, identification of effective treatments that prevent the onset or halt progression of CLAD is urgently needed. As a key effector cell in its pathophysiology, lymphocytes have been considered a therapeutic target in CLAD. The aim of this review is to evaluate the use and efficacy of lymphocyte depleting and immunomodulating therapies in progressive CLAD beyond usual maintenance immunosuppressive strategies. Modalities used include anti-thymocyte globulin, alemtuzumab, methotrexate, cyclophosphamide, total lymphoid irradiation, and extracorporeal photopheresis, and to explore possible future strategies. When considering both efficacy and risk of side effects, extracorporeal photopheresis, anti-thymocyte globulin and total lymphoid irradiation appear to offer the best treatment options currently available for progressive CLAD patients. SIGNIFICANCE STATEMENT: Effective treatments to prevent the onset and progression of chronic lung rejection after lung transplantation are still a major shortcoming. Based on existing data to date, considering both efficacy and risk of side effects, extracorporeal photopheresis, anti-thymocyte globulin, and total lymphoid irradiation are currently the most viable second-line treatment options. However, it is important to note that interpretation of most results is hampered by the lack of randomized controlled trials.
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Affiliation(s)
- Saskia Bos
- Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom (S.B., P.P., A.J.F.); Institute of Transplantation, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle Upon Tyne, United Kingdom (S.B., A.J.F.); Hôpital Marie Lannelongue, Groupe Hospitalier Paris Saint Joseph and Paris Saclay University, Department of Respiratory Diseases, Paris, France (P.P.); Department of CHROMETA, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium (H.B., B.M.V., R.V.); Prague Lung Transplant Program, University Hospital Motol, Department of Pneumology, Prague, Czech Republic (A.Z.); and University Hospitals Leuven, Department of Respiratory Diseases, Leuven, Belgium (R.V.)
| | - Pauline Pradère
- Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom (S.B., P.P., A.J.F.); Institute of Transplantation, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle Upon Tyne, United Kingdom (S.B., A.J.F.); Hôpital Marie Lannelongue, Groupe Hospitalier Paris Saint Joseph and Paris Saclay University, Department of Respiratory Diseases, Paris, France (P.P.); Department of CHROMETA, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium (H.B., B.M.V., R.V.); Prague Lung Transplant Program, University Hospital Motol, Department of Pneumology, Prague, Czech Republic (A.Z.); and University Hospitals Leuven, Department of Respiratory Diseases, Leuven, Belgium (R.V.)
| | - Hanne Beeckmans
- Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom (S.B., P.P., A.J.F.); Institute of Transplantation, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle Upon Tyne, United Kingdom (S.B., A.J.F.); Hôpital Marie Lannelongue, Groupe Hospitalier Paris Saint Joseph and Paris Saclay University, Department of Respiratory Diseases, Paris, France (P.P.); Department of CHROMETA, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium (H.B., B.M.V., R.V.); Prague Lung Transplant Program, University Hospital Motol, Department of Pneumology, Prague, Czech Republic (A.Z.); and University Hospitals Leuven, Department of Respiratory Diseases, Leuven, Belgium (R.V.)
| | - Andrea Zajacova
- Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom (S.B., P.P., A.J.F.); Institute of Transplantation, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle Upon Tyne, United Kingdom (S.B., A.J.F.); Hôpital Marie Lannelongue, Groupe Hospitalier Paris Saint Joseph and Paris Saclay University, Department of Respiratory Diseases, Paris, France (P.P.); Department of CHROMETA, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium (H.B., B.M.V., R.V.); Prague Lung Transplant Program, University Hospital Motol, Department of Pneumology, Prague, Czech Republic (A.Z.); and University Hospitals Leuven, Department of Respiratory Diseases, Leuven, Belgium (R.V.)
| | - Bart M Vanaudenaerde
- Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom (S.B., P.P., A.J.F.); Institute of Transplantation, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle Upon Tyne, United Kingdom (S.B., A.J.F.); Hôpital Marie Lannelongue, Groupe Hospitalier Paris Saint Joseph and Paris Saclay University, Department of Respiratory Diseases, Paris, France (P.P.); Department of CHROMETA, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium (H.B., B.M.V., R.V.); Prague Lung Transplant Program, University Hospital Motol, Department of Pneumology, Prague, Czech Republic (A.Z.); and University Hospitals Leuven, Department of Respiratory Diseases, Leuven, Belgium (R.V.)
| | - Andrew J Fisher
- Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom (S.B., P.P., A.J.F.); Institute of Transplantation, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle Upon Tyne, United Kingdom (S.B., A.J.F.); Hôpital Marie Lannelongue, Groupe Hospitalier Paris Saint Joseph and Paris Saclay University, Department of Respiratory Diseases, Paris, France (P.P.); Department of CHROMETA, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium (H.B., B.M.V., R.V.); Prague Lung Transplant Program, University Hospital Motol, Department of Pneumology, Prague, Czech Republic (A.Z.); and University Hospitals Leuven, Department of Respiratory Diseases, Leuven, Belgium (R.V.)
| | - Robin Vos
- Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom (S.B., P.P., A.J.F.); Institute of Transplantation, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle Upon Tyne, United Kingdom (S.B., A.J.F.); Hôpital Marie Lannelongue, Groupe Hospitalier Paris Saint Joseph and Paris Saclay University, Department of Respiratory Diseases, Paris, France (P.P.); Department of CHROMETA, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium (H.B., B.M.V., R.V.); Prague Lung Transplant Program, University Hospital Motol, Department of Pneumology, Prague, Czech Republic (A.Z.); and University Hospitals Leuven, Department of Respiratory Diseases, Leuven, Belgium (R.V.)
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13
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Barber VS, Peckham N, Duley L, Francis A, Abhishek A, Moss P, Cook JA, Parry HM. Protocol for a multicentre randomised controlled trial examining the effects of temporarily pausing Bruton tyrosine kinase inhibitor therapy to coincide with SARS-CoV-2 vaccination and its impact on immune responses in patients with chronic lymphocytic leukaemia. BMJ Open 2023; 13:e077946. [PMID: 37770269 PMCID: PMC10546125 DOI: 10.1136/bmjopen-2023-077946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 08/10/2023] [Indexed: 09/30/2023] Open
Abstract
INTRODUCTION People who are immunocompromised have a poor biological response to vaccinations. This study aims to determine in patients with chronic lymphocytic leukaemia (CLL) if a 3-week pause in Bruton tyrosine kinase inhibitor therapy (BTKi) starting 1 week before delivery of SARS-CoV-2 vaccine booster, improves vaccine immune response when compared with continuation of BTKi. METHODS AND ANALYSIS An open-label, randomised controlled superiority trial will be conducted in haematology clinics in approximately 10 UK National Health Service (NHS) hospitals. The sample size is 120, randomised 1:1 to intervention and usual care arms. The primary outcome is anti-spike-receptor binding domain (RBD) antibody level at 3 weeks post-SARS-CoV-2 booster vaccination. Secondary outcomes are RBD antibody levels at 12 weeks postbooster vaccination, participant global assessments of disease activity, blood films, full blood count and lactate dehydrogenase levels, impact on quality of life, self-reported adherence with request to temporarily pause or continue BTKi, T cell response against spike protein and relative neutralising antibody titre against SARS-CoV-2 viral variants. Additionally, there will be an investigation of any effects in those given influenza vaccination contemporaneously versus COVID-19 alone.The primary analysis will be performed on the as randomised groups ('intention to treat'). The difference between the study arms in anti-spike-RBD antibody level will be estimated using a mixed effects regression model, allowing for repeated measures clustered within participants. The model will be adjusted for randomisation factor (first line or subsequent line of therapy), and prior infection status obtained from prerandomisation antinucleocapsid antibodies as fixed effects. ETHICS AND DISSEMINATION This study has been approved by Leeds East Research Ethics Committee and Health Research Authority (REC Reference:22/YH/0226, IRAS ID: 319057). Dissemination will be via peer-review publications, newsletters and conferences. Results will be communicated to participants, the CLL patient and clinical communities and health policy-makers. TRIAL REGISTRATION NUMBER ISRCTN14197181.
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Affiliation(s)
- Vicki S Barber
- Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, Oxford Clinical Trials Research Unit (OCTRU), University of Oxford, Oxford, UK
| | - Nicholas Peckham
- Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, Oxford Clinical Trials Research Unit (OCTRU), University of Oxford, Oxford, UK
| | - Lelia Duley
- Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, UK
| | - Anne Francis
- Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, Oxford Clinical Trials Research Unit (OCTRU), University of Oxford, Oxford, UK
| | | | - Paul Moss
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Jonathan A Cook
- Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, Oxford Clinical Trials Research Unit (OCTRU), University of Oxford, Oxford, UK
| | - Helen M Parry
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
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14
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Ismaeel A, Farid E, Majed KS, Mansoor EJ, Toorani J, Tufail F, Aldanasoury RA, Alsuwaidi SA, Shome DK. Hematologic malignancies of primary bone marrow involvement: a decade's experience in Bahrain. Hematol Transfus Cell Ther 2023; 45 Suppl 2:S68-S75. [PMID: 35643916 PMCID: PMC10433317 DOI: 10.1016/j.htct.2022.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 01/31/2022] [Accepted: 02/08/2022] [Indexed: 11/21/2022] Open
Abstract
INTRODUCTION The data on the pattern of primary hematologic malignancies in Bahrain is sparse, although previously published studies suggested rising trends in their incidence. This study aimed to compare with regional and world data and identify any changing trends. METHODS A retrospective cross-sectional chart analysis study was done on all cases of primary hematologic malignancies of bone marrow origin of Bahraini nationals presenting during the 10-year period from January 2005 to December 2014 at the sole oncology referral center in Bahrain during the study period. RESULTS In a total of 272 cases, the primary hematologic malignancies in decreasing order of frequency with respective median ages at diagnosis were: acute myeloid leukemia (AML; 26.1%, 39 years), acute lymphoblastic leukemia (ALL; 22.8%, 9 years), multiple myeloma (MM, 16.2%, 57 years), chronic myeloid leukemia (CML, 14%, 39.5 years), myelodysplastic syndromes (MDS; 12.5%, 56 years) and chronic lymphocytic leukemia (CLL; 5.5%, 65 years). The overall crude annual incidence rate of these malignancies was 4.8/105 population. Age-specific incidence rates were found to increase dramatically with age, except for ALL, for which it peaked in the pediatric age group. The age-standardized incidence rates (ASIRs) per 105 per year were 1.47 (AML), 1.13 (MM), 0.93 (ALL), 0.85 (MDS), 0.81 (CML) and 0.44 (CLL). CONCLUSION The pattern of primary hematologic malignancies in Bahrain shows unique features that distinguish it from trends reported in Eastern and Western world populations. Compared to previously published reports, ASIR trends decreased in CML and ALL but increased in MDS and MM.
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Affiliation(s)
- Amina Ismaeel
- Department of Pathology, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain
| | - Eman Farid
- Department of Pathology, Salmaniya Medical Complex, Manama, Bahrain; Department of Microbiology and Immunology, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain
| | - Kameela S Majed
- Department of Pathology, Salmaniya Medical Complex, Manama, Bahrain
| | | | - Jalal Toorani
- Department of Pathology, Blood Bank and Laboratory Medicine, King Hamad University Hospital, Bahrain
| | - Faisal Tufail
- Department of Pathology, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain
| | | | - Sara Ali Alsuwaidi
- Department of Pathology, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain
| | - Durjoy Kumar Shome
- Department of Pathology, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain; Department of Pathology, Blood Bank and Laboratory Medicine, King Hamad University Hospital, Bahrain.
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15
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Santos AS, Andrade JPD, Freitas DA, Gonçalves ÉS, Borges DL, Carvalho LMDA, Noronha KVDS, Andrade MV. Cost-Effectiveness Analysis of Rituximab for Chronic Lymphocytic Leukemia Using A Semi-Markovian Model Approach in R. Value Health Reg Issues 2023; 36:10-17. [DOI: 10.1016/j.vhri.2023.01.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 10/07/2022] [Accepted: 01/26/2023] [Indexed: 03/29/2023]
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16
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Addisia GD, Tegegne AS, Belay DB, Kassaw MA, Muluneh MW, Abebe KB, Masresha BM, Mulugeta SS, Fentaw SM, Damtie DG. Determinants of Time-to-Death of Chronic Lymphocytic Leukemia Patients at Felege Hiwot Referral Hospital, Bahir Dar, Ethiopia. Cancer Inform 2023; 22:11769351231183849. [PMID: 37426051 PMCID: PMC10328045 DOI: 10.1177/11769351231183849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 06/06/2023] [Indexed: 07/11/2023] Open
Abstract
Background Leukemia is a group of cancers that usually begin in the bone marrow and results in a large number of abnormal white blood cells. Chronic Lymphocytic Leukemia is the most prevalent leukemia in Western countries, with an estimated incidence rate of less than 1 to 5.5 per 100 000 people, and average age at diagnosis of 64 to 72 years. It is more common in men among Chronic Lymphocytic Leukemia patients in Ethiopia's hospitals at Felege Hiwot Referal Hospital. Methods A retrospective cohort research design was employed to acquire critical information from patients' medical records in order to achieve the study's purpose. The study comprised the medical records of 312 Chronic Lymphocytic Leukemia who were followed from January 1, 2018 to December 31, 2020. A Cox proportional hazard model was used to determine the risk factors for time to death in Chronic Lymphocytic Leukemia patients. Results Accordingly the Cox proportional hazard model, age (Hazard Ratio = 11.36; P < .001), sex of male (Hazard Ratio = 1.04; P = .004), married status (Hazard Ratio = 0.03; P = .003), medium stages of Chronic Lymphocytic Leukemia (Hazard Ratio = 1.29; P = .024), high stages of Chronic Lymphocytic Leukemia (Hazard Ratio = 1.99; P < .001), presence of anemia (Hazard Ratio =0.09; P = .005), platelets (Hazard Ratio = 2.11; P = .007), hemoglobin (Hazard Ratio = 0.02; P < .001), lymphocytes (Hazard Ratio = 0.29; P = .006), red blood cell (Hazard Ratio = 0.02; P < .001), which patients with Chronic Lymphocytic Leukemia had a significant relationship with time to death. Conclusions Age, sex, Chronic Lymphocytic Leukemia stage, anemia, platelets, hemoglobin, lymphocytes, and red blood cells were all statistically significant determinants in the time to death of Chronic Lymphocytic Leukemia patients, according to the data. As a result, healthcare providers should pay particular attention to and emphasize the identified characteristics, as well as provide frequent counseling on how to enhance the health of Chronic Lymphocytic Leukemia patients.
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Alotaibi MA. Empirical Study on Exploring the Role of CD180 and MD-1 Prognostic Indicators for the Chronic Lymphocytic Leukaemia (CLL) Disease. Pak J Biol Sci 2023; 26:311-320. [PMID: 37902045 DOI: 10.3923/pjbs.2023.311.320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2023]
Abstract
<b>Background and Objective:</b> Chronic Lymphocytic Leukaemia (CLL) is a frequent type of leukaemia disease. This study was focused on investigating the role of prognostic indicators, such as CD180 and MD-1 for Chronic Lymphocytic Leukaemia (CLL) pathogenesis because they involve cell signalling and proliferation. <b>Materials and Methods:</b> A total of 12 normal controls and 52 patients were taken to determine the expressions of CD180 and MD-1 with different variations in comparison with the IgVH (Immunoglobulin Heavy Chain variable region gene) mutational status, FISH (fluorescence <i>in situ</i> hybridization) and Rai staging. <b>Results:</b> The quantitative data findings were evident that CD180 and MD-1 expressions showed insignificant differences among CLL patients at the protein level based on SPSS results. On the contrary, they resulted in significant differences for subgroups of established biomarkers like Rai staging (stages 0, I, II and III), FISH (13q and non-13q deletions) and IgVH (mutated and unmutated). <b>Conclusion:</b> The CD180 and MD-1 have been used as prognostic indicators to evaluate the outcomes relevant to the cell cycle and survival rate of CLL cells.
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MESH Headings
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/metabolism
- Prognosis
- In Situ Hybridization, Fluorescence
- Mutation
- Biomarkers
- Antigens, CD/genetics
- Antigens, CD/metabolism
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18
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Mir SA, Madkhali Y, Firoz A, Al Othaim A, Alturaiki W, Almalki SG, Algarni A, Alsagaby SA. Inhibitory Potential of the Ocimum sanctum Phytochemicals on Bruton's Tyrosine Kinase, a Well-Known Drug Target for Treatment of Chronic Lymphocytic Leukemia: An In Silico Investigation. Molecules 2023; 28:3287. [PMID: 37110523 PMCID: PMC10144307 DOI: 10.3390/molecules28083287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 03/28/2023] [Accepted: 03/31/2023] [Indexed: 04/29/2023] Open
Abstract
Chronic lymphocytic leukemia (CLL) is an incurable neoplasm of B-lymphocytes, which accounts for about one-third of all leukemias. Ocimum sanctum, an herbaceous perennial, is considered as one of the important sources of drugs for the treatment of various diseases, including cancers and autoimmune diseases. The present study was designed to screen various phytochemicals of O. sanctum for discovering their potential to inhibit Bruton's tyrosine kinase (BTK), a well-known drug target of CLL. Various phytochemicals of O. sanctum were screened for their potential to inhibit BTK using several in silico protocols. First, the molecular docking approach was used to calculate the docking scores of the selected phytochemicals. Then, the selected top-ranked phytochemicals were screened for their physicochemical characteristics using ADME analysis. Finally, the stability of the selected compounds in their corresponding docking complexes with BTK was analysed using molecular dynamics simulations. Primarily, our observations revealed that, out of the 46 phytochemicals of O. sanctum, six compounds possessed significantly better docking scores (ranging from -9.2 kcal/mol to -10 kcal/mol). Their docking scores were comparable to those of the control inhibitors, acalabrutinib (-10.3 kcal/mol), and ibrutinib (-11.3 kcal/mol). However, after ADME analysis of these top-ranked six compounds, only three compounds (Molludistin, Rosmarinic acid, and Vitexin) possessed drug likeliness characteristics. During the MD analysis, the three compounds Molludistin, Rosmarinic acid, and Vitexin were found to remain stable in the binding pocket in their corresponding docking complexes with BTK. Therefore, among the 46 phytochemicals of O. sanctum tested in this study, the three compounds, Molludistin, Rosmarinic acid, and Vitexin are the best inhibitors of BTK. However, these findings need to be confirmed by biological experiments in the laboratory.
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Affiliation(s)
- Shabir Ahmad Mir
- Department of Medical Laboratory Sciences, College of Applied Medical Science, Majmaah University, Al Majmaah 11952, Saudi Arabia
- Health and Basic Sciences Research Center, Majmaah University, Al Majmaah 11952, Saudi Arabia
| | - Yahya Madkhali
- Department of Medical Laboratory Sciences, College of Applied Medical Science, Majmaah University, Al Majmaah 11952, Saudi Arabia
| | - Ahmad Firoz
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Ayoub Al Othaim
- Department of Medical Laboratory Sciences, College of Applied Medical Science, Majmaah University, Al Majmaah 11952, Saudi Arabia
| | - Wael Alturaiki
- Department of Medical Laboratory Sciences, College of Applied Medical Science, Majmaah University, Al Majmaah 11952, Saudi Arabia
| | - Sami G. Almalki
- Department of Medical Laboratory Sciences, College of Applied Medical Science, Majmaah University, Al Majmaah 11952, Saudi Arabia
| | - Abdulrahman Algarni
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Northern Border University, Arar 91431, Saudi Arabia
| | - Suliman A. Alsagaby
- Department of Medical Laboratory Sciences, College of Applied Medical Science, Majmaah University, Al Majmaah 11952, Saudi Arabia
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Chatterjee A, van de Wetering G, Goeree R, Owen C, Desbois AM, Barakat S, Manzoor BS, Sail K. A Probabilistic Cost-Effectiveness Analysis of Venetoclax and Obinutuzumab as a First-Line Therapy in Chronic Lymphocytic Leukemia in Canada. PHARMACOECONOMICS - OPEN 2023; 7:199-216. [PMID: 36334238 PMCID: PMC10043091 DOI: 10.1007/s41669-022-00375-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 09/26/2022] [Indexed: 06/16/2023]
Abstract
BACKGROUND Venetoclax is a first-in-class targeted therapy option that is an inducer of apoptosis in chronic lymphocytic leukemia (CLL) cells. The open-label phase III CLL14 clinical trial showed that venetoclax combined with obinutuzumab (VEN+O) is superior to obinutuzumab combined with chlorambucil in newly diagnosed patients with CLL. The aim of this study was to assess the health economic value of VEN+O for the frontline treatment of CLL in Canada from a publicly funded healthcare system perspective. METHODS A partitioned survival analyses model was developed including three health states: progression free, progressed, and death. A cycle length of 28 days and a time horizon of 10 years was assumed. VEN+O treatment for a fixed duration of 12 months was compared to obinutuzumab combined with chlorambucil, fludarabine plus cyclophosphamide plus rituximab, bendamustine plus rituximab, chlorambucil plus rituximab, ibrutinib, and acalabrutinib. The population in the model included both unfit and overall frontline CLL patients, two subgroups were also assessed (patients with del17p/TP53 mutations and patients without del17p/TP53 mutations). Survival data extrapolated from the CLL14 trial were used to populate the model. Uncertainty was assessed via one-way sensitivity analyses, probabilistic analyses, and scenario analyses. RESULTS Based on the probabilistic analyses, unfit frontline CLL patients receiving VEN+O were estimated to incur costs of Canadian dollars ($) 217,727 [confidence interval (CI) $170,725, $300,761] (del17p/TP53: $209,102 [CI $159,698, $386,190], non-del17p/TP53: $217,732 [CI $171,232, $299,063]) and accrue 4.96 [CI 4.04, 5.82] quality-adjusted life-years (del17p/TP53: 3.11 [CI 2.00, 4.20], non-del17p/TP53: 5.04 [CI 4.05, 5.92]). Obinutuzumab combined with chlorambucil, bendamustine plus rituximab, chlorambucil plus rituximab, and ibrutinib accrued lower quality-adjusted life-years and higher costs and as such, VEN+O was the dominant treatment option. The full incremental analysis showed that acalabrutinib was more expensive and more efficacious compared with VEN+O with an incremental-cost-effectiveness-ratio of $2,139,180/quality-adjusted life-year versus VEN+O and not a cost-effective option in Canada. Probabilistic analyses show that at a willingness to pay of $50,000/quality-adjusted life-year gained, VEN+O has the greatest probability of being cost effective. CONCLUSIONS VEN+O is a cost-effective treatment option for unfit frontline CLL patients and provides value for money to healthcare payers.
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Affiliation(s)
| | | | - Ron Goeree
- Goeree Consulting Ltd., Mount Hope, ON, Canada
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20
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Development and Validation of an Efficient and Highly Sensitive Enzyme-Linked Immunosorbent Assay for Alemtuzumab Quantification in Human Serum and Plasma. Ther Drug Monit 2023; 45:79-86. [PMID: 36150715 PMCID: PMC9819214 DOI: 10.1097/ftd.0000000000001037] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 08/12/2022] [Indexed: 02/01/2023]
Abstract
BACKGROUND Alemtuzumab is a humanized monoclonal antibody that targets the CD52 glycoprotein expressed on most lymphocytes, subsequently inducing complement-mediated and antibody-mediated cytotoxicity. Owing to its ability to induce profound immune depletion, alemtuzumab is frequently used in patients before allogeneic hematopoietic stem cell transplantation to prevent graft rejection and acute graft-versus-host disease. In this clinical context, a stable immunoassay with high sensitivity and specificity to determine alemtuzumab levels is essential for performing pharmacokinetic and pharmacodynamic analyses; however, the available methods have several limitations. Here, we report the successful development and validation of an efficient and highly sensitive enzyme-linked immunosorbent assay technique based on commercially available reagents to quantify alemtuzumab in human serum or plasma. METHODS This enzyme-linked immunosorbent assay technique was developed and validated in accordance with the European Medicines Agency guidelines on bioanalytical method validation. RESULTS The assay sensitivity (lower limit of quantification) is 0.5 ng·mL -1 , and the dynamic range is 0.78-25 ng·mL -1 . To accommodate quantification of peak concentration and concentrations below the lympholytic level (<0.1 mcg·mL -1 ), patients' serum samples were prediluted 20-400 times according to the expected alemtuzumab concentration. The overall within-run accuracy was between 96% and 105%, whereas overall within-run precision (coefficient of variation) was between 3% and 9%. The between-run assessment provided an overall accuracy between 86% and 95% and an overall coefficient of variation between 5% and 14%. CONCLUSIONS The developed assay provides accurate insight into alemtuzumab exposure and its effects on the clinical response to treatment, which is key to optimizing treatment strategies.
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21
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Tariq B, Ou YC, Stern JC, Mundra V, Wong Doo N, Walker P, Lewis KL, Lin C, Novotny W, Sahasranaman S, Opat S. A phase 1, open-label, randomized drug-drug interaction study of zanubrutinib with moderate or strong CYP3A inhibitors in patients with B-cell malignancies. Leuk Lymphoma 2023; 64:329-338. [PMID: 36480811 DOI: 10.1080/10428194.2022.2150820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BTK inhibitor exposure increases significantly when coadministered with CYP3A inhibitors, which may lead to dose-related toxicities. This study explored the pharmacokinetics, efficacy, and safety of zanubrutinib when coadministered with moderate or strong CYP3A inhibitors in 26 patients with relapsed or refractory B-cell malignancies. Coadministration of zanubrutinib (80 mg BID) with moderate CYP3A inhibitors fluconazole and diltiazem or zanubrutinib (80 mg QD) with strong CYP3A inhibitor voriconazole resulted in comparable exposures to zanubrutinib (320 mg QD) with AUC0-24h geometric least squares mean ratios approaching 1 (0.94, 0.81, and 0.83, for fluconazole, diltiazem, and voriconazole, respectively). The most common treatment-emergent adverse events were contusion (26.9%), back pain (19.2%), constipation and neutropenia (15.4% each), and rash, diarrhea, and fall (11.5% each). This study supports current United States Prescribing Information dose recommendations for the coadministration of reduced-dose zanubrutinib with moderate or strong CYP3A inhibitors and confirms the favorable efficacy and safety profile of zanubrutinib.
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Affiliation(s)
- Bilal Tariq
- Clinical Pharmacology, BeiGene USA, Inc, Fulton, MD, USA
| | - Ying C Ou
- Clinical Pharmacology, BeiGene USA, Inc, San Mateo, CA, USA
| | | | - Vaibhav Mundra
- Clinical Pharmacology, BeiGene USA, Inc, San Mateo, CA, USA
| | - Nicole Wong Doo
- Department of Hematology, Concord Repatriation General Hospital, Concord, Australia.,Concord Clinical School, University of Sydney, Sydney, Australia
| | - Patricia Walker
- Department of Hematology, Peninsula Health and Peninsula Private Hospitals, Frankston, Australia
| | - Katharine L Lewis
- Department of Haematology, Sir Charles Gairdner Hospital and Linear Clinical Research, Nedlands, Australia
| | - Chester Lin
- Biostatistics, BeiGene, Ltd, Emeryville, CA, USA
| | - William Novotny
- Clinical Development, Hematology, BeiGene USA, Inc, San Mateo, CA, USA
| | | | - Stephen Opat
- Clinical Hematology, Monash Health and Monash University, Clayton, Australia
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Geres H, Krishnan N, Kotchetkov R. Delayed Diagnosis of T-Cell Prolymphocytic Leukemia: Approach to Chronic Lymphocytosis. Case Rep Oncol 2023; 16:568-576. [PMID: 37900812 PMCID: PMC10601740 DOI: 10.1159/000531592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 06/09/2023] [Indexed: 10/31/2023] Open
Abstract
We present a case of lymphocytosis assumed and managed initially as a chronic lymphocytic leukemia. Shortly after initial visit, the patient's condition deteriorated rapidly with hepatosplenomegaly, pleural effusion, ascites, and skin lesions. Flow cytometry (FC) showed the presence of clonal T-cell population, reported as T-cell lymphoma. Due to rapid clinical deterioration, urgent therapy with cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone was initiated, but with minimal response. This prompted further diagnostic testing and demonstrated tumor cells positivity for CD3, CD30, and TCL1 markers. The diagnosis was changed to T-cell prolymphocytic leukemia. The patient responded well to alemtuzumab (anti-CD52 monoclonal antibody) and reached complete remission. FC is an essential modality for assessing and screening circulating lymphocytes when a lymphoproliferative disorder (LPD) is suspected. There are several LPDs that present with different degrees of clonal lymphocytosis. Reactive lymphocytosis should be appropriately investigated. Indolent LPDs can be surveyed by the internist or family physician, while more aggressive LPDs typically require management by hematologists.
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Affiliation(s)
- Hana Geres
- Department of Medicine, Western University, London, ON, Canada
| | - Nupur Krishnan
- Department of Medical Sciences, Western University, London, ON, Canada
| | - Rouslan Kotchetkov
- Department of Medical Oncology, Royal Victoria Regional Health Centre, Barrie, ON, Canada
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23
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Toia P, Galia M, Filorizzo G, La Grutta L, Midiri F, Alongi P, Grassedonio E, Midiri M. Myeloid and Lymphoid Disorders in Geriatric Patients. PRACTICAL ISSUES IN GERIATRICS 2023:427-444. [DOI: 10.1007/978-3-031-14877-4_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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24
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Liao Y, Xiong S, Ur Rehman Z, He X, Peng H, Liu J, Sun S. The Research Advances of Aptamers in Hematologic Malignancies. Cancers (Basel) 2023; 15:300. [PMID: 36612296 PMCID: PMC9818631 DOI: 10.3390/cancers15010300] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 12/28/2022] [Accepted: 12/28/2022] [Indexed: 01/03/2023] Open
Abstract
Currently, research for hematological malignancies is very intensive, with many breakthroughs. Among them, aptamer-based targeted therapies could be counted. Aptamer is a targeting tool with many unique advantages (easy synthesis, low toxicity, easy modification, low immunogenicity, nano size, long stability, etc.), therefore many experts screened corresponding aptamers in various hematological malignancies for diagnosis and treatment. In this review, we try to summarize and provide the recent progress of aptamer research in the diagnosis and treatment of hematologic malignancies. Until now, 29 aptamer studies were reported in hematologic malignancies, of which 12 aptamers were tested in vivo and the remaining 17 aptamers were only tested in vitro. In this case, 11 aptamers were combined with chemotherapeutic drugs for the treatment of hematologic malignancies, 4 aptamers were used in combination with nanomaterials for the diagnosis and treatment of hematologic malignancies, and some studies used aptamers for the targeted transportation of siRNA and miRNA for targeted therapeutic effects. Their research provides multiple approaches to achieve more targeted goals. These findings show promising and encouraging future for both hematological malignancies basic and clinical trials research.
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Affiliation(s)
| | | | | | | | | | | | - Shuming Sun
- Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, Center for Medical Genetics, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha 410011, China
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25
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Leslie LA, Gangan N, Tan H, Huang Q. Clinical and economic burden of first-line chemoimmunotherapy by risk status in chronic lymphocytic leukemia. Curr Med Res Opin 2022; 38:2149-2161. [PMID: 36205521 DOI: 10.1080/03007995.2022.2133468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
OBJECTIVES To evaluate the trend in cytogenetic/molecular testing rate in chronic lymphocytic leukemia (CLL) and assess the clinical and economic burden of first-line (1 L) treatment with chemoimmunotherapy (CIT) by risk status. METHODS This retrospective cohort study identified patients with CLL from a U.S. managed care population. Medical records were obtained for eligible patients who initiated 1 L CIT between 1/1/2007 and 7/31/2019 and underwent prognostic testing to classify them as high risk (del(17p), TP53 mutation, del(11q), unmutated IGHV or complex karyotype) or as non-high risk by FISH only (non-del(17p) and non-del(11q)). Study outcomes included testing rate, time to next treatment (TTNT) or death, time to treatment failure (defined as time to change of therapy, non-chemotherapy intervention, hospice care or death), and total plan paid costs (medical + pharmacy) per patient per month (PPPM) in the 1 L period. Cox proportional hazard models and generalized linear models were used to calculate adjusted hazard ratio or rate ratio. RESULTS Among the 1,808 patients with CLL, 612 were FISH or IGHV tested and the rate of testing increased from 30% to 44% from 2007-2019. High-risk patients (n = 119) had 65% higher risk of next treatment or death (median time: 2.4 vs 3.7 years), 65% higher risk of treatment failure (median time: 3.0 vs 4.9 years), and 33% higher costs ($12,194 vs $9,055, p = 0.027) during 1 L treatment than non-high risk patients (n = 134). CONCLUSIONS High-risk CLL patients treated with 1 L chemoimmunotherapy have poorer clinical and economic outcomes compared to non-high risk patients. Assessment of genetic risk remains suboptimal.
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Affiliation(s)
| | | | | | - Qing Huang
- Janssen Scientific Affairs, LLC, Horsham, PA, USA
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26
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Herbst SA, Vesterlund M, Helmboldt AJ, Jafari R, Siavelis I, Stahl M, Schitter EC, Liebers N, Brinkmann BJ, Czernilofsky F, Roider T, Bruch PM, Iskar M, Kittai A, Huang Y, Lu J, Richter S, Mermelekas G, Umer HM, Knoll M, Kolb C, Lenze A, Cao X, Österholm C, Wahnschaffe L, Herling C, Scheinost S, Ganzinger M, Mansouri L, Kriegsmann K, Kriegsmann M, Anders S, Zapatka M, Del Poeta G, Zucchetto A, Bomben R, Gattei V, Dreger P, Woyach J, Herling M, Müller-Tidow C, Rosenquist R, Stilgenbauer S, Zenz T, Huber W, Tausch E, Lehtiö J, Dietrich S. Proteogenomics refines the molecular classification of chronic lymphocytic leukemia. Nat Commun 2022; 13:6226. [PMID: 36266272 PMCID: PMC9584885 DOI: 10.1038/s41467-022-33385-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 09/14/2022] [Indexed: 12/24/2022] Open
Abstract
Cancer heterogeneity at the proteome level may explain differences in therapy response and prognosis beyond the currently established genomic and transcriptomic-based diagnostics. The relevance of proteomics for disease classifications remains to be established in clinically heterogeneous cancer entities such as chronic lymphocytic leukemia (CLL). Here, we characterize the proteome and transcriptome alongside genetic and ex-vivo drug response profiling in a clinically annotated CLL discovery cohort (n = 68). Unsupervised clustering of the proteome data reveals six subgroups. Five of these proteomic groups are associated with genetic features, while one group is only detectable at the proteome level. This new group is characterized by accelerated disease progression, high spliceosomal protein abundances associated with aberrant splicing, and low B cell receptor signaling protein abundances (ASB-CLL). Classifiers developed to identify ASB-CLL based on its characteristic proteome or splicing signature in two independent cohorts (n = 165, n = 169) confirm that ASB-CLL comprises about 20% of CLL patients. The inferior overall survival in ASB-CLL is also independent of both TP53- and IGHV mutation status. Our multi-omics analysis refines the classification of CLL and highlights the potential of proteomics to improve cancer patient stratification beyond genetic and transcriptomic profiling.
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Affiliation(s)
- Sophie A. Herbst
- grid.7700.00000 0001 2190 4373Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany ,grid.4709.a0000 0004 0495 846XEuropean Molecular Biology Laboratory (EMBL), Heidelberg, Germany ,Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany ,grid.461742.20000 0000 8855 0365Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany ,grid.7700.00000 0001 2190 4373Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany
| | - Mattias Vesterlund
- grid.452834.c0000 0004 5911 2402Department of Oncology-Pathology, Karolinska Institute and Science for Life Laboratory, Stockholm, Sweden
| | - Alexander J. Helmboldt
- grid.4709.a0000 0004 0495 846XEuropean Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Rozbeh Jafari
- grid.452834.c0000 0004 5911 2402Department of Oncology-Pathology, Karolinska Institute and Science for Life Laboratory, Stockholm, Sweden
| | - Ioannis Siavelis
- grid.452834.c0000 0004 5911 2402Department of Oncology-Pathology, Karolinska Institute and Science for Life Laboratory, Stockholm, Sweden
| | - Matthias Stahl
- grid.452834.c0000 0004 5911 2402Department of Oncology-Pathology, Karolinska Institute and Science for Life Laboratory, Stockholm, Sweden
| | - Eva C. Schitter
- grid.7700.00000 0001 2190 4373Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany
| | - Nora Liebers
- grid.7700.00000 0001 2190 4373Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany ,grid.4709.a0000 0004 0495 846XEuropean Molecular Biology Laboratory (EMBL), Heidelberg, Germany ,Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany ,grid.461742.20000 0000 8855 0365Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Berit J. Brinkmann
- grid.7700.00000 0001 2190 4373Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany ,grid.4709.a0000 0004 0495 846XEuropean Molecular Biology Laboratory (EMBL), Heidelberg, Germany ,Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany ,grid.7700.00000 0001 2190 4373Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany ,grid.7497.d0000 0004 0492 0584Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Felix Czernilofsky
- grid.7700.00000 0001 2190 4373Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany
| | - Tobias Roider
- grid.7700.00000 0001 2190 4373Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany ,grid.4709.a0000 0004 0495 846XEuropean Molecular Biology Laboratory (EMBL), Heidelberg, Germany ,Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany
| | - Peter-Martin Bruch
- grid.7700.00000 0001 2190 4373Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany ,grid.4709.a0000 0004 0495 846XEuropean Molecular Biology Laboratory (EMBL), Heidelberg, Germany ,Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany
| | - Murat Iskar
- grid.7497.d0000 0004 0492 0584Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Adam Kittai
- grid.261331.40000 0001 2285 7943Department of Internal Medicine, Division of Hematology, The Ohio State University, Columbus, OH USA
| | - Ying Huang
- grid.261331.40000 0001 2285 7943Department of Internal Medicine, Division of Hematology, The Ohio State University, Columbus, OH USA
| | - Junyan Lu
- grid.4709.a0000 0004 0495 846XEuropean Molecular Biology Laboratory (EMBL), Heidelberg, Germany ,Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany
| | - Sarah Richter
- grid.7700.00000 0001 2190 4373Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany
| | - Georgios Mermelekas
- grid.452834.c0000 0004 5911 2402Department of Oncology-Pathology, Karolinska Institute and Science for Life Laboratory, Stockholm, Sweden
| | - Husen Muhammad Umer
- grid.452834.c0000 0004 5911 2402Department of Oncology-Pathology, Karolinska Institute and Science for Life Laboratory, Stockholm, Sweden
| | - Mareike Knoll
- grid.7700.00000 0001 2190 4373Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany
| | - Carolin Kolb
- grid.7700.00000 0001 2190 4373Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany
| | - Angela Lenze
- grid.7700.00000 0001 2190 4373Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany
| | - Xiaofang Cao
- grid.452834.c0000 0004 5911 2402Department of Oncology-Pathology, Karolinska Institute and Science for Life Laboratory, Stockholm, Sweden
| | - Cecilia Österholm
- grid.4714.60000 0004 1937 0626Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Linus Wahnschaffe
- grid.6190.e0000 0000 8580 3777Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf (CIO ABCD), Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Carmen Herling
- grid.6190.e0000 0000 8580 3777Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf (CIO ABCD), Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Sebastian Scheinost
- grid.461742.20000 0000 8855 0365Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Matthias Ganzinger
- grid.7700.00000 0001 2190 4373Institute of Medical Biometry and Informatics, Heidelberg University, Heidelberg, Germany
| | - Larry Mansouri
- grid.4714.60000 0004 1937 0626Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Katharina Kriegsmann
- grid.7700.00000 0001 2190 4373Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany
| | - Mark Kriegsmann
- grid.7700.00000 0001 2190 4373Institute of Pathology, University of Heidelberg, Heidelberg, Germany
| | - Simon Anders
- grid.7700.00000 0001 2190 4373Center for Molecular Biology of the University of Heidelberg (ZMBH), Heidelberg, Germany
| | - Marc Zapatka
- grid.7497.d0000 0004 0492 0584Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Giovanni Del Poeta
- grid.6530.00000 0001 2300 0941Division of Hematology, University of Tor Vergata, Rome, Italy
| | - Antonella Zucchetto
- grid.418321.d0000 0004 1757 9741Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
| | - Riccardo Bomben
- grid.418321.d0000 0004 1757 9741Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
| | - Valter Gattei
- grid.418321.d0000 0004 1757 9741Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
| | - Peter Dreger
- grid.7700.00000 0001 2190 4373Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany
| | - Jennifer Woyach
- grid.261331.40000 0001 2285 7943Department of Internal Medicine, Division of Hematology, The Ohio State University, Columbus, OH USA
| | - Marco Herling
- grid.6190.e0000 0000 8580 3777Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf (CIO ABCD), Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Carsten Müller-Tidow
- grid.7700.00000 0001 2190 4373Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany ,grid.4709.a0000 0004 0495 846XEuropean Molecular Biology Laboratory (EMBL), Heidelberg, Germany ,Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany
| | - Richard Rosenquist
- grid.4714.60000 0004 1937 0626Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden ,grid.24381.3c0000 0000 9241 5705Clinical Genetics, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden
| | - Stephan Stilgenbauer
- grid.6582.90000 0004 1936 9748Department of Internal Medicine III, University of Ulm, Ulm, Germany
| | - Thorsten Zenz
- grid.461742.20000 0000 8855 0365Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany ,grid.412004.30000 0004 0478 9977Department of Medical Oncology and Hematology, University Hospital Zürich, Zürich, Switzerland
| | - Wolfgang Huber
- grid.4709.a0000 0004 0495 846XEuropean Molecular Biology Laboratory (EMBL), Heidelberg, Germany ,Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany
| | - Eugen Tausch
- grid.6582.90000 0004 1936 9748Department of Internal Medicine III, University of Ulm, Ulm, Germany
| | - Janne Lehtiö
- grid.452834.c0000 0004 5911 2402Department of Oncology-Pathology, Karolinska Institute and Science for Life Laboratory, Stockholm, Sweden
| | - Sascha Dietrich
- grid.7700.00000 0001 2190 4373Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany ,grid.4709.a0000 0004 0495 846XEuropean Molecular Biology Laboratory (EMBL), Heidelberg, Germany ,Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany ,grid.461742.20000 0000 8855 0365Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany ,grid.14778.3d0000 0000 8922 7789Department of Hematolgy, Oncology and Immunolgy, University Hospital of Düsseldorf, Düsseldorf, Germany
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Conte HA, Biondi MC, Janket SJ, Ackerson LK, Diamandis EP. Babesia microti-induced fulminant sepsis in an immunocompromised host: A case report and the case-specific literature review. Open Life Sci 2022; 17:1200-1207. [PMID: 36185407 PMCID: PMC9483830 DOI: 10.1515/biol-2022-0448] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 03/30/2022] [Accepted: 05/09/2022] [Indexed: 11/21/2022] Open
Abstract
Babesia microti is an obligate intra-erythrocytic parasite transmitted by infected ticks. B. microti is a eukaryote much larger than prokaryotic microbes and more similar to human hosts in their biochemistry and metabolism. Moreover, Babesia spp. possess various immune evasion mechanisms leading to persistent and sometimes life-threatening diseases in immunocompromised hosts. Chronic lymphocytic leukemia (CLL) is the most prevalent adult B-cell malignancy, and a small percentage of CLL transforms into aggressive lymphomas. CLL also causes immune dysfunction due to the over-expansion of immature and ineffective B-cells. When our patient with indolent CLL presented with anemia, pancytopenia, and splenomegaly, all his healthcare providers presumptively assumed a malignant transformation of CLL. However, these are also the signs and symptoms of babesiosis. Herein, we report a case where B. microti infection was presumed as a malignant transformation of CLL and narrowly avoided a devastating outcome. Although the patient developed fulminant sepsis, he finally received the correct diagnosis and treatment. Unfortunately, the disease recrudesced twice. Each time, it became more difficult to control the infection. We describe the clinical course of the case and discuss the case-specific literature review. This report highlights the importance of differential diagnoses ruling out infections which include babesiosis, prior to initiating the treatment of B-cell malignancy.
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Affiliation(s)
- Harry A Conte
- Department of Infectious Diseases, Saint Francis Hospital, Hartford, CT, USA.,Department of Infectious Diseases, Johnson Memorial Hospital, Stafford Springs, CT, USA
| | - Michael C Biondi
- Department of Radiology, Saint Francis Hospital, Hartford, CT, USA
| | - Sok-Ja Janket
- Center for Clinical and Translational Research, The Forsyth Institute, Cambridge, MA, USA
| | - Leland K Ackerson
- Department of Public Health, University of Massachusetts at Lowell, Lowell, MA, USA
| | - Eleftherios P Diamandis
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, 60 Murray St. Box 32, Floor 6, Rm L6-201. Toronto, ON, M5T 3L9, Canada
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28
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An Integrated Study on the Differential Expression of the FOX Gene Family in Cancer and Their Response to Chemotherapy Drugs. Genes (Basel) 2022; 13:genes13101754. [PMID: 36292640 PMCID: PMC9602029 DOI: 10.3390/genes13101754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/09/2022] [Accepted: 09/23/2022] [Indexed: 11/17/2022] Open
Abstract
The Forkhead-box (FOX) transcription factors, as one of the largest gene families in humans, play key roles in cancer. Although studies have suggested that several FOX transcription factors have a significant impact on cancer, the functions of most of the FOX genes in cancer remain elusive. In the study, the expression of 43 FOX genes in 63 kinds of cancer diseases (including many subtypes of same cancer) and in response to 60 chemical substances was obtained from the Gene Expression Atlas database of the European Bioinformatics Institute. Based on the high degree of overlap in FOXO family members differentially expressed in various cancers and their particular responses to chemotherapeutic drugs, our data disclosed the FOX genes that played an important role in the development and progression of cancer. More importantly, we predicted the role of one or several combinatorial FOX genes in the diagnosis and prognostic assessment of a specific cancer and evaluated the potential of a certain anticancer drug therapy for this type of cancer by integrating patterns of FOX genes expression with anticancer drugs sensitivity.
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29
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Sha Y, Jiang R, Miao Y, Qin S, Wu W, Xia Y, Wang L, Fan L, Jin H, Xu W, Li J, Zhu H. The pyroptosis-related gene signature predicts prognosis and indicates the immune microenvironment status of chronic lymphocytic leukemia. Front Immunol 2022; 13:939978. [PMID: 36177050 PMCID: PMC9513039 DOI: 10.3389/fimmu.2022.939978] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 08/22/2022] [Indexed: 12/04/2022] Open
Abstract
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world with great heterogeneity. Pyroptosis has recently been recognized as an inflammatory form of programmed cell death (PCD) and shares a close relationship with apoptosis. Although the role of apoptosis in CLL was comprehensively studied and successfully applied in clinical treatment, the relationship between pyroptosis genes and CLL remained largely unknown. In this study, eight differentially expressed pyroptosis-related genes (PRGs) were identified between CLL and normal B cells. In order to screen out the prognostic value of differentially expressed PRGs, univariate and multivariate Cox regression analyses were conducted and a risk model with three PRG signatures (GSDME, NLRP3, and PLCG1) was constructed. All CLL samples were stratified into high- and low-risk subgroups according to risk scores. The risk model showed high efficacy in predicting both overall survival (OS) and time to first treatment (TTFT). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) showed the dysregulation of immune and inflammatory response in the high-risk group. Single-sample GSEA (ssGSEA) of immune cell infiltration and the activity of immune-related pathways also displayed decreased antitumor immunity in the high-risk group. In conclusion, PRGs are of prognostic value in CLL and may play important roles in tumor immunity, and the underlying relationship between PRGs and CLL needs to be explored further.
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MESH Headings
- Gene Ontology
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/metabolism
- NLR Family, Pyrin Domain-Containing 3 Protein
- Prognosis
- Pyroptosis/genetics
- Tumor Microenvironment/genetics
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Affiliation(s)
- Yeqin Sha
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
- Pukou Chronic Lymphocytic Leukemia (CLL) Center, Pukou Division of Jiangsu Province Hospital, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Rui Jiang
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
- Pukou Chronic Lymphocytic Leukemia (CLL) Center, Pukou Division of Jiangsu Province Hospital, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Yi Miao
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
- Pukou Chronic Lymphocytic Leukemia (CLL) Center, Pukou Division of Jiangsu Province Hospital, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Shuchao Qin
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
- Pukou Chronic Lymphocytic Leukemia (CLL) Center, Pukou Division of Jiangsu Province Hospital, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Wei Wu
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
- Pukou Chronic Lymphocytic Leukemia (CLL) Center, Pukou Division of Jiangsu Province Hospital, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Yi Xia
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
- Pukou Chronic Lymphocytic Leukemia (CLL) Center, Pukou Division of Jiangsu Province Hospital, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Li Wang
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
- Pukou Chronic Lymphocytic Leukemia (CLL) Center, Pukou Division of Jiangsu Province Hospital, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Lei Fan
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
- Pukou Chronic Lymphocytic Leukemia (CLL) Center, Pukou Division of Jiangsu Province Hospital, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Hui Jin
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
- Pukou Chronic Lymphocytic Leukemia (CLL) Center, Pukou Division of Jiangsu Province Hospital, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Wei Xu
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
- Pukou Chronic Lymphocytic Leukemia (CLL) Center, Pukou Division of Jiangsu Province Hospital, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
- *Correspondence: Wei Xu, ; Jianyong Li, ; Huayuan Zhu,
| | - Jianyong Li
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
- Pukou Chronic Lymphocytic Leukemia (CLL) Center, Pukou Division of Jiangsu Province Hospital, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
- National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Suzhou, China
- *Correspondence: Wei Xu, ; Jianyong Li, ; Huayuan Zhu,
| | - Huayuan Zhu
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
- Pukou Chronic Lymphocytic Leukemia (CLL) Center, Pukou Division of Jiangsu Province Hospital, Nanjing, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China
- *Correspondence: Wei Xu, ; Jianyong Li, ; Huayuan Zhu,
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30
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Sahu T, Verma HK, Lvks B. Management of SARS-CoV-2 infection is a major challenge in patients with lymphoid malignancies: Warrants a clear therapeutic strategy. World J Virol 2022; 11:204-207. [PMID: 36159615 PMCID: PMC9372783 DOI: 10.5501/wjv.v11.i4.204] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 07/28/2021] [Accepted: 05/27/2022] [Indexed: 02/06/2023] Open
Abstract
Patients with lymphoid malignancies are at a higher risk of coronavirus disease 2019 (COVID-19) infection due to their immunocompromised state and results in higher mortality rates in these patients. Anti-CD 20 therapy is one of the leading causes of immunosuppression that worsens in COVID-19 cases. COVID-19 vaccines, on the other hand, appear to be less beneficial to these patients. App-ropriate treatment and recommendations are required for these COVID-19 patients with lymphoid malignancies.
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Affiliation(s)
- Tarun Sahu
- Physiology, All India Institute of Medical Science, Raipur 492001, Chhattisgarh, India
| | - Henu Kumar Verma
- Department of Immunopathology, Institute of Lung Health and Immunity, Comprehensive Pneumology Center, Helmholtz Zentrum, Munich 80331, Bayren, Germany
| | - Bhaskar Lvks
- Zoology, Guru Ghasidas Vishwavidyalaya, Bilaspur 495001, Chhattisgarh, India
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31
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Du J, Jia F, Wang L. Advances in the Study of circRNAs in Hematological Malignancies. Front Oncol 2022; 12:900374. [PMID: 35795049 PMCID: PMC9250989 DOI: 10.3389/fonc.2022.900374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 05/23/2022] [Indexed: 11/26/2022] Open
Abstract
Circular RNAs (circRNAs) are non–protein-coding RNAs that have a circular structure and do not possess a 5` cap or 3` poly-A tail. Their structure is more stable than that of linear RNAs, and they are difficult to deform via hydrolysis. Advancements in measurement technology such as RNA sequencing have enabled the detection of circRNAs in various eukaryotes in both in vitro and in vivo studies. The main function of circRNAs involves sponging of microRNAs (MiRNAs) and interaction with proteins associated with physiological and pathological processes, while some circRNAs are involved in translation. circRNAs act as tumor suppressors or oncogenes during the development of many tumors and are emerging as new diagnostic and prognostic biomarkers. They also affect resistance to certain chemotherapy drugs such as imatinib. The objective of this review is to investigate the expression and clinical significance of circRNAs in hematological malignancies. We will also explore the effect of circRNAs on proliferation and apoptosis in hematological malignancy cells and their possible use as biomarkers or targets to determine prognoses. The current literature indicates that circRNAs may provide new therapeutic strategies for patients with hematologic malignancies.
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Affiliation(s)
- Jingyi Du
- School of Clinical Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
- Central Laboratory, Linyi People’s Hospital, Linyi, China
| | - Feiyu Jia
- Department of Education and Teaching, Linyi People’s Hospital, Linyi, China
- *Correspondence: Lijuan Wang, ; Feiyu Jia,
| | - Lijuan Wang
- Central Laboratory, Linyi People’s Hospital, Linyi, China
- Linyi Key Laboratory of Tumor Biology, Linyi, China
- *Correspondence: Lijuan Wang, ; Feiyu Jia,
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32
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Samineni D, Gibiansky L, Wang B, Vadhavkar S, Rajwanshi R, Tandon M, Sinha A, Al-Sawaf O, Fischer K, Hallek M, Salem AH, Li C, Miles D. Pharmacokinetics and Exposure-Response Analysis of Venetoclax + Obinutuzumab in Chronic Lymphocytic Leukemia: Phase 1b Study and Phase 3 CLL14 Trial. Adv Ther 2022; 39:3635-3653. [PMID: 35708885 PMCID: PMC9309146 DOI: 10.1007/s12325-022-02170-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 04/21/2022] [Indexed: 11/24/2022]
Abstract
INTRODUCTION This study aims to investigate pharmacokinetics (PK) and exposure-response parameters of the 400 mg once-daily venetoclax dose regimen in combination with obinutuzumab, which was approved for the first-line (1L) treatment of chronic lymphocytic leukemia (CLL) based on data from the phase 3 CLL14 study and the phase 1b dose-finding GP28331 study. METHODS Parameter estimates and uncertainty, which were estimated by a previously developed population PK (popPK) model, were used as informative priors for this analysis. They were re-estimated, and then used to evaluate additional covariate effects, describe venetoclax PK when administered with obinutuzumab, and provide empirical Bayes estimates of PK parameters and exposure. Exposure-progression-free survival (PFS) and exposure-safety relationships were assessed using data from CLL14, with steady-state nominal venetoclax exposure (CmeanSS,nominal) as the predictor variable. Exposure-safety analyses were conducted using logistic regression for selected treatment-emergent grade ≥ 3 adverse events (AEs) and serious AEs (SAEs). Dose intensities were summarized by tertiles of CmeanSS,nominal. RESULTS PK data from 274 patients (CLL14, n = 194; GP28331, n = 80) were included. The final model provided good fit of the observed data. Obinutuzumab co-administration, history of prior treatments, and disease severity at baseline had no appreciable influence on venetoclax steady-state exposure. No significant correlations were observed between venetoclax exposure and PFS, or between venetoclax exposure and the probability of treatment-emergent grade ≥ 3 neutropenia, grade ≥ 3 thrombocytopenia, grade ≥ 3 infections, and SAEs. Median dose intensities for venetoclax and obinutuzumab remained similar across venetoclax exposure tertiles. CONCLUSION PopPK and exposure-efficacy, exposure-safety, and exposure-tolerability analyses support the 400 mg once-daily venetoclax dose plus obinutuzumab for 1L treatment in patients with CLL. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov Identifiers NCT02242942 and NCT02339181.
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Affiliation(s)
- Divya Samineni
- Genentech, Inc., 1 DNA Way, South San Francisco, CA, USA.
| | | | - Bei Wang
- Genentech, Inc., 1 DNA Way, South San Francisco, CA, USA
| | | | | | | | | | - Othman Al-Sawaf
- Faculty of Medicine, University of Cologne, Cologne, Germany.,Department I of Internal Medicine, German CLL Study Group, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, University Hospital Cologne, Cologne, Germany
| | - Kirsten Fischer
- Faculty of Medicine, University of Cologne, Cologne, Germany.,Department I of Internal Medicine, German CLL Study Group, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, University Hospital Cologne, Cologne, Germany
| | - Michael Hallek
- Faculty of Medicine, University of Cologne, Cologne, Germany.,Department I of Internal Medicine, German CLL Study Group, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, University Hospital Cologne, Cologne, Germany
| | - Ahmed Hamed Salem
- AbbVie Inc., North Chicago, IL, USA.,Department of Clinical Pharmacy, Ain Shams University, Cairo, Egypt
| | - Chunze Li
- Genentech, Inc., 1 DNA Way, South San Francisco, CA, USA
| | - Dale Miles
- Genentech, Inc., 1 DNA Way, South San Francisco, CA, USA
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33
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Ghosh K, Ghosh K. Monoclonal antibodies used for the management of haematological disorders. Expert Rev Hematol 2022; 15:443-455. [PMID: 35504000 DOI: 10.1080/17474086.2022.2073213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Monoclonal antibodies Ab (MoAb) are increasingly becoming part of therapeutic armamentarium for haematologists and haemato-oncologists. This review brings together commonly used antibodies in one place for brevity and novel understanding. AREAS COVERED Pubmed and Scopus databases were explored focusing on MoAb in clinical haematological practice. Emphasis was given to current review articles. The data base was searched from 1997 till present. 24 different antibodies, most of which are in use were discussed. Antibodies are used for diverse conditions i.e. malignant and benign haematological conditions, treatment at various phases of stem cell transplantation. These antibodies were used both alone or in combination with various chemotherapy, targeted small molecules or as immunoconjugates. Some of the side effect profiles of these antibodies were common and some were unique. Unusual infections or organ dysfunctions were noted. Improved function of antibodies by protein engineering is also advancing rapidly. Dosage, frequency and route of administration depended on the convenience and condition for which the antibody is used. EXPERT OPINION : MoAbs are increasingly used in haematology practice either alone or in combination with other types of therapy for improved out come in various haematological conditions.
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Affiliation(s)
- Kanjaksha Ghosh
- National Institute of Immunohaematology. 13th fl. KEM Hospital MS Building, Parel, Mumbai 400012. India
| | - Kinjalka Ghosh
- Department of Clinical Biochemistry , Tata Memorial Hospital. & Homi Bhaba National Institute. Parel, Mumbai 400012.India
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34
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The emerging landscape of exosomal CircRNAs in solid cancers and hematological malignancies. Biomark Res 2022; 10:28. [PMID: 35505392 PMCID: PMC9066734 DOI: 10.1186/s40364-022-00375-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 04/05/2022] [Indexed: 12/24/2022] Open
Abstract
Circular RNAs (circRNAs) are a type of recently discovered noncoding RNA. They exert their biological functions by competitively binding to microRNAs (miRNAs) as miRNA sponges, promoting gene transcription and participating in the regulation of selective splicing, interacting with proteins and being translated into proteins. Exosomes are derived from intracavitary vesicles (ILVs), which are formed by the inward budding of multivesicular bodies (MVBs), and exosome release plays a pivotal role in intercellular communication. Accumulating evidence indicates that circRNAs in exosomes are associated with solid tumor invasion and metastasis. Additionally, emerging studies in the last 1 ~ 2 years have revealed that exosomal circRNA also have effect on hematological malignancies. In this review, we outline the properties and biological functions of circRNAs and exosomes. In particular, we summarize in detail the mechanism and roles of exosomal circRNAs and highlight their application as novel biomarkers in malignant tumors.
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Abstract
Blood cell analysis is essential for the diagnosis and identification of hematological malignancies. The use of digital microscopy systems has been extended in clinical laboratories. Super-resolution microscopy (SRM) has attracted wide attention in the medical field due to its nanoscale spatial resolution and high sensitivity. It is considered to be a potential method of blood cell analysis that may have more advantages than traditional approaches such as conventional optical microscopy and hematology analyzers in certain examination projects. In this review, we firstly summarize several common blood cell analysis technologies in the clinic, and analyze the advantages and disadvantages of these technologies. Then, we focus on the basic principles and characteristics of three representative SRM techniques, as well as the latest advances in these techniques for blood cell analysis. Finally, we discuss the developmental trend and possible research directions of SRM, and provide some discussions on further development of technologies for blood cell analysis.
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Ci T, Zhang W, Qiao Y, Li H, Zang J, Li H, Feng N, Gu Z. Delivery strategies in treatments of leukemia. Chem Soc Rev 2022; 51:2121-2144. [PMID: 35188506 DOI: 10.1039/d1cs00755f] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Leukemia is a hematological malignancy associated with the uncontrolled proliferation of mutant progenitors, suppressing the production of normal blood cells. Current treatments, including chemotherapy, radiotherapy, and immunotherapy, still lead to unsatisfactory results with a 5 year survival rate of only 30-50%. The poor prognosis is related to both disease relapse and treatment-associated toxicity. Delivery strategies can improve the in vivo pharmacokinetics of drugs, navigating the therapeutics to target cells or the tumor microenvironment and reversing drug resistance, which maximizes tumor elimination and alleviates systematic adverse effects. This review discusses available FDA-approved anti-leukemia drugs and therapies with a focus on the advances in the development of anti-leukemia drug delivery systems. Additionally, challenges in clinical translation of the delivery strategies and future research opportunities in leukemia treatment are also included.
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Affiliation(s)
- Tianyuan Ci
- Department of Pharmaceutical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Wentao Zhang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
| | - Yingyu Qiao
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing, Jiangsu Province, 210009, China
| | - Huangjuan Li
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing, Jiangsu Province, 210009, China
| | - Jing Zang
- Department of Pharmaceutical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Hongjun Li
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
| | - Nianping Feng
- Department of Pharmaceutical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Zhen Gu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. .,Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.,Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China.,Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311121, China.,MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027, China
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Bendamustine versus chlorambucil in treatment of chronic lymphocytic leukaemia in China: a randomized, open-label, parallel-controlled, phase III clinical trial. Invest New Drugs 2022; 40:349-360. [PMID: 35031896 DOI: 10.1007/s10637-021-01206-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 12/08/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND Chronic lymphoblastic leukemia (CLL) is the most common adult leukemia and mainly affects the elderly. Chemoimmunotherapy still has a role in the standard frontline therapy for specific population. However, the clinical activity of bendamustine has not been investigated in unfit Chinese patients with CLL. This study aimed to compare the efficacy and safety of bendamustine versus chlorambucil for untreated Chinese patients with Binet stage B/C CLL. METHODS In this multi-center, randomized, open-label, parallel-controlled, phase III trial, patients with previously untreated CLL were enrolled and randomly assigned (1:1) to receive bendamustine or chlorambucil. The primary endpoint was the objective response rate. Secondary endpoints included progression-free survival, the duration of response, and overall survival. Adverse events were recorded to evaluate safety. RESULTS Of 158 screened patients, 147 were enrolled and randomly allocated to receive bendamustine (n = 72) or chlorambucil (n = 75). After a median follow-up of 25.6 months (IQR 12.5-27.7), 69.0% (95% CI, 56.9-79.5) of bendamustine-treated patients achieved objective response and 37.0% (95% CI, 26.0-49.1) of chlorambucil with a difference of 32.0% (95%CI: 16.6-47.5), demonstrating the superiority of bendamustine to chlorambucil (p < 0.001). The median progression-free survival was longer for bendamustine (16.5 months; 95% CI, 11.3-24.7) versus chlorambucil (9.6 months; 95% CI, 8.7-11.8; p < 0.001). A longer median duration of response was seen in those receiving bendamustine (19.2 months; 95% CI, 11.8-29.1) than chlorambucil (10.7 months; 95% CI, 5.6-13.6; p = 0.0018). Median overall survival was not reached in either group. Overall survival at 18 months was 88% for bendamustine versus 85% for chlorambucil. Most common adverse events in both groups were neutropenia and thrombocytopenia. CONCLUSION In untreated Chinese patients with Binet stage B/C CLL, bendamustine induced the better objective response and resulted in longer progression-free survival than chlorambucil. Overall, these results validate the role of bendamustine as an effective and safe first-line therapy in this population.
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Yao Y, Lin X, Li F, Jin J, Wang H. The global burden and attributable risk factors of chronic lymphocytic leukemia in 204 countries and territories from 1990 to 2019: analysis based on the global burden of disease study 2019. Biomed Eng Online 2022; 21:4. [PMID: 35016695 PMCID: PMC8753864 DOI: 10.1186/s12938-021-00973-6] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 12/21/2021] [Indexed: 12/24/2022] Open
Abstract
Background Chronic lymphocytic leukemia (CLL) is the most prevalent subtype of leukemia in Western countries, causing a substantial health burden on patients and society. Comprehensive evaluation of the epidemiological characteristics of CLL is warranted, especially in the current context of global population aging. The main objective of this study is evaluating the disease burden of CLL at global, regional, and national levels from 1990 to 2019. As secondary objectives, we studied the influence of demographic factors and performed risk factor analysis. We hope this study could provide evidence for the evaluation of the effectiveness of previous prevention strategies and the formulation of future global health policies. Results Based on data of CLL between 1990 to 2019 from the Global Burden of Disease (GBD) study 2019, we depicted the age, gender, and regional structure of the CLL burden population and described the impact of social development on the disease burden of CLL. The distribution and changing trends of attributable risk factors were also investigated. The global burden of CLL has increased dramatically. A high incidence has been achieved in males and elder people. Countries and territories with high social-demographic index (SDI) tended to have higher global burden than low-SDI region. Of risk factors, high body mass index and smoking were the major contributors for CLL-related mortality and disability adjusted life-years (DALYs). Conclusion In summary, the global CLL burden continues to rise over the past 30 years. The relocation of medical resource should be considered on a global scale. Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s12938-021-00973-6.
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A novel differential diagnosis algorithm for chronic lymphocytic leukemia using immunophenotyping with flow cytometry. Hematol Transfus Cell Ther 2021:S2531-1379(21)01317-1. [PMID: 35216960 DOI: 10.1016/j.htct.2021.08.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 07/13/2021] [Accepted: 08/10/2021] [Indexed: 12/11/2022] Open
Abstract
INTRODUCTION The availability of a clinical decision algorithm for diagnosis of chronic lymphocytic leukemia (CLL) may greatly contribute to the diagnosis of CLL, particularly in cases with ambiguous immunophenotypes. Herein we propose a novel differential diagnosis algorithm for the CLL diagnosis using immunophenotyping with flow cytometry. METHODS The hierarchical logistic regression model (Backward LR) was used to build a predictive algorithm for the diagnosis of CLL, differentiated from other lymphoproliferative disorders (LPDs). RESULTS A total of 302 patients, of whom 220 (72.8%) had CLL and 82 (27.2%), B-cell lymphoproliferative disorders other than CLL, were included in the study. The Backward LR model comprised the variables CD5, CD43, CD81, ROR1, CD23, CD79b, FMC7, sIg and CD200 in the model development process. The weak expression of CD81 and increased intensity of expression in markers CD5, CD23 and CD200 increased the probability of CLL diagnosis, (p < 0.05). The odd ratio for CD5, C23, CD200 and CD81 was 1.088 (1.050 - 1.126), 1.044 (1.012 - 1.077), 1.039 (1.007 - 1.072) and 0.946 (0.921 - 0.970) [95% C.I.], respectively. Our model provided a novel diagnostic algorithm with 95.27% of sensitivity and 91.46% of specificity. The model prediction for 97.3% (214) of 220 patients diagnosed with CLL, was CLL and for 91.5% (75) of 82 patients diagnosed with an LPD other than CLL, was others. The cases were correctly classified as CLL and others with a 95.7% correctness rate. CONCLUSIONS Our model highlighting 4 markers (CD81, CD5, CD23 and CD200) provided high sensitivity and specificity in the CLL diagnosis and in distinguishing of CLL among other LPDs.
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Barbour M, Wood R, Harte T, Bushell TJ, Jiang HR. Anti-CD52 antibody treatment in murine experimental autoimmune encephalomyelitis induces dynamic and differential modulation of innate immune cells in peripheral immune and central nervous systems. Immunology 2021; 165:312-327. [PMID: 34826154 PMCID: PMC9426620 DOI: 10.1111/imm.13437] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 10/31/2021] [Accepted: 11/22/2021] [Indexed: 12/18/2022] Open
Abstract
Anti‐CD52 antibody (anti‐CD52‐Ab) leads to a rapid depletion of T and B cells, followed by reconstitution of immune cells with tolerogenic characteristics. However, very little is known about its effect on innate immune cells. In this study, experimental autoimmune encephalomyelitis mice were administered murine anti‐CD52‐Ab to investigate its effect on dendritic cells and monocytes/macrophages in the periphery lymphoid organs and the central nervous system (CNS). Our data show that blood and splenic innate immune cells exhibited significantly increased expression of MHC‐II and costimulatory molecules, which was associated with increased capacity of activating antigen‐specific T cells, at first day but not three weeks after five daily treatment with anti‐CD52‐Ab in comparison with controls. In contrast to the periphery, microglia and infiltrating macrophages in the CNS exhibited reduced expression levels of MHC‐II and costimulatory molecules after antibody treatment at both time‐points investigated when compared to controls. Furthermore, the transit response of peripheral innate immune cells to anti‐CD52‐Ab treatment was also observed in the lymphocyte‐deficient SCID mice, suggesting the changes are not a direct consequence of the mass depletion of lymphocytes in the periphery. Our study demonstrates a dynamic and tissue‐specific modulation of the innate immune cells in their phenotype and function following the antibody treatment. The findings of differential modulation of the microglia and infiltrating macrophages in the CNS in comparison with the innate immune cells in the peripheral organs support the CNS‐specific beneficial effect of alemtuzumab treatment on inhibiting neuroinflammation in multiple sclerosis patients.
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Affiliation(s)
- Mark Barbour
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
| | - Rachel Wood
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
| | - Tanith Harte
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
| | - Trevor J Bushell
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
| | - Hui-Rong Jiang
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
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Immunoprofiling of 4-1BB Expression Predicts Outcome in Chronic Lymphocytic Leukemia (CLL). Diagnostics (Basel) 2021; 11:diagnostics11112041. [PMID: 34829391 PMCID: PMC8622208 DOI: 10.3390/diagnostics11112041] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/29/2021] [Accepted: 11/02/2021] [Indexed: 12/28/2022] Open
Abstract
Recent success of novel therapies has improved treatment of chronic lymphocytic leukemia (CLL) patients, but most of them still require several treatment regimes. To improve treatment choice, prognostic markers suitable for prediction of disease outcome are required. Several molecular/genetic markers have been established, but accessibility for the entirety of all patients is limited. We here evaluated the relevance of GITR/4-1BB as well as their ligands for the prognosis of CLL patients. Surface expression of GITR/GITRL and 4-1BB/4-1BBL was correlated with established prognostic markers. Next, we separated our patient population according to GITR/GITRL and 4-1BB/4-1BBL expression in groups with high/low expression levels and performed Kaplan-Meier analyses. Interestingly, no correlation was observed with the defined prognostic markers. Whereas no significant difference between high and low expression of GITR, GITRL and 4-1BBL was observed, high 4-1BB levels on leukemic cells were associated with significantly shorter survival. Thereby we identify 4-1BB as prognostic marker for CLL.
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Cochrane T, Enrico A, Gomez-Almaguer D, Hadjiev E, Lech-Maranda E, Masszi T, Nikitin E, Robak T, Weinkove R, Wu SJ, Sail KR, Pesko J, Pai M, Komlosi V, Anderson MA. Impact of venetoclax monotherapy on the quality of life of patients with relapsed or refractory chronic lymphocytic leukemia: results from the phase 3b VENICE II trial. Leuk Lymphoma 2021; 63:304-314. [PMID: 34632935 DOI: 10.1080/10428194.2021.1986217] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Venetoclax, a potent B-cell lymphoma-2 (BCL-2) inhibitor, has demonstrated clinical efficacy in chronic lymphocytic leukemia (CLL). VENICE II is an open-label, single-arm, phase 3b study (NCT02980731) evaluating the impact of venetoclax monotherapy (400 mg once daily) for ≤2 years on health-related quality of life (HRQoL) of patients with relapsed/refractory CLL. The primary endpoint was mean change in the global health status (GHS)/quality of life (QoL) subscale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) from baseline to Week 48. Overall, 210 patients received ≥1 dose of venetoclax; median treatment duration was 67.4 weeks. The primary endpoint was met with mean improvement of +9.3 points (n = 156, 95% confidence interval 6.1-12.5; p=.004) in GHS/QoL. At Week 48, clinically meaningful improvements were observed for role functioning, fatigue, and insomnia domains of EORTC QLQ-C30, suggesting venetoclax monotherapy has a positive impact on HRQoL. No new safety signals were reported.
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Affiliation(s)
- Tara Cochrane
- Department of Haematology, Gold Coast University Hospital, Southport, Australia.,Griffiths University, Parkwood, Australia
| | - Alicia Enrico
- Area Hematology, Hospital Italiano La Plata, Buenos Aires, Argentina
| | - David Gomez-Almaguer
- Hematology Service, Hospital Universitario, Universidad Autónoma de Nuevo León, San Nicolás de los Garza, Mexico
| | - Evgueniy Hadjiev
- Department of Internal Medicine, Medical University Sofia, University Hospital Alexandrovska, Sofia, Bulgaria
| | - Ewa Lech-Maranda
- Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Tamas Masszi
- Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary
| | - Eugene Nikitin
- Department of Hematology, Oncology and Chemotherapy, S. P. Botkin's City Hospital, Moscow, Russia
| | - Tadeusz Robak
- Medical University of Lodz and Copernicus Memorial Hospital, Lodz, Poland
| | - Robert Weinkove
- Wellington Blood & Cancer Centre, Capital & Coast District Health Board, Wellington, New Zealand.,Cancer Immunotherapy Programme, Malaghan Institute of Medical Research, Wellington, New Zealand
| | - Shang-Ju Wu
- Department of Internal Medicine, Division of Haematology, National Taiwan University Hospital, Taipei City, Taiwan
| | | | | | | | | | - Mary Ann Anderson
- The Clinical Haematology Department of the Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Parkville, Australia.,Division of Blood Cells and Blood Cancer, The Walter and Eliza Hall Institute, Parkville, Australia
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Mosejová E, Bosnjakovic R, Kubala L, Vašíček O. Pseurotin D Induces Apoptosis through Targeting Redox Sensitive Pathways in Human Lymphoid Leukemia Cells. Antioxidants (Basel) 2021; 10:antiox10101576. [PMID: 34679711 PMCID: PMC8533295 DOI: 10.3390/antiox10101576] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/23/2021] [Accepted: 10/01/2021] [Indexed: 01/23/2023] Open
Abstract
Chronic lymphocytic leukemia (CLL) is the most prevalent lymphoid malignancy in many geographical regions of the world. Pseurotin D, a secondary metabolite of fungi, represents a group of bioactive natural products with a newly ascribed range of interesting biological activities. The purpose of this study was to bring new insights into the mechanism behind the effects of pseurotin D on MEC-1 cells as a representative CLL cell line, with a particular focus on selected signaling pathways important in the proliferation of cells and targeting mitochondrial metabolism. Our results showed that pseurotin D was able to significantly inhibit the proliferation of MEC-1 cells and arrested them in the G2/M cell cycle phase. In addition, pseurotin D was able to induce apoptosis. We found that all of these effects were associated with a change in mitochondrial membrane potential and the production of mitochondrial reactive oxygen species (ROS). We showed for the first time that pseurotin D suppresses MEC-1 cell proliferation and induces apoptotic cell death via induction of the collapse of the mitochondria respiratory chain and the ROS-related caspase pathway. Our results show the pseurotins family as promising compounds which could serve as a basis for the development of new compounds in the treatment of lymphoma.
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Affiliation(s)
- Eva Mosejová
- Institute of Biophysics of the Czech Academy of Sciences, 612 65 Brno, Czech Republic; (E.M.); (R.B.); (L.K.)
| | - Rebeka Bosnjakovic
- Institute of Biophysics of the Czech Academy of Sciences, 612 65 Brno, Czech Republic; (E.M.); (R.B.); (L.K.)
| | - Lukáš Kubala
- Institute of Biophysics of the Czech Academy of Sciences, 612 65 Brno, Czech Republic; (E.M.); (R.B.); (L.K.)
- Institute of Experimental Biology, Faculty of Science, Masaryk University, 625 00 Brno, Czech Republic
- International Clinical Research Center, St. Anne’s University Hospital, 656 91 Brno, Czech Republic
| | - Ondřej Vašíček
- Institute of Biophysics of the Czech Academy of Sciences, 612 65 Brno, Czech Republic; (E.M.); (R.B.); (L.K.)
- Institute of Experimental Biology, Faculty of Science, Masaryk University, 625 00 Brno, Czech Republic
- Correspondence: ; Tel.: +420-541-517-207
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Immunomolecular evaluation of dihydroartemisinin effects on apoptosis in chronic lymphocytic leukemia cell lines. Leuk Res 2021; 110:106702. [PMID: 34571432 DOI: 10.1016/j.leukres.2021.106702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 08/20/2021] [Accepted: 08/30/2021] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, has recently shown to induce apoptosis in many types of cancer cells. In this study, we aimed to determine the effects of DHA on apoptosis in human chronic lymphocytic leukemia (CLL) cell lines. METHODS The cells were treated separately and combined by DHA and Fludurabine (FLU) during 24, 48 and 72 hours. The cell viabilities determined by XTT method. Following separate and combined treatment of IC50 concentrations of DHA and FLU to the cells during 24 hours, the cells were analyzed by flow cytometry to determine the effects on apopotis staining with AnnexinV FITC and PI. mRNA and protein expression levels of TCTP, Mcl-1, Bcl-2, Bax and Caspase-3 were analyzed to find out the molecular mechanisms of apoptosis by using quantitative real-time PCR and flow cytometric methods. RESULTS Treatment with DHA alone or in combination with FLU induced apoptosis in a dose dependent manner in CLL cells. DHA alone was more effective than FLU alone or combined treatment with DHA and FLU. Our results suggest that Bcl-2 protein family member Bax was active in the apoptotic response of CLL cells after DHA treatment. Moreover, the apoptotic response induced by DHA was independent from the p53 mutation status of the CLL cells. CONCLUSION DHA might be a potential anti-cancer therapeutic for CLL.
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Balla B, Tripon F, Banescu C. From Descriptive to Functional Genomics of Leukemias Focusing on Genome Engineering Techniques. Int J Mol Sci 2021; 22:10065. [PMID: 34576226 PMCID: PMC8470190 DOI: 10.3390/ijms221810065] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 09/10/2021] [Accepted: 09/15/2021] [Indexed: 12/17/2022] Open
Abstract
Genome engineering makes the precise manipulation of DNA sequences possible in a cell. Therefore, it is essential for understanding gene function. Meganucleases were the start of genome engineering, and it continued with the discovery of Zinc finger nucleases (ZFNs), followed by Transcription activator-like effector nucleases (TALENs). They can generate double-strand breaks at a desired target site in the genome, and therefore can be used to knock in mutations or knock out genes in the same way. Years later, genome engineering was transformed by the discovery of clustered regularly interspaced short palindromic repeats (CRISPR). Implementation of CRISPR systems involves recognition guided by RNA and the precise cleaving of DNA molecules. This property proves its utility in epigenetics and genome engineering. CRISPR has been and is being continuously successfully used to model mutations in leukemic cell lines and control gene expression. Furthermore, it is used to identify targets and discover drugs for immune therapies. The descriptive and functional genomics of leukemias is discussed in this study, with an emphasis on genome engineering methods. The CRISPR/Cas9 system's challenges, viewpoints, limits, and solutions are also explored.
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Affiliation(s)
- Beata Balla
- Genetics Department, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, Strada Gheorghe Marinescu 38, 540139 Târgu Mureș, Romania; (B.B.); (C.B.)
- Center for Advanced Medical and Pharmaceutical Research, Genetics Laboratory, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, Strada Gheorghe Marinescu 38, 540139 Târgu Mureș, Romania
| | - Florin Tripon
- Genetics Department, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, Strada Gheorghe Marinescu 38, 540139 Târgu Mureș, Romania; (B.B.); (C.B.)
- Center for Advanced Medical and Pharmaceutical Research, Genetics Laboratory, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, Strada Gheorghe Marinescu 38, 540139 Târgu Mureș, Romania
| | - Claudia Banescu
- Genetics Department, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, Strada Gheorghe Marinescu 38, 540139 Târgu Mureș, Romania; (B.B.); (C.B.)
- Center for Advanced Medical and Pharmaceutical Research, Genetics Laboratory, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, Strada Gheorghe Marinescu 38, 540139 Târgu Mureș, Romania
- Clinical and Emergency County Hospital of Târgu Mureș, Strada Gheorghe Marinescu 50, 540136 Târgu Mureș, Romania
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Putowski M, Giannopoulos K. Perspectives on Precision Medicine in Chronic Lymphocytic Leukemia: Targeting Recurrent Mutations-NOTCH1, SF3B1, MYD88, BIRC3. J Clin Med 2021; 10:jcm10163735. [PMID: 34442029 PMCID: PMC8396993 DOI: 10.3390/jcm10163735] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 08/13/2021] [Accepted: 08/19/2021] [Indexed: 12/15/2022] Open
Abstract
Chronic lymphocytic leukemia (CLL) is highly heterogeneous, with extremely variable clinical course. The clinical heterogeneity of CLL reflects differences in the biology of the disease, including chromosomal alterations, specific immunophenotypic patterns and serum markers. The application of next-generation sequencing techniques has demonstrated the high genetic and epigenetic heterogeneity in CLL. The novel mutations could be pharmacologically targeted for individualized approach in some of the CLL patients. Potential neurogenic locus notch homolog protein 1 (NOTCH1) signalling targeting mechanisms in CLL include secretase inhibitors and specific antibodies to block NOTCH ligand/receptor interactions. In vitro studies characterizing the effect of the splicing inhibitors resulted in increased apoptosis of CLL cells regardless of splicing factor 3B subunit 1 (SF3B1) status. Several therapeutic strategies have been also proposed to directly or indirectly inhibit the toll-like receptor/myeloid differentiation primary response gene 88 (TLR/MyD88) pathway. Another potential approach is targeting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and inhibition of this prosurvival pathway. Newly discovered mutations and their signalling pathways play key roles in the course of the disease. This opens new opportunities in the management and treatment of CLL.
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Affiliation(s)
- Maciej Putowski
- Department of Experimental Hematooncology, Medical University of Lublin, 20-093 Lublin, Poland;
- Correspondence: ; Tel.: +48-81-448-66-32
| | - Krzysztof Giannopoulos
- Department of Experimental Hematooncology, Medical University of Lublin, 20-093 Lublin, Poland;
- Department of Hematology, St. John’s Cancer Center, 20-090 Lublin, Poland
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Beckmann L, Berg V, Dickhut C, Sun C, Merkel O, Bloehdorn J, Robrecht S, Seifert M, da Palma Guerreiro A, Claasen J, Loroch S, Oliverio M, Underbayev C, Vaughn L, Thomalla D, Hülsemann MF, Tausch E, Fischer K, Fink AM, Eichhorst B, Sickmann A, Wendtner CM, Stilgenbauer S, Hallek M, Wiestner A, Zahedi RP, Frenzel LP. MARCKS affects cell motility and response to BTK inhibitors in CLL. Blood 2021; 138:544-556. [PMID: 33735912 PMCID: PMC8377477 DOI: 10.1182/blood.2020009165] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 03/18/2021] [Accepted: 03/06/2021] [Indexed: 12/26/2022] Open
Abstract
Bruton tyrosine kinase (BTK) inhibitors are highly active drugs for the treatment of chronic lymphocytic leukemia (CLL). To understand the response to BTK inhibitors on a molecular level, we performed (phospho)proteomic analyses under ibrutinib treatment. We identified 3466 proteins and 9184 phosphopeptides (representing 2854 proteins) in CLL cells exhibiting a physiological ratio of phosphorylated serines (pS), threonines (pT), and tyrosines (pY) (pS:pT:pY). Expression of 83 proteins differed between unmutated immunoglobulin heavy-chain variable region (IGHV) CLL (UM-CLL) and mutated IGHV CLL (M-CLL). Strikingly, UM-CLL cells showed higher basal phosphorylation levels than M-CLL samples. Effects of ibrutinib on protein phosphorylation levels were stronger in UM-CLL, especially on phosphorylated tyrosines. The differentially regulated phosphopeptides and proteins clustered in pathways regulating cell migration, motility, cytoskeleton composition, and survival. One protein, myristoylated alanine-rich C-kinase substrate (MARCKS), showed striking differences in expression and phosphorylation level in UM-CLL vs M-CLL. MARCKS sequesters phosphatidylinositol-4,5-bisphosphate, thereby affecting central signaling pathways and clustering of the B-cell receptor (BCR). Genetically induced loss of MARCKS significantly increased AKT signaling and migratory capacity. CD40L stimulation increased expression of MARCKS. BCR stimulation induced phosphorylation of MARCKS, which was reduced by BTK inhibitors. In line with our in vitro findings, low MARCKS expression is associated with significantly higher treatment-induced leukocytosis and more pronounced decrease of nodal disease in patients with CLL treated with acalabrutinib.
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Affiliation(s)
- Laura Beckmann
- Department I of Internal Medicine and
- Center of Integrated Oncology Aachen Bonn Cologne Dusseldorf (ABCD), University Hospital Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Valeska Berg
- Department I of Internal Medicine and
- Center of Integrated Oncology Aachen Bonn Cologne Dusseldorf (ABCD), University Hospital Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Clarissa Dickhut
- Leibniz-Institut für Analytische Wissenschaften (ISAS) eV, Dortmund, Germany
| | - Clare Sun
- Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
| | - Olaf Merkel
- Department I of Internal Medicine and
- Center of Integrated Oncology Aachen Bonn Cologne Dusseldorf (ABCD), University Hospital Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | | | - Sandra Robrecht
- Department I of Internal Medicine and
- Center of Integrated Oncology Aachen Bonn Cologne Dusseldorf (ABCD), University Hospital Cologne, Cologne, Germany
| | - Marc Seifert
- Institute of Cell Biology (Cancer Research), Medical Faculty, University of Duisburg-Essen, Essen, Germany
| | - Alexandra da Palma Guerreiro
- Department I of Internal Medicine and
- Center of Integrated Oncology Aachen Bonn Cologne Dusseldorf (ABCD), University Hospital Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Julia Claasen
- Department I of Internal Medicine and
- Center of Integrated Oncology Aachen Bonn Cologne Dusseldorf (ABCD), University Hospital Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Stefan Loroch
- Leibniz-Institut für Analytische Wissenschaften (ISAS) eV, Dortmund, Germany
| | - Matteo Oliverio
- Department I of Internal Medicine and
- Center of Integrated Oncology Aachen Bonn Cologne Dusseldorf (ABCD), University Hospital Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Chingiz Underbayev
- Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
| | - Lauren Vaughn
- Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
| | - Daniel Thomalla
- Department I of Internal Medicine and
- Center of Integrated Oncology Aachen Bonn Cologne Dusseldorf (ABCD), University Hospital Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Malte F Hülsemann
- Department I of Internal Medicine and
- Center of Integrated Oncology Aachen Bonn Cologne Dusseldorf (ABCD), University Hospital Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Eugen Tausch
- Department of Internal Medicine III, Ulm University, Ulm, Germany
| | - Kirsten Fischer
- Department I of Internal Medicine and
- Center of Integrated Oncology Aachen Bonn Cologne Dusseldorf (ABCD), University Hospital Cologne, Cologne, Germany
| | - Anna Maria Fink
- Department I of Internal Medicine and
- Center of Integrated Oncology Aachen Bonn Cologne Dusseldorf (ABCD), University Hospital Cologne, Cologne, Germany
| | - Barbara Eichhorst
- Department I of Internal Medicine and
- Center of Integrated Oncology Aachen Bonn Cologne Dusseldorf (ABCD), University Hospital Cologne, Cologne, Germany
| | - Albert Sickmann
- Leibniz-Institut für Analytische Wissenschaften (ISAS) eV, Dortmund, Germany
| | - Clemens M Wendtner
- Department I of Internal Medicine and
- Munich Clinic Schwabing, Academic Teaching Hospital, Ludwig Maximilian University (LMU), Munich, Germany
| | - Stephan Stilgenbauer
- Department of Internal Medicine III, Ulm University, Ulm, Germany
- Department of Internal Medicine I, Saarland University, Homburg, Germany
| | - Michael Hallek
- Department I of Internal Medicine and
- Center of Integrated Oncology Aachen Bonn Cologne Dusseldorf (ABCD), University Hospital Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Adrian Wiestner
- Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
| | - René P Zahedi
- Leibniz-Institut für Analytische Wissenschaften (ISAS) eV, Dortmund, Germany
- Segal Cancer Proteomics Centre, Lady Davis Institute and
- Gerald Bronfman Department of Oncology, Jewish General Hospital, McGill University, QC, Canada; and
- Center for Computational and Data-Intensive Science and Engineering, Skolkovo Institute of Science and Technology, Moscow, Russia
| | - Lukas P Frenzel
- Department I of Internal Medicine and
- Center of Integrated Oncology Aachen Bonn Cologne Dusseldorf (ABCD), University Hospital Cologne, Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
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Yuan Y, Li J, He Z, Fan X, Mao X, Yang M, Yang D. tRNA-derived fragments as New Hallmarks of Aging and Age-related Diseases. Aging Dis 2021; 12:1304-1322. [PMID: 34341710 PMCID: PMC8279533 DOI: 10.14336/ad.2021.0115] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 01/15/2021] [Indexed: 01/02/2023] Open
Abstract
tRNA-derived fragments (tRFs), which are non-coding RNAs produced via tRNA cleavage with lengths of 14 to 50 nucleotides, originate from precursor tRNAs or mature tRNAs and exist in a wide range of organisms. tRFs are produced not by random fracture of tRNAs but by specific mechanisms. Considerable evidence shows that tRFs are detectable in model organisms of different ages and are associated with age-related diseases in humans, such as cancer and neurodegenerative diseases. In this literature review, the origin and classification of tRFs and the regulatory mechanisms of tRFs in aging and age-related diseases are summarized. We also describe the available tRF databases and research techniques and lay a foundation for the exploration of tRFs as biomarkers for the diagnosis and treatment of aging and age-related diseases.
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Affiliation(s)
- Ya Yuan
- 1Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| | - Jiamei Li
- 1Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| | - Zhi He
- 1Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| | - Xiaolan Fan
- 1Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.,2Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| | - Xueping Mao
- 1Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.,2Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| | - Mingyao Yang
- 1Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.,2Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| | - Deying Yang
- 1Institute of Animal Genetics and Breeding, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.,2Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
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Balakrishna J, Basumallik N, Matulonis R, Scott D, Salem D, Jasper G, Wiestner A, Stetler-Stevenson M, Marti G, Sun C, Yuan CM. Intensity of antigen expression reflects IGHV mutational status and Dohner-defined prognostic categories in chronic lymphocytic leukemia, monoclonal B-cell lymphocytosis, and small lymphocytic lymphoma. Leuk Lymphoma 2021; 62:1828-1839. [PMID: 33734005 PMCID: PMC9464423 DOI: 10.1080/10428194.2021.1894641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 02/04/2021] [Accepted: 02/14/2021] [Indexed: 10/21/2022]
Abstract
We demonstrate the prognostic utility of antigen quantitation in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and monoclonal B-cell lymphocytosis (MBL). Median antibody-bound-per-cell (ABC) of CD20, CD22, CD25, CD19, and %CD38(+) was determined in CLL (185/208), SLL (8/208) and MBL (15/208) cases by flow cytometry, then compared to Dohner-classification, immunoglobulin status (mutated, IGHV-M; unmutated, IGHV-U), CLL-IPI risk and time to first treatment (TTFT). Trisomy 12 cases showed increased %CD38-expression (p = .0379). Higher %CD38 was observed in IGHV-U versus IGHV-M (p = .0003). CD20ABC was increased in IGHV-U versus IGHV-M (p = .006). Del13q cases demonstrated lower CD22ABC (p = .0198). Cases without cytogenetic abnormality exhibited higher CD19ABC (p = .0295) and CD22ABC (p = .0078). Del17p cases demonstrated lower CD25ABC (p = .0097). High and very-high CLL-IPI risk groups were associated with high CD38-expression (p = .02) and low CD25ABC (p = .0004). Shortened TTFT was associated with high CD38-expression (p < .0001). Interestingly, high CD25ABC trended toward shortened TTFT (p = .07). Quantitative antigen expression reflects CLL-IPI risk groups and Dohner-classification.
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Affiliation(s)
- Jayalakshmi Balakrishna
- Flow Cytometry, Laboratory of Pathology, Center for Cancer Research, NCI, NIH
- Hematopathology, Ohio State University Wexner Medical Center
| | | | - Robert Matulonis
- Walter Reed National Military Medical Center, Bethesda, Maryland, USA
| | - Drake Scott
- Flow Cytometry, Laboratory of Pathology, Center for Cancer Research, NCI, NIH
| | - Dalia Salem
- Flow Cytometry, Laboratory of Pathology, Center for Cancer Research, NCI, NIH
- Clinical Pathology Department, Faculty of Medicine, Mansoura University, Egypt
| | - Gregory Jasper
- Flow Cytometry, Laboratory of Pathology, Center for Cancer Research, NCI, NIH
| | | | | | | | | | - Constance M. Yuan
- Flow Cytometry, Laboratory of Pathology, Center for Cancer Research, NCI, NIH
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50
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Mavridou D, Psatha K, Aivaliotis M. Proteomics and Drug Repurposing in CLL towards Precision Medicine. Cancers (Basel) 2021; 13:cancers13143391. [PMID: 34298607 PMCID: PMC8303629 DOI: 10.3390/cancers13143391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/25/2021] [Accepted: 06/29/2021] [Indexed: 11/30/2022] Open
Abstract
Simple Summary Despite continued efforts, the current status of knowledge in CLL molecular pathobiology, diagnosis, prognosis and treatment remains elusive and imprecise. Proteomics approaches combined with advanced bioinformatics and drug repurposing promise to shed light on the complex proteome heterogeneity of CLL patients and mitigate, improve, or even eliminate the knowledge stagnation. In relation to this concept, this review presents a brief overview of all the available proteomics and drug repurposing studies in CLL and suggests the way such studies can be exploited to find effective therapeutic options combined with drug repurposing strategies to adopt and accost a more “precision medicine” spectrum. Abstract CLL is a hematological malignancy considered as the most frequent lymphoproliferative disease in the western world. It is characterized by high molecular heterogeneity and despite the available therapeutic options, there are many patient subgroups showing the insufficient effectiveness of disease treatment. The challenge is to investigate the individual molecular characteristics and heterogeneity of these patients. Proteomics analysis is a powerful approach that monitors the constant state of flux operators of genetic information and can unravel the proteome heterogeneity and rewiring into protein pathways in CLL patients. This review essences all the available proteomics studies in CLL and suggests the way these studies can be exploited to find effective therapeutic options combined with drug repurposing approaches. Drug repurposing utilizes all the existing knowledge of the safety and efficacy of FDA-approved or investigational drugs and anticipates drug alignment to crucial CLL therapeutic targets, leading to a better disease outcome. The drug repurposing studies in CLL are also discussed in this review. The next goal involves the integration of proteomics-based drug repurposing in precision medicine, as well as the application of this procedure into clinical practice to predict the most appropriate drugs combination that could ensure therapy and the long-term survival of each CLL patient.
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Affiliation(s)
- Dimitra Mavridou
- Laboratory of Biochemistry, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece;
- Functional Proteomics and Systems Biology (FunPATh)—Center for Interdisciplinary Research and Innovation (CIRI-AUTH), GR-57001 Thessaloniki, Greece
- Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece
| | - Konstantina Psatha
- Laboratory of Biochemistry, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece;
- Functional Proteomics and Systems Biology (FunPATh)—Center for Interdisciplinary Research and Innovation (CIRI-AUTH), GR-57001 Thessaloniki, Greece
- Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece
- Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology, GR-70013 Heraklion, Greece
- Correspondence: (K.P.); (M.A.)
| | - Michalis Aivaliotis
- Laboratory of Biochemistry, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece;
- Functional Proteomics and Systems Biology (FunPATh)—Center for Interdisciplinary Research and Innovation (CIRI-AUTH), GR-57001 Thessaloniki, Greece
- Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece
- Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology, GR-70013 Heraklion, Greece
- Correspondence: (K.P.); (M.A.)
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