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Dreisinger M, Roškar Z, Goropevšek A, Zakelšek A, Čurič S, Živko N, Bevc S, Homšak E. Increased STAT3 Phosphorylation in CD4 + T-Cells of Treated Patients with Chronic Lymphocytic Leukemia and Changes in Circulating Regulatory T-Cell Subsets Relative to Tumor Mass Distribution Value and Disease Duration. Biomedicines 2025; 13:1204. [PMID: 40427031 DOI: 10.3390/biomedicines13051204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2025] [Revised: 04/25/2025] [Accepted: 05/06/2025] [Indexed: 05/29/2025] Open
Abstract
Introduction: In mouse models of chronic lymphocytic leukemia (CLL), an effective anti-leukemia immune response was obtained by depleting a specific regulatory T-cell (Treg) subset. While STAT5 signaling could alter the homeostasis of naïve (nTreg) and activated (aTreg) subsets, which are capable of suppressing also CLL patients' responses to microbial antigens, perturbed STAT3 signaling could drive CXCR5 expression in circulating T-follicular regulatory cells (Tfr) and their entry into the lymph node/tumor microenvironment. Materials and Methods: By using phospho-specific flow cytometry, we monitored STAT signaling/phosphorylation (pSTAT), in vitro responses to Sars-Cov2-antigen-specific stimulation, and circulating Treg subsets in relation to Binet stage and total tumor mass/tumor distribution (TTM/TD) scoring in 62 patients with CLL. Results: The percentage of CXCR5+ Treg significantly increased in patients with Binet stage B disease, and Tfr-like subsets were associated with higher TTM and lower TD. The pSTAT3 levels in CD4+ T-cells were only significantly increased in patients undergoing therapy. Lower nTreg percentages correlated with increased disease duration, and an increased aTreg/nTreg ratio correlated with SARS-CoV-2-antigen-induced STAT5 signaling responses. Conclusions: The results show increased amounts of circulating CXCR5+ Tfr-like subsets in patients with extensive lymph node involvement and augmented STAT3 signaling in patients on therapy. While STAT5 responses may drive nTreg differentiation into aTreg, nTreg decline is associated with increased disease duration.
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Affiliation(s)
- Mojca Dreisinger
- Department of Haematology, University Medical Centre Maribor, 2000 Maribor, Slovenia
| | - Zlatko Roškar
- Department of Haematology, University Medical Centre Maribor, 2000 Maribor, Slovenia
| | - Aleš Goropevšek
- Department of Laboratory Diagnostics, University Medical Centre Maribor, 2000 Maribor, Slovenia
| | - Andreja Zakelšek
- Department of Laboratory Diagnostics, University Medical Centre Maribor, 2000 Maribor, Slovenia
| | - Sara Čurič
- Department of Laboratory Diagnostics, University Medical Centre Maribor, 2000 Maribor, Slovenia
| | - Nada Živko
- Department of Laboratory Diagnostics, University Medical Centre Maribor, 2000 Maribor, Slovenia
| | - Sebastjan Bevc
- Faculty of Medicine, University of Maribor, 2000 Maribor, Slovenia
- Department of Nephrology, University Medical Centre Maribor, 2000 Maribor, Slovenia
| | - Evgenija Homšak
- Department of Laboratory Diagnostics, University Medical Centre Maribor, 2000 Maribor, Slovenia
- Faculty of Medicine, University of Maribor, 2000 Maribor, Slovenia
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Hu M, Zhang T, Liu B, Guo Q, Zhao B, Lin J, Lv Z, Wang R. Association of rituximab use with adverse events in adults with lymphoma or autoimmune disease: a single center experience. Front Med (Lausanne) 2025; 12:1567886. [PMID: 40351469 PMCID: PMC12061919 DOI: 10.3389/fmed.2025.1567886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Accepted: 04/11/2025] [Indexed: 05/14/2025] Open
Abstract
Objective Rituximab (RTX) is a chimeric human/murine CD20 monoclonal antibody, which has been administered in treating hematological malignancies and various autoimmune disorders. This study aimed to present our center's experience in RTX use in adults with lymphoma and autoimmune diseases (AID) including primary membranous nephropathy (pMN), as well as therapeutic effects of RTX on clinical outcome of pMN patients. Methods A total of 761 Chinese patients were retrospectively included, who received RTX treatment at Shandong Provincial Hospital between January 1st, 2017 and December 31st, 2021, with person time of exposure spanning between their first dose of RTX and last follow-up date or the end of the study period. Results Adverse events (AEs) occurred in 487 patients (64.0%), with a majority of infection (309, 40.6%) and a minority of non-infectious AEs (178, 23.4%); and the incidences of AEs were higher in lymphoma patients (381, 65.8%) than that in AID patients (106, 58.2%). Respiratory infections (215, 28.3%), gastrointestinal infections (49, 6.4%), urinary tract infections (41, 5.4%), cutaneous and mucosal infections (31, 4.1%), and infections in the abdominal cavity or pleurisy (4, 0.5%) were the leading types of infections. Cancer diagnosis [hazard ratio (HR), 3.926; 95% confidence interval (CI), 1.730-8.913] and prophylactic sulfamethoxazole/trimethoprim (SMZ/TMP) administration (HR, 3.793; 95% CI, 1.101-13.069) were associated with increased risk of infections. Immediate non-infectious AEs included anaphylaxis (44, 5.8%) and infusion reactions (99, 13.0%). Long-term non-infectious AEs included hypogammaglobulinemia (106, 28.6%), neutropenia (11, 5.5%) and interstitial lung disease (1, 0.1%). Female sex (HR, 0.515; 95% CI, 0.289-0.918) and cancer diagnosis (HR, 0.126; 95% CI, 0.049-0.323) were associated with higher risk of hypogammaglobulinemia. In 74 pMN patients, 13 (17.6%) patients experienced infections, with 2 cases of non-infectious AEs (2.7%). 6-month follow-up showed remission was achieved in 45 patients (60.8%), either as initial (61.0%) or alternative therapy (60.7%), without significant impacts on kidney function (p > 0.05). Conclusion Our findings indicated AEs were common during RTX treatment, particularly in lymphoma patients, most of which were moderate and mild, highlighting a whole-process monitoring, timely interference and caring. And RTX was a safe and effective therapeutic option for pMN either as initial or alternative therapy in adult Chinese patients.
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Affiliation(s)
- Mengsi Hu
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Department of Nephrology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Tingwei Zhang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Department of Nephrology, The Affiliated Taian City Central Hospital of Qingdao University, Taian, China
| | - Bing Liu
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Qi Guo
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Bing Zhao
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Jiangong Lin
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Zhimei Lv
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Department of Nephrology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Rong Wang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Department of Nephrology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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3
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Gamal W, Mediavilla-Varela M, Kunta V, Sahakian E, Pinilla-Ibarz J. Impact of mitochondrial metabolism on T-cell dysfunction in chronic lymphocytic leukemia. Front Cell Dev Biol 2025; 13:1577081. [PMID: 40313718 PMCID: PMC12043688 DOI: 10.3389/fcell.2025.1577081] [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: 02/15/2025] [Accepted: 03/31/2025] [Indexed: 05/03/2025] Open
Abstract
T cells play a central role in anti-tumor immunity, yet their function is often compromised within the immunosuppressive tumor microenvironment, leading to cancer progression and resistance to immunotherapies. T-cell activation and differentiation require dynamic metabolic shifts, with mitochondrial metabolism playing a crucial role in sustaining their function. Research in cancer immunometabolism has revealed key mitochondrial abnormalities in tumor-infiltrating lymphocytes, including reduced mitochondrial capacity, depolarization, structural defects, and elevated reactive oxygen species. While these mitochondrial disruptions are well-characterized in solid tumors and linked to T-cell exhaustion, their impact on T-cell immunity in lymphoproliferative disorders remains underexplored. Chronic lymphocytic leukemia (CLL), the most prevalent chronic adult leukemia, is marked by profound T-cell dysfunction that limits the success of adoptive cell therapies. Emerging studies are shedding light on the role of mitochondrial disturbances in CLL-related T-cell dysfunction, but significant knowledge gaps remain. This review explores mitochondrial metabolism in T-cell exhaustion, emphasizing recent findings in CLL. We also discuss therapeutic strategies to restore T-cell mitochondrial function and identify key research gaps.
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Affiliation(s)
- Wael Gamal
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States
| | - Melanie Mediavilla-Varela
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States
| | - Vishaal Kunta
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States
| | - Eva Sahakian
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States
- Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States
| | - Javier Pinilla-Ibarz
- Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States
- Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States
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4
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Mauro FR. Improving SARS-CoV-2 vaccine response is challenging in chronic lymphocytic leukaemia. Lancet Haematol 2025; 12:e238-e239. [PMID: 40174993 DOI: 10.1016/s2352-3026(25)00069-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Accepted: 02/27/2025] [Indexed: 04/04/2025]
Affiliation(s)
- Francesca Romana Mauro
- Haematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy.
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5
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Cook JA, Patten PEM, Peckham N, Moss P, Phillips N, Abhishek A, Roberts T, Hodges M, Talbot G, Barber V, Francis A, Shields AM, Duley L, Hoogeboom R, Willett BJ, Scott S, Parry-Jones N, Eyre TA, Plested G, Vandici G, Wandroo FA, Hutchinson C, Paneesha S, Murray DJ, Martinez-Calle N, Jenkins S, Heartin E, Parry HM. A 3-week pause versus continued Bruton tyrosine kinase inhibitor use during COVID-19 vaccination in individuals with chronic lymphocytic leukaemia (IMPROVE trial): a randomised, open-label, superiority trial. Lancet Haematol 2025; 12:e294-e303. [PMID: 40175001 DOI: 10.1016/s2352-3026(25)00008-0] [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: 10/15/2024] [Revised: 01/06/2025] [Accepted: 01/17/2025] [Indexed: 04/04/2025]
Abstract
BACKGROUND Chronic lymphocytic leukaemia is the commonest leukaemia and is associated with profound immunosuppression. Bruton tyrosine kinase inhibitors (BTKi) have revolutionised chronic lymphocytic leukaemia management; however, therapy impairs vaccine-induced immunity. We evaluated whether a 3-week pause of BTKi treatment improved spike protein receptor binding domain (RBD) immunity to SARS-CoV-2 booster vaccination while maintaining disease control. METHODS We performed an open-label, two-arm, parallel-group, randomised trial in secondary-care haematology clinics in 11 UK hospitals. Participants aged 18 years or older, diagnosed with chronic lymphocytic leukaemia, and currently taking BTKi therapy (frontline or relapsed setting) for at least 12 months were eligible. Participants were randomly allocated (1:1, by a centralised computer randomisation program, stratified by BTKi therapy line) to pause BTKi for 3 weeks, starting 6 days before their SARS-CoV-2 vaccination booster date, or to continue therapy as usual. Neither participants nor clinical staff were blinded but laboratory staff were. Intramuscular injection of either original BA.1 or original BA.4/5 bivalent mRNA vaccine (50 μg mRNA-1273 or 30 μg BNT162b2), or 5 μg protein-based Vidprevtyn Beta (Sanofi Pasteur, Lyon, France) were received according to the national vaccination programme schedule. The primary outcome measure was anti-spike-RBD-specific antibody titre 3 weeks after vaccination and analysis performed by intention to treat (as randomly allocated, irrespective of compliance) following trial completion. This trial is registered with ISRCTN, 14197181, and has been completed. FINDINGS Between Oct 10, 2022, and June 8, 2023, 99 individuals (71 [72%] male and 28 [28%] female, with 89 [90%] of White ethnicity) were randomly allocated to groups pausing (n=50 [51%]) or continuing (n=49 [49%]) their BTKi therapy, and followed up for 12 weeks. At 3 weeks after vaccination, the geometric mean anti-spike-RBD-specific antibody titre was 218·8 U/mL (SD 122·9) in the continue group and 153·4 U/mL (103·2) in the pause group, with geometric mean ratio 1·104 (95% CI 0·565-2·158, p=0·77) using a mixed-effects model. The only serious adverse event during the 12-week follow-up was the death of one participant in the pause group due to COVID-19 infection 2 months after randomisation. INTERPRETATION Although the study was slightly underpowered, the results suggest that pausing BTKi around the time of vaccination is not beneficial for immunity and should not be recommended in clinical practice. FUNDING National Institute for Health and Care Research.
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Affiliation(s)
- Jonathan A Cook
- Oxford Clinical Trials Research Unit, University of Oxford, Oxford, UK
| | - Piers E M Patten
- Comprehensive Cancer Centre, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Nicholas Peckham
- Oxford Clinical Trials Research Unit, University of Oxford, Oxford, UK
| | - Paul Moss
- Department of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Neil Phillips
- Department of Haematology, University Hospitals of North Midlands NHS Trust, Stoke-on-Trent, UK
| | | | - Thomas Roberts
- Department of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Marie Hodges
- Department of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Georgina Talbot
- Department of Haematology, University Hospitals of North Midlands NHS Trust, Stoke-on-Trent, UK
| | - Vicki Barber
- Oxford Clinical Trials Research Unit, University of Oxford, Oxford, UK
| | - Anne Francis
- Oxford Clinical Trials Research Unit, University of Oxford, Oxford, UK
| | - Adrian M Shields
- Department of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | | | - Robbert Hoogeboom
- Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Brian J Willett
- MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, UK
| | - Sam Scott
- MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, UK
| | - Nilima Parry-Jones
- Department of Haematology, Aneurin Bevan University Health Board, Abergavenny, UK
| | - Toby A Eyre
- Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Churchill Cancer Centre, Oxford, UK
| | - Gareth Plested
- Oxford Clinical Trials Research Unit, University of Oxford, Oxford, UK
| | - Gratian Vandici
- Oxford Clinical Trials Research Unit, University of Oxford, Oxford, UK
| | - Farooq Ahmad Wandroo
- Department of Haematology, Sandwell and West Birmingham Hospitals, NHS Trust, West Bromwich, UK
| | - Claire Hutchinson
- Department of Haematology, University Hospitals Plymouth NHS Trust, Plymouth, UK
| | - Shankara Paneesha
- Department of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Duncan J Murray
- University Hospitals Coventry and Warwickshire, Coventry, UK
| | | | - Stephen Jenkins
- Department of Haematology, The Dudley Group NHS Foundation Trust, Dudley, UK
| | - Earnest Heartin
- Department of Haematology, Betsi Cadwaladr University Health Board, Bangor, UK
| | - Helen M Parry
- Department of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
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Zheng W, Wang S, Peng B, Gao X. A Population-Based Study of Infectious Diseases Mortality Risk in Patients With Hematologic Malignancies 2000-2020. Cancer Med 2025; 14:e70850. [PMID: 40167017 PMCID: PMC11959415 DOI: 10.1002/cam4.70850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 03/10/2025] [Accepted: 03/24/2025] [Indexed: 04/02/2025] Open
Abstract
BACKGROUND Patients with hematologic malignancies are at high risk of dying from infectious diseases. However, little attention has been paid to infectious diseases mortality (IDM) in these patients. The aim of our study is to determine the incidence and trends of IDM in patients with hematologic malignancies, identify risk factors associated with IDM, and compare the risk of IDM in patients with the general United States population. METHODS The data of patients with hematologic malignancies between 2000 and 2020 was retrieved from the Surveillance, Epidemiology, and End Results program. Standardized mortality ratios (SMRs) and IDM rates were calculated. A competing risk model was performed to identify potential risk factors of IDM. RESULTS Among 700,678 patients, 15,028 IDM were identified with an IDM rate of 401.31/100,000 person-years. Compared with the general population, the SMR of IDM was 3.34, and the elevated risk of IDM ran through the follow-up period. For all cancer subtypes, the IDM rates were highest in the first 2 months after diagnosis and gradually declined thereafter. For all patients, the early period of diagnosis, older age, male, non-Hispanic black, single or divorced/separated/widowed status, no chemotherapy, and no radiation were risk factors for IDM. For patients with Hodgkin lymphoma or non-Hodgkin lymphoma, advanced stage was also a risk factor for IDM. CONCLUSION Given the high risk of IDM in patients with hematologic malignancies, it is extremely important to identify patients at high risk of IDM and provide timely intervention to prevent early death from infections and improve prognosis.
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Affiliation(s)
- Wenshuai Zheng
- Department of HematologyHainan Hospital of Chinese PLA General HospitalSanyaHainanChina
| | - Shenyu Wang
- Senior Department of HematologyFifth Medical Center of Chinese PLA General HospitalBeijingChina
| | - Bo Peng
- Senior Department of HematologyFifth Medical Center of Chinese PLA General HospitalBeijingChina
| | - Xiaoning Gao
- Senior Department of HematologyFifth Medical Center of Chinese PLA General HospitalBeijingChina
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Medina Á, Muntañola A, Crespo M, Ramírez Á, Hernández-Rivas JÁ, Abrisqueta P, Alcoceba M, Delgado J, de la Serna J, Espinet B, González M, Loscertales J, Serrano A, Terol MJ, Yáñez L, Bosch F. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia and small lymphocytic lymphoma from Chronic Lymphocytic Leukemia Spanish Group (GELLC). Med Clin (Barc) 2025; 164:305-305.e17. [PMID: 39799061 DOI: 10.1016/j.medcli.2024.10.018] [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: 08/16/2024] [Revised: 10/28/2024] [Accepted: 10/30/2024] [Indexed: 01/15/2025]
Abstract
INTRODUCTION Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults in Western countries, with a median age at diagnosis of 72 years. This guide, developed by the Spanish Group for Chronic Lymphocytic Leukemia (GELLC), addresses the most relevant aspects of CLL, with the objectives of facilitating and aiding the diagnostic process, establishing therapeutic recommendations for choosing the best treatment for each type of patient, as well as standardizing the management of CLL and ensuring equity across different hospitals in terms of the use of the various available treatment regimens. METHODOLOGY The references obtained were classified according to the level of evidence and following the criteria established by the Agency for Health Research and Quality, and the recommendations were classified according to the criteria of the National Comprehensive Cancer Network (NCCN). DIAGNOSIS The diagnosis of CLL requires the presence of 5 × 109/l clonal B lymphocytes with the characteristic phenotype (CD19, CD5, CD20, CD23, and kappa or lambda chain restriction) demonstrated by flow cytometry in peripheral blood and maintained for at least 3 months. The presence of cytopenia caused by a typical bone marrow infiltrate establishes the diagnosis of CLL, regardless of the number of circulating lymphocytes or existing lymph node involvement. CLL and small lymphocytic lymphoma (SLL) are the same disease with different presentations, so they should be treated the same way. Current international guidelines recommend FISH with the 4 probes as a mandatory test in clinical practice to guide the prognosis of patients. They also recommend determining the mutational status of the immunoglobulin heavy chain variable region (IGHV) before the first treatment and detecting TP53 mutations before the first and subsequent relapses. TREATMENT Treatment should be initiated in symptomatic patients with criteria for active disease according to iwCLL. The first aspect to highlight is the prioritization of targeted therapies over immunochemotherapy. In first-line treatment, for patients with del(17p) and/or TP53 mutation, the best therapeutic option is a second-generation covalent Bruton's tyrosine kinase inhibitor (BTKi) administered indefinitely, while in cases without del(17p) or TP53 mutation with mutated IGHV, time-limited therapy with a combination including a BCL2 inhibitor (BCL2i) should be considered as the first therapeutic option. For patients with unmutated IGHV, both continuous BTKi and finite therapy with BCL2i are valid options that should be individually evaluated considering potential toxicities, drug interactions, patient preference, and logistical aspects. In very frail patients, supportive treatment should be considered. In relapse/refractory patients, prior treatment, the biological risk of CLL, the duration of response (if prior finite treatment), or the reason for stopping BTKi (if prior continuous treatment) should be considered.
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MESH Headings
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis
- Leukemia, Lymphocytic, Chronic, B-Cell/therapy
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
- Spain
- Aged
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Affiliation(s)
- Ángeles Medina
- Servicio de Hematología, Hospital Costa del Sol, Marbella, Málaga, España
| | - Ana Muntañola
- Servicio de Hematología, Hospital de la Santa Creu i Sant Pau, Barcelona, España
| | - Marta Crespo
- Servicio de Hematología, Hospital Universitario Vall d'Hebron, Barcelona, España
| | - Ángel Ramírez
- Servicio de Hematología, Hospital Universitario Central de Asturias, Oviedo, Asturias, España.
| | | | - Pau Abrisqueta
- Servicio de Hematología, Hospital Universitario Vall d'Hebron, Barcelona, España
| | - Miguel Alcoceba
- Servicio de Hematología, Hospital Universitario de Salamanca, Salamanca, España
| | - Julio Delgado
- Servicio de Hematología, Hospital Clínic, Barcelona, España
| | - Javier de la Serna
- Servicio de Hematología, Hospital Universitario 12 de Octubre, Madrid, España
| | - Blanca Espinet
- Servicio de Anatomía Patológica, Hospital del Mar, Barcelona, España
| | - Marcos González
- Servicio de Hematología, Hospital Universitario de Salamanca, Salamanca, España
| | - Javier Loscertales
- Servicio de Hematología, Hospital Universitario La Princesa, Madrid, España
| | - Alicia Serrano
- Servicio de Hematología, Hospital Clínico Universitario de Valencia, Valencia, España
| | - María José Terol
- Servicio de Hematología, Hospital Clínico Universitario de Valencia, Valencia, España
| | - Lucrecia Yáñez
- Servicio de Hematología, Hospital Universitario Marqués de Valdecilla, Santander, Cantabria, España
| | - Francesc Bosch
- Servicio de Hematología, Hospital Universitario Vall d'Hebron, Barcelona, España
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Gong E, Zawacki L, Fan X, Hippe DS, Menon AA, Remington AJ, Lachance K, Akaike T, Tachiki L, Park SY, Nghiem P. Immunotherapy response in immunosuppressed patients with Merkel cell carcinoma: analysis of 183 patients. BMJ ONCOLOGY 2025; 4:e000654. [PMID: 40099002 PMCID: PMC11911694 DOI: 10.1136/bmjonc-2024-000654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 02/07/2025] [Indexed: 03/19/2025]
Abstract
Objective Merkel cell carcinoma (MCC) is an aggressive skin cancer with poor outcomes in immunosuppressed patients. While immune checkpoint inhibitors (ICIs) achieve ~60% response rates in immunocompetent MCC patients, their efficacy in immunosuppressed patients remains unclear due to exclusion from trials. This study compares ICI outcomes, safety and the impact of immunosuppression subtypes between these groups. Methods and analysis This retrospective study analysed 183 advanced MCC patients on first-line ICIs from a Seattle-based data repository. Of these, 147 were immunocompetent, and 36 were immunosuppressed (chronic lymphocytic leukaemia (CLL) n=10, autoimmune disorders n=10, other haematologic malignancies n=9, solid organ transplants n=4 and HIV/AIDS n=3). Outcomes included objective response rate, disease progression, MCC-specific and overall survival probability, adjusted for age, sex and stage at ICI initiation. Results Initial ICI response rates at 6 months were 50% in immunosuppressed and 61.5% in immunocompetent patients (HR=0.71, p=0.17). Immunosuppressed patients had higher risks of disease progression (2 years: 53.9% vs 42.1%, HR=1.65, p=0.05) and MCC-specific mortality (2 years: 38.7% vs 24.4%, HR=1.85, p=0.04). CLL patients (n=10) had a particularly low response rate (response rate: 20.0% vs 61.5%, HR=0.18, p=0.02) and high progression risk (2 years: 80.0% vs 42.1%, HR=4.09, p=0.01). Immunosuppressed patients faced higher rates of ICI toxicity (6-month risk: 51.6% vs 36.6%, HR=1.79, p=0.03). Conclusions ICIs provide meaningful benefits to immunosuppressed MCC patients, though their response rates are lower, and progression risk is higher compared with immunocompetent patients.
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Affiliation(s)
- Emily Gong
- Department of Dermatology, University of Washington, Seattle, Washington, USA
| | - Lauren Zawacki
- Department of Dermatology, University of Washington, Seattle, Washington, USA
| | - Xinyi Fan
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Daniel S Hippe
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Ankita A Menon
- Department of Dermatology, University of Washington, Seattle, Washington, USA
| | - Allison J Remington
- Department of Dermatology, University of Washington, Seattle, Washington, USA
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Kristina Lachance
- Department of Dermatology, University of Washington, Seattle, Washington, USA
| | - Tomoko Akaike
- Department of Dermatology, University of Washington, Seattle, Washington, USA
| | - Lisa Tachiki
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Medicine, Division of Hematology/Oncology, University of Washington, Seattle, Washington, USA
| | - Song Y Park
- Department of Dermatology, University of Washington, Seattle, Washington, USA
| | - Paul Nghiem
- Department of Dermatology, University of Washington, Seattle, Washington, USA
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
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9
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Basile V, Allegra A, Marini HR, Berretta M, Granata B, Freni J, Puzzolo D, Stagno F, Midiri P, Urzì Brancati V, Minutoli L. Influence of Vitamin D and Its Analogues in Type-B Lymphomas. Curr Oncol 2025; 32:135. [PMID: 40136339 PMCID: PMC11941339 DOI: 10.3390/curroncol32030135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 02/19/2025] [Accepted: 02/24/2025] [Indexed: 03/27/2025] Open
Abstract
Lymphomas represent a heterogeneous group of blood tumors, generally divided into non-Hodgkin lymphoma (NHL) (90% of all lymphomas) and Hodgkin lymphoma (HL). High-grade NHL can rapidly progress so that new strategies and potentially therapeutical options are needed. Recently, it was shown that Vitamin D (VitD) inhibits the growth of cancer cells, controls their invasion and metastasis, and strengthens the antitumor activity of various types of chemotherapeutic anticancer agents. Therefore, we reviewed the recent literature about the influence of VitD and its analogues (VDAs) on the treatment and the prognosis of B-cell lymphomas. As to the in vitro studies in different cell lines, VitD3 and VDAs enhanced the anti-proliferative efficacy of various chemotherapeutics and increased the expression of VitD receptor. In in vivo studies, blood levels of VitD were considered: higher values of plasma bioavailable VitD were correlated with better progression-free survival (PFS) and overall survival (OS), while an unfavorable PFS and OS were observed in VitD deficient groups. No clinical trial was made on the analogs, thus confirming the absence of in vivo positive role of these synthetic drugs. In conclusion, higher levels of circulating VitD are related to improved OS, reduced cancer-specific mortality, and better disease-free survival. VitD and analogs showed also positive effects in in vitro studies, while only VitD was able to improve clinical parameters. Furthermore, a complex approach with plant-based diet, adequate levels for motor exercise, and/or eventual VitD supplementation could be a valuable strategy to challenge lymphomas.
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Affiliation(s)
- Valerio Basile
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (V.B.); (M.B.); (B.G.); (P.M.); (V.U.B.); (L.M.)
| | - Alessandro Allegra
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood, University of Messina, 98125 Messina, Italy; (A.A.); (F.S.)
| | - Herbert Ryan Marini
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (V.B.); (M.B.); (B.G.); (P.M.); (V.U.B.); (L.M.)
| | - Massimiliano Berretta
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (V.B.); (M.B.); (B.G.); (P.M.); (V.U.B.); (L.M.)
| | - Barbara Granata
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (V.B.); (M.B.); (B.G.); (P.M.); (V.U.B.); (L.M.)
| | - José Freni
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, 98125 Messina, Italy; (J.F.); (D.P.)
| | - Domenico Puzzolo
- Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, 98125 Messina, Italy; (J.F.); (D.P.)
| | - Fabio Stagno
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood, University of Messina, 98125 Messina, Italy; (A.A.); (F.S.)
| | - Paola Midiri
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (V.B.); (M.B.); (B.G.); (P.M.); (V.U.B.); (L.M.)
| | - Valentina Urzì Brancati
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (V.B.); (M.B.); (B.G.); (P.M.); (V.U.B.); (L.M.)
| | - Letteria Minutoli
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (V.B.); (M.B.); (B.G.); (P.M.); (V.U.B.); (L.M.)
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10
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Liang H, Cao Z, Ren Y, Li Y, Wang H, Sun F, Xue M, Zhu G, Zhou Y. Raman spectroscopy and bioinformatics-based identification of key genes and pathways capable of distinguishing between diffuse large B cell lymphoma and chronic lymphocytic leukemia. Front Immunol 2025; 16:1516946. [PMID: 40070829 PMCID: PMC11893875 DOI: 10.3389/fimmu.2025.1516946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Accepted: 02/10/2025] [Indexed: 03/14/2025] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL) are subtypes of non-Hogkin lymphoma (NHL) that are generally distinct form one cases, but the transformation of one of these diseases into the other is possible. Some patients with CLL, for instance, have the potential to develop Richter transformation such that they are diagnosed with a rare, invasive DLBCL subtype. In this study, bioinformatics analyses of these two NHL subtypes were conducted, identifying key patterns of gene expression and then experimentally validating the results. Disease-related gene expression datasets from the GEO database were used to identify differentially expressed genes (DEGs) and DEG functions were examined using GO analysis and protein-protein interaction network construction. This strategy revealed many up- and down-regulated DEGs, with functional enrichment analyses identifying these genes as being closely associated with inflammatory and immune response activity. PPI network analyses and the evaluation of clustered network modules indicated the top 10 up- and down-regulated genes involved in disease onset and development. Serological analyses revealed significantly higher ALB, TT, and WBC levels in CLL patients relative to DLBCL patients, whereas the opposite was true with respect to TG, HDL, GGT, ALP, ALT, and NEUT% levels. In comparison to the CLL and DLBCL groups, the healthy control samples demonstrated higher signals of protein peak positions (621, 643, 848, 853, 869, 935, 1003, 1031, 1221, 1230, 1260, 1344, 1443, 1446, 1548, 1579, 1603, 1647 cm-1), nucleic acid peak positions (726, 781, 786, 1078, 1190, 1415, 1573, 1579 cm-1), beta carotene peak positions (957, 1155, 1162 cm-1), carbohydrate peak positions (842 cm-1), collagen peak positions (1345 cm-1), and lipid peak positions (957, 1078, 1119, 1285, 1299, 1437, 1443, 1446 cm-1) compared to the CLL and DLBCL groups. Verification of these key genes in patient samples yielded results consistent with findings derived from bioinformatics analyses, highlighting their relevance to diagnosing and treating these forms of NHL. Together, these analyses identified genes and pathways involved in both DLBCL and CLL. The set of molecular markers established herein can aid in patient diagnosis and prognostic evaluation, providing a valuable foundation for their therapeutic application.
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MESH Headings
- Humans
- Lymphoma, Large B-Cell, Diffuse/genetics
- Lymphoma, Large B-Cell, Diffuse/diagnosis
- Lymphoma, Large B-Cell, Diffuse/metabolism
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis
- Leukemia, Lymphocytic, Chronic, B-Cell/metabolism
- Computational Biology/methods
- Protein Interaction Maps
- Gene Expression Profiling
- Diagnosis, Differential
- Biomarkers, Tumor/genetics
- Gene Regulatory Networks
- Gene Expression Regulation, Neoplastic
- Female
- Male
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Affiliation(s)
- Haoyue Liang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, China
| | - Zhijie Cao
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, China
| | - Yansong Ren
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, China
| | - Yihan Li
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, China
| | - Haoyu Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, China
| | - Fanfan Sun
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, China
| | - Mei Xue
- School of Medical Technology, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Guoqing Zhu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, China
| | - Yuan Zhou
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Institutes of Health Science, Tianjin, China
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11
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Ikeda D, Nunomura T, Muta T, Matsue K. Cause-Specific Mortality and Prognostic Impact of Comorbidity in Japanese Patients With Chronic Lymphocytic Leukemia. Cancer Med 2025; 14:e70613. [PMID: 39873172 PMCID: PMC11773378 DOI: 10.1002/cam4.70613] [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: 09/27/2024] [Revised: 12/24/2024] [Accepted: 01/04/2025] [Indexed: 01/30/2025] Open
Abstract
BACKGROUND Due to its rarity, there are very limited data available on the cause of death (COD) and its association with comorbidities in Japanese chronic lymphocytic leukemia (CLL) patients. METHODS To investigate the prevalence of comorbidities and their impact on cause-specific mortality, we retrospectively reviewed 121 Japanese patients with CLL. RESULTS The median age was 69 years, with 47.9% having at least one comorbidity listed in the Charlson Comorbidity Index (CCI), and 12.4% were multimorbid. With a median follow-up of 74 months, the 5- and 10-year overall survival rates were 80.6% and 60.1%, respectively. Among the 44 deaths observed, CLL progression was the leading COD (38.6%), which together with infections and other malignancies accounted for nearly 80%. Patients with higher CCI risk categories had significantly higher 5-year all-cause mortality (CCI 1-2: 22.9% and ≥ 3: 31.4%) and non-CLL-specific mortality (CCI 1-2: 18.8% and ≥ 3: 31.4%) compared to those without (CCI 0: 12.6%, p = 0.005; 3.5%, p < 0.001, respectively), whereas CLL-specific mortality was not influenced. On multivariate analysis, age and CCI retained a significant prognostic impact on all-cause mortality (hazard ratio [HR] 1.08, p < 0.001 and HR 1.88, p = 0.004, respectively) and non-CLL-specific mortality (HR 1.12, p < 0.001 and HR 3.81, p < 0.001, respectively). CONCLUSIONS Our study showed that CLL itself was the leading COD, and comorbidity burden was associated with non-CLL-specific deaths. This highlights the importance of better disease control and effective management of comorbidities.
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Affiliation(s)
- Daisuke Ikeda
- Division of Hematology/Oncology, Department of Internal MedicineKameda Medical CenterChibaJapan
| | - Takuya Nunomura
- Department of HematologyHiroshima Red Cross Hospital and Atomic‐Bomb Survivors HospitalHiroshimaJapan
| | - Tsuyoshi Muta
- Department of HematologyHiroshima Red Cross Hospital and Atomic‐Bomb Survivors HospitalHiroshimaJapan
| | - Kosei Matsue
- Division of Hematology/Oncology, Department of Internal MedicineKameda Medical CenterChibaJapan
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12
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Ferrer G, Palacios F, Chiu PY, Wong K, Bueno-Costa A, Barrientos JC, Kolitz JE, Allen SL, Rai KR, Chen SS, Sherry B, Chiorazzi N. CLL crosstalk with naïve T cells enhances the differentiation of IL-22-producing T cells and CLL -cell survival. Leukemia 2025; 39:499-502. [PMID: 39578533 PMCID: PMC11794130 DOI: 10.1038/s41375-024-02463-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 09/29/2024] [Accepted: 11/05/2024] [Indexed: 11/24/2024]
Affiliation(s)
- Gerardo Ferrer
- Karches Center for Oncology Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA.
- Cancer Epigenetics, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Spain.
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Madrid, Spain.
| | - Florencia Palacios
- Karches Center for Oncology Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
- Chronic Lymphocytic Leukemia laboratory Research, Institut Pasteur Montevideo, Montevideo, Uruguay
| | - Pui Yan Chiu
- Center for Immunology & Inflammation, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
| | - Kelly Wong
- Karches Center for Oncology Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
| | - Alberto Bueno-Costa
- Cancer Epigenetics, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Madrid, Spain
| | - Jacqueline C Barrientos
- Karches Center for Oncology Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
- Department of Medicine, Northwell Health, Manhasset and New Hyde Park, Manhasset, NY, USA
- Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, 11549, USA
| | - Jonathan E Kolitz
- Karches Center for Oncology Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
- Department of Medicine, Northwell Health, Manhasset and New Hyde Park, Manhasset, NY, USA
- Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, 11549, USA
| | - Steven L Allen
- Karches Center for Oncology Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
- Department of Medicine, Northwell Health, Manhasset and New Hyde Park, Manhasset, NY, USA
- Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, 11549, USA
| | - Kanti R Rai
- Karches Center for Oncology Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
- Department of Medicine, Northwell Health, Manhasset and New Hyde Park, Manhasset, NY, USA
- Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, 11549, USA
| | - Shih-Shih Chen
- Karches Center for Oncology Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
| | - Barbara Sherry
- Center for Immunology & Inflammation, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
- Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, 11549, USA
- Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, 11549, USA
| | - Nicholas Chiorazzi
- Karches Center for Oncology Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, 11030, USA
- Department of Medicine, Northwell Health, Manhasset and New Hyde Park, Manhasset, NY, USA
- Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, 11549, USA
- Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, 11549, USA
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13
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Solano F, Criado I, Moreno N, Gomez-Gonzalez C, Lerma-Verdejo A, Teodosio C, Martinez-Moya MD, Luts I, Contreras T, Oliva-Ariza G, Fuentes Herrero B, Serrano-Lozano JM, Almeida J, Orfao A. Normal Residual Lymphoid Cell Populations in Blood as Surrogate Biomarker of the Leukemia Cell Kinetics in CLL BinetA/Rai 0. Cancers (Basel) 2025; 17:347. [PMID: 39941719 PMCID: PMC11815973 DOI: 10.3390/cancers17030347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 01/15/2025] [Accepted: 01/17/2025] [Indexed: 02/16/2025] Open
Abstract
BACKGROUND/OBJECTIVES Despite the current international prognostic index for chronic lymphocytic leukemia (CLL) being widely accepted and broadly used, it does not consider the kinetics of the B-cell clone over time. Here, we investigated the potential association between distinct features of leukemic cells and other immune cells in blood and the kinetics of clonal B-cells in CLL stage Binet A/Rai 0 (A/0) patients; Methods: Based on the leukemia cell kinetics, 69 CLL A/0 cases followed for a median of 105 months were classified as carrying stable (n = 53) vs. rapidly increasing in size (n = 16) CLL clones; Results: Patients with increasing CLL clones had a significantly higher risk of disease progression and shortened time to first therapy vs. those carrying stable B-cell clones (p ≤ 0.001). Strikingly, the distribution of various immune-cell populations in blood at diagnosis also differed significantly between the two groups, with lower Tαβ CD4+CD8lo cell counts (p = 0.03), a greater switched/unswitched memory B-cell ratio (p = 0.01), and higher plasma cell counts (p = 0.05) in CLL with increasing vs. stable clones. Multivariate analysis revealed that the number of circulating clonal B-cells (≥15 × 109/L) and Tαβ CD4+CD8lo cells (≤35 cells/µL), together with an IGHV unmutated gene status at diagnosis, were independent predictors of an increasing CLL clone; Conclusions: Altogether, these data suggest that the expansion of the CLL clone in stage A/0 patients may depend on both the intrinsic characteristics of CLL cells and the surrounding immune microenvironment.
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Affiliation(s)
- Fernando Solano
- Hematology Service, Hospital General Universitario Nuestra Señora del Prado, 45600 Talavera de la Reina, Spain; (F.S.); (N.M.); (C.G.-G.); (A.L.-V.); (M.D.M.-M.); (I.L.)
| | - Ignacio Criado
- Translational and Clinical Research Program, Cancer Research Center (IBMCC, CSIC—University of Salamanca), 37007 Salamanca, Spain; (I.C.); (C.T.); (G.O.-A.); (B.F.H.); (J.M.S.-L.); (J.A.)
- Cytometry Service, NUCLEUS, Department of Medicine, University of Salamanca (Universidad de Salamanca), 37007 Salamanca, Spain
- Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain
- Biomedical Research Networking Centre Consortium of Oncology (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Nahir Moreno
- Hematology Service, Hospital General Universitario Nuestra Señora del Prado, 45600 Talavera de la Reina, Spain; (F.S.); (N.M.); (C.G.-G.); (A.L.-V.); (M.D.M.-M.); (I.L.)
| | - Carlos Gomez-Gonzalez
- Hematology Service, Hospital General Universitario Nuestra Señora del Prado, 45600 Talavera de la Reina, Spain; (F.S.); (N.M.); (C.G.-G.); (A.L.-V.); (M.D.M.-M.); (I.L.)
| | - Ana Lerma-Verdejo
- Hematology Service, Hospital General Universitario Nuestra Señora del Prado, 45600 Talavera de la Reina, Spain; (F.S.); (N.M.); (C.G.-G.); (A.L.-V.); (M.D.M.-M.); (I.L.)
| | - Cristina Teodosio
- Translational and Clinical Research Program, Cancer Research Center (IBMCC, CSIC—University of Salamanca), 37007 Salamanca, Spain; (I.C.); (C.T.); (G.O.-A.); (B.F.H.); (J.M.S.-L.); (J.A.)
- Cytometry Service, NUCLEUS, Department of Medicine, University of Salamanca (Universidad de Salamanca), 37007 Salamanca, Spain
- Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain
| | - María Dolores Martinez-Moya
- Hematology Service, Hospital General Universitario Nuestra Señora del Prado, 45600 Talavera de la Reina, Spain; (F.S.); (N.M.); (C.G.-G.); (A.L.-V.); (M.D.M.-M.); (I.L.)
| | - Iryna Luts
- Hematology Service, Hospital General Universitario Nuestra Señora del Prado, 45600 Talavera de la Reina, Spain; (F.S.); (N.M.); (C.G.-G.); (A.L.-V.); (M.D.M.-M.); (I.L.)
| | - Teresa Contreras
- Biochemistry Service, University Hospital of Salamanca, 37007 Salamanca, Spain;
| | - Guillermo Oliva-Ariza
- Translational and Clinical Research Program, Cancer Research Center (IBMCC, CSIC—University of Salamanca), 37007 Salamanca, Spain; (I.C.); (C.T.); (G.O.-A.); (B.F.H.); (J.M.S.-L.); (J.A.)
- Cytometry Service, NUCLEUS, Department of Medicine, University of Salamanca (Universidad de Salamanca), 37007 Salamanca, Spain
- Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Blanca Fuentes Herrero
- Translational and Clinical Research Program, Cancer Research Center (IBMCC, CSIC—University of Salamanca), 37007 Salamanca, Spain; (I.C.); (C.T.); (G.O.-A.); (B.F.H.); (J.M.S.-L.); (J.A.)
- Cytometry Service, NUCLEUS, Department of Medicine, University of Salamanca (Universidad de Salamanca), 37007 Salamanca, Spain
- Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Jose Manuel Serrano-Lozano
- Translational and Clinical Research Program, Cancer Research Center (IBMCC, CSIC—University of Salamanca), 37007 Salamanca, Spain; (I.C.); (C.T.); (G.O.-A.); (B.F.H.); (J.M.S.-L.); (J.A.)
- Cytometry Service, NUCLEUS, Department of Medicine, University of Salamanca (Universidad de Salamanca), 37007 Salamanca, Spain
- Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain
- Biomedical Research Networking Centre Consortium of Oncology (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Julia Almeida
- Translational and Clinical Research Program, Cancer Research Center (IBMCC, CSIC—University of Salamanca), 37007 Salamanca, Spain; (I.C.); (C.T.); (G.O.-A.); (B.F.H.); (J.M.S.-L.); (J.A.)
- Cytometry Service, NUCLEUS, Department of Medicine, University of Salamanca (Universidad de Salamanca), 37007 Salamanca, Spain
- Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain
- Biomedical Research Networking Centre Consortium of Oncology (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Alberto Orfao
- Translational and Clinical Research Program, Cancer Research Center (IBMCC, CSIC—University of Salamanca), 37007 Salamanca, Spain; (I.C.); (C.T.); (G.O.-A.); (B.F.H.); (J.M.S.-L.); (J.A.)
- Cytometry Service, NUCLEUS, Department of Medicine, University of Salamanca (Universidad de Salamanca), 37007 Salamanca, Spain
- Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain
- Biomedical Research Networking Centre Consortium of Oncology (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain
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14
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Kozarac S, Ivanovic J, Mitrovic M, Tomic Vujovic K, Arsenovic I, Suvajdzic-Vukovic N, Bogdanovic A, Vidovic A, Todorovic-Balint M, Bila J, Mitrovic M, Lekovic D, Djunic I, Virijevic M, Trivic A, Micic J, Antic D. Managing novel therapies and concomitant medications in chronic lymphocytic leukemia: key challenges. Front Pharmacol 2025; 15:1517972. [PMID: 39830358 PMCID: PMC11739332 DOI: 10.3389/fphar.2024.1517972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Accepted: 12/10/2024] [Indexed: 01/22/2025] Open
Abstract
The treatment of chronic lymphocytic leukemia (CLL) consists of the continuous use of Bruton tyrosine kinase inhibitors (BTKis) such as ibrutinib, acalabrutinib, zanubrutinib and pirtobrutinib, or Bcl-2 inhibitors, such as venetoclax. Overall survival (OS) and progression-free survival (PFS) of CLL patients are significantly improved with the use of these therapies. Adverse effects (AEs) that can occur during treatment and the presence of pre-existing comorbidities in patients can influence subsequent treatment outcomes and, consequently, OS and PFS. Managing these AEs, including cardiologic toxicity and infections (including fungal infections), as well as treating cardiovascular and other comorbidities, can be challenging due to potential drug interactions with the medications used for the management of AEs and comorbidities. Therefore, this review examined the key challenges associated with the concomitant use of novel CLL therapies and medications for managing comorbidities and AEs. This review aims to enhance and facilitate the management of patients with CLL.
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Affiliation(s)
- Sofija Kozarac
- Clinic of Hematology, University Clinical Centre of Serbia, Belgrade, Serbia
| | - Jelena Ivanovic
- Clinic of Hematology, University Clinical Centre of Serbia, Belgrade, Serbia
| | - Marko Mitrovic
- Clinic of Hematology, University Clinical Centre of Serbia, Belgrade, Serbia
| | | | - Isidora Arsenovic
- Clinic of Hematology, University Clinical Centre of Serbia, Belgrade, Serbia
| | - Nada Suvajdzic-Vukovic
- Clinic of Hematology, University Clinical Centre of Serbia, Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Andrija Bogdanovic
- Clinic of Hematology, University Clinical Centre of Serbia, Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Ana Vidovic
- Clinic of Hematology, University Clinical Centre of Serbia, Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Milena Todorovic-Balint
- Clinic of Hematology, University Clinical Centre of Serbia, Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Jelena Bila
- Clinic of Hematology, University Clinical Centre of Serbia, Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Mirjana Mitrovic
- Clinic of Hematology, University Clinical Centre of Serbia, Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Danijela Lekovic
- Clinic of Hematology, University Clinical Centre of Serbia, Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Irena Djunic
- Clinic of Hematology, University Clinical Centre of Serbia, Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Marijana Virijevic
- Clinic of Hematology, University Clinical Centre of Serbia, Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Aleksandar Trivic
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
- Clinic for Otorhinolaryngology and Maxillofacial Surgery, University Clinical Centre of Serbia, Belgrade, Serbia
| | - Jelena Micic
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
- Clinic for Obstetrics and Gynecology, University Clinical Centre of Serbia, Belgrade, Serbia
| | - Darko Antic
- Clinic of Hematology, University Clinical Centre of Serbia, Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
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15
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Molica S, Allsup D. Chronic Lymphocytic Leukemia Care and Beyond: Navigating the Needs of Long-Term Survivors. Cancers (Basel) 2025; 17:119. [PMID: 39796746 PMCID: PMC11720366 DOI: 10.3390/cancers17010119] [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: 12/04/2024] [Revised: 12/20/2024] [Accepted: 12/31/2024] [Indexed: 01/13/2025] Open
Abstract
Chronic lymphocytic leukemia (CLL) treatment has undergone a significant evolution with a shift from historical chemotherapeutic regimens to targeted therapies such as Bruton tyrosine kinase (BTK) and BCL-2 inhibitors. These advancements have been associated with a notable improvement in survival rates with a transformation of CLL into a chronic and manageable condition for most persons with this disease. However, as a consequence of improved outcomes, long-term CLL survivors now face emergent challenges which include a risk of infections, cardiovascular complications, and secondary malignancies. In this changed scenario, holistic models of care are essential to address emergent health risks. Such models of care for CLL patients require a multidisciplinary approach that integrates CLL treatment with the proactive management of frailty, comorbidities, and psychosocial well-being to enhance both survival and quality of life (QoL). CLL predominantly affects older persons, many of whom present with concurrent frailty and comorbidities that may complicate CLL treatment and impact QoL. Comprehensive geriatric assessments (GA) may play a critical role in the identification of persons at a heightened risk of treatment-related toxicity and may help guide rational therapy selection, particularly in very frail persons. In addition to the assessment of hematological responses, the prospective assessment of patient-reported outcomes (PROs) and frailty metrics may offer a more nuanced understanding of the global treatment benefits. A survivorship-focused care model is crucial to address the multifaceted needs of CLL patients with the extension of patient care into the broader domain of long-term health maintenance with associated improvements in QoL.
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Affiliation(s)
- Stefano Molica
- Department of Hematology, Hull University Teaching Hospitals NHS Trust, Hull HU3 2JZ, UK;
| | - David Allsup
- Department of Hematology, Hull University Teaching Hospitals NHS Trust, Hull HU3 2JZ, UK;
- Centre for Biomedicine, Hull York Medical School, University of Hull, Hull HU6 7RX, UK
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16
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D’Arena G, Palladino C, Bosco M, Gambardella M. West Nile Virus Encephalitis in a Patient with Chronic Lymphocytic Leukemia. Mediterr J Hematol Infect Dis 2025; 17:e2025010. [PMID: 39830796 PMCID: PMC11740906 DOI: 10.4084/mjhid.2025.010] [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: 12/11/2024] [Accepted: 12/19/2024] [Indexed: 01/22/2025] Open
Affiliation(s)
- Giovanni D’Arena
- Immunohematology and Transfusional Medicine Unit, “San Luca” Hospital, Vallo della Lucania, Italy
| | - Carmela Palladino
- Immunohematology and Transfusional Medicine Unit, “San Luca” Hospital, Vallo della Lucania, Italy
| | - Michele Bosco
- Intensive Cure Unit, “San Luca” Hospital, Vallo della Lucania, Italy
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17
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Prajapati AK, Venate P, Monika T, Huddar VG. Effect of Ayurveda and Siddha interventions in the management of chronic lymphocytic leukemia: A case report. J Ayurveda Integr Med 2025; 16:101017. [PMID: 39673829 PMCID: PMC11699455 DOI: 10.1016/j.jaim.2024.101017] [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: 05/28/2023] [Revised: 06/13/2024] [Accepted: 06/17/2024] [Indexed: 12/16/2024] Open
Abstract
Chronic Lymphocytic Leukemia (CLL) is a hematological malignancy marked by the clonal proliferation of the mature, yet dysfunctional B lymphocytes in blood and its subsequent infiltration of the marrow, lymphoid tissues and spleen. The resultant immune dysfunction exposes the body to multiple infections and is a cause of major mortality. Here, we discuss the case of a 46-year-old male suffering from CLL who presented with long-standing episodes of low-grade fever, productive cough and throat irritation, lethargy and pedal edema. He was treatment-naïve at the time of presentation. He was treated in lines of Rajayakshma as per Ayurveda, and Kuruthiputru as per Siddha medicine. After three years of treatment with continued follow up till date, comprising of Shamana Chikitsa (Ayurveda and Siddha internal medications), Sodhana (bio purificatory methods)through Mridu Virechana (therapeutic purgation) using Trivrut Avaleha 35g, Guduchi Rasayana (Tinospora cordifolia) and Yashtimadhu Rasayana(Glycyrrhiza glabra), patient reported reduction in frequency of infections, improved performance score with a mean reduction in TLC counts by 100 thousand/cu. mm in 10 months starting intervention. Presently the patient is stable with occasional episodes of dry cough and generalized weakness. Integrated practices involving Ayurveda and Siddha medicines may be beneficial to patients suffering from CLL by reducing the episodes of infections, improving the quality of life while pacifying the deranged hematological parameters to certain extent.
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Affiliation(s)
- Abhay Kumar Prajapati
- Department of Kayachikitsa, All India Institute of Ayurveda, New Delhi, 110076, India
| | - Parvathy Venate
- Department of Kayachikitsa, All India Institute of Ayurveda, New Delhi, 110076, India
| | - T Monika
- National Institute of Siddha Chennai, Tamil Nadu, 600047, India
| | - V G Huddar
- Department of Kayachikitsa, All India Institute of Ayurveda, New Delhi, 110076, India.
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18
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Koehler AB, Rabe KG, Crusan DJ, Call TG, Achenbach SJ, Hampel PJ, Kenderian SS, Leis JF, Wang Y, Muchtar E, Tsang M, Hilal T, Parrondo R, Bailey KR, Ding W, Bailen R, Schwager SM, Shi M, Hanson CA, Slager SL, Kay NE, Ashrani AA, Parikh SA. Incidence, risk factors, and outcomes of patients with monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia who develop venous thromboembolism. J Thromb Haemost 2025; 23:149-157. [PMID: 39343103 DOI: 10.1016/j.jtha.2024.08.029] [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: 03/26/2024] [Revised: 07/05/2024] [Accepted: 08/19/2024] [Indexed: 10/01/2024]
Abstract
BACKGROUND The incidence, risk factors, and outcomes of venous thromboembolism (VTE) in patients with chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL) are not well described. OBJECTIVES We aimed to determine the clinical characteristics, risk factors, and outcomes of incident VTE in patients with newly diagnosed MBL/CLL and compare the incidence to the age- and sex-matched general population. METHODS Using the Mayo Clinic CLL Database, we identified 946 patients with newly diagnosed MBL/CLL between 1998 and 2021. Incidence of VTE was identified by querying the electronic health record for VTE-specific International Classification of Diseases-9 and -10 codes and reviewing results of radiographic studies. RESULTS Eighty patients developed VTE. The incidence of VTE in patients with newly diagnosed MBL/CLL was ∼1% per year. In multivariable analyses, prior history of VTE (hazard ratio [HR]: 5.33; 95% CI: 1.93-14.68, P = .001) and high/very high-risk CLL-International Prognostic Index score (HR: 2.63; 95% CI: 1.31-5.26; P = .006) were associated with an increased risk of VTE; receipt of CLL treatment or occurrence of nonhematologic malignancy was not. Development of VTE was associated with shorter overall survival (HR: 1.82, 95% CI: 1.30-2.55) after adjusting for age, sex, prior history of VTE, and Rai stage. The age- and sex-adjusted VTE incidence rate for patients with MBL/CLL and no prior history of VTE (n = 904) was 1254 per 100 000 person-years compared with 204 per 100 000 person-years in the general population, reflecting a 5.9-fold increase. CONCLUSION Our study demonstrates a 6-fold increased risk of VTE in patients with MBL/CLL compared with the age- and sex-matched general population.
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MESH Headings
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell/epidemiology
- Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis
- Leukemia, Lymphocytic, Chronic, B-Cell/mortality
- Leukemia, Lymphocytic, Chronic, B-Cell/therapy
- Female
- Male
- Incidence
- Venous Thromboembolism/epidemiology
- Venous Thromboembolism/diagnosis
- Venous Thromboembolism/mortality
- Risk Factors
- Middle Aged
- Aged
- Lymphocytosis/epidemiology
- Lymphocytosis/diagnosis
- Lymphocytosis/mortality
- Risk Assessment
- Aged, 80 and over
- Retrospective Studies
- Databases, Factual
- B-Lymphocytes/pathology
- Adult
- Prognosis
- Time Factors
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Affiliation(s)
- Amber B Koehler
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA. https://twitter.com/hemepa_c
| | - Kari G Rabe
- Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA
| | - Daniel J Crusan
- Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA
| | - Timothy G Call
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Sara J Achenbach
- Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA
| | - Paul J Hampel
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Saad S Kenderian
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Jose F Leis
- Division of Hematology and Oncology, Mayo Clinic, Phoenix, Arizona, USA
| | - Yucai Wang
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Eli Muchtar
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Mazie Tsang
- Division of Hematology and Oncology, Mayo Clinic, Phoenix, Arizona, USA
| | - Talal Hilal
- Division of Hematology and Oncology, Mayo Clinic, Phoenix, Arizona, USA
| | - Ricardo Parrondo
- Department of Hematology and Oncology, Mayo Clinic, Jacksonville, Florida, USA
| | - Kent R Bailey
- Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA
| | - Wei Ding
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Rachel Bailen
- Department of Pharmacy, Mayo Clinic, Rochester, Minnesota, USA
| | - Susan M Schwager
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Min Shi
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Curtis A Hanson
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Susan L Slager
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA; Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA
| | - Neil E Kay
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA; Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA
| | - Aneel A Ashrani
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
| | - Sameer A Parikh
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
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19
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Kontandreopoulou CN, Solomou EE, Kolorizos E, Diamantopoulos PT. Vaccine challenges in CLL: a comprehensive exploration of efficacy of SARS-CoV-2 immunization for patients with chronic lymphocytic leukemia. Ann Hematol 2024; 103:4971-4980. [PMID: 39008060 DOI: 10.1007/s00277-024-05869-8] [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: 06/04/2024] [Accepted: 06/26/2024] [Indexed: 07/16/2024]
Abstract
Chronic lymphocytic leukemia (CLL) is characterized by disease- and treatment-related immunosuppression. Patients with CLL comprise a vulnerable population to coronavirus disease 2019 (COVID-19), while the protective effect of COVID-19 vaccination remains uncertain.We conducted a systematic review to evaluate published data reporting response to COVID-19 vaccination in patients with CLL. The primary outcome was the rate of seropositivity after full primary vaccination, while secondary outcomes were rates of positive neutralizing antibodies, cellular responses, and adverse events. Response after booster doses of vaccination was also evaluated.Twenty-three studies of full primary vaccination (12 CLL-specific with 1747 patients, 11 with mixed hematologic diseases including 1044 patients with CLL) with a total of 2791 patients, and eight studies on booster doses with 389 patients were included in the analysis. The serologic response varied between studies with a median of 55%. Where reported, the median neutralizing antibody response rate was 61.2% and the cellular response rate was 44.2%. Poor serologic response was noted in patients under active treatment with anti-CD20 monoclonal antibodies, BCL2, and BTK inhibitors.The present review highlights the substantially impaired humoral and cellular response to COVID-19 vaccination in patients with CLL with patients under active treatment being the most vulnerable.
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Affiliation(s)
- Christina-Nefeli Kontandreopoulou
- Hematology Unit, First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Elena E Solomou
- Department of Internal Medicine, University of Patras Medical School, Rion, Greece.
| | - Epaminondas Kolorizos
- Hematology Unit, First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis T Diamantopoulos
- Hematology Unit, First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
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20
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Zhu H, Lu X, Zhang X, Hua H, Zhang J, Miao Y, Gu W, Xu M, Lu X, Li B, Wang C, Ni H, Qian J, Shi J, Xu M, Wu G, Zhang Y, Shen Q, Wang Z, Zhu J, Cheng Z, Zhuang W, Lin G, Hu Y, Shan Q, Chen Y, Qiu H, Li J, Shi W. Multi-center study of COVID-19 infection in elderly patients with lymphoma: on behalf of Jiangsu Cooperative Lymphoma Group (JCLG). Ann Hematol 2024; 103:5713-5727. [PMID: 38649594 DOI: 10.1007/s00277-024-05744-6] [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: 12/13/2023] [Accepted: 04/03/2024] [Indexed: 04/25/2024]
Abstract
Elderly patients with lymphoproliferative diseases (LPD) are vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we retrospectively described the clinical features and outcomes of the first time infection of Omicron SARS-CoV-2 in 364 elderly patients with lymphoma enrolled in Jiangsu Cooperative Lymphoma Group (JCLG) between November 2022 and April 2023 in China. Median age was 69 years (range 60-92). 54.4% (198/364) of patients were confirmed as severe and critical COVID-19 infection. In univariable analysis, Age > 70 years (OR 1.88, p = 0.003), with multiple comorbidities (OR 1.41, p = 0.005), aggressive lymphoma (OR 2.33, p < 0.001), active disease (progressive or relapsed/refractory, OR 2.02, p < 0.001), and active anti-lymphoma therapy (OR 1.90, p < 0.001) were associated with severe COVID-19. Multiple (three or more) lines of previous anti-lymphoma therapy (OR 3.84, p = 0.021) remained an adverse factor for severe COVID-19 in multivariable analysis. Moreover, CD20 antibody (Rituximab or Obinutuzumab)-based treatments within the last 6 months was associated with severe COVID-19 in the entire cohort (OR 3.42, p < 0.001). Continuous BTK inhibitors might be protective effect on the outcome of COVID-19 infection (OR 0.44, p = 0.043) in the indolent lymphoma cohort. Overall, 7.7% (28/364) of the patients ceased, multiple lines of previous anti-lymphoma therapy (OR 3.46, p = 0.016) remained an adverse factor for mortality.
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Affiliation(s)
- Huayuan Zhu
- Department of Hematology, Lymphoma Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
- Jiangsu Cooperative Lymphoma Group (JCLG), Nanjing, China.
| | - Xiao Lu
- Department of Hematology, Lymphoma Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Jiangsu Cooperative Lymphoma Group (JCLG), Nanjing, China
| | - Xiaoping Zhang
- Department of Hematology, The Affiliated Zhongda Hospital of Southeast University Medical College, Nanjing, 210044, China
- Jiangsu Cooperative Lymphoma Group (JCLG), Nanjing, China
| | - Haiying Hua
- Department of Hematology, Wuxi Third People's Hospital, Wuxi, 214045, China
- Jiangsu Cooperative Lymphoma Group (JCLG), Nanjing, China
| | - Jie Zhang
- Department of Oncology, Affiliated Hospital of Nantong University, Nantong, 226001, China
- Jiangsu Cooperative Lymphoma Group (JCLG), Nanjing, China
| | - Yuqing Miao
- Department of Hematology, Yancheng First People's Hospital, Yancheng, 224006, China
- Jiangsu Cooperative Lymphoma Group (JCLG), Nanjing, China
| | - Weiying Gu
- Department of Hematology, The First People's Hospital of Changzhou and The Third Affiliated Hospital of Soochow University, Changzhou, 213004, China
- Jiangsu Cooperative Lymphoma Group (JCLG), Nanjing, China
| | - Min Xu
- Department of Hematology, Zhangjiagang First Affiliated Hospital of Soochow University, Zhangjiagang, 215699, China
- Jiangsu Cooperative Lymphoma Group (JCLG), Nanjing, China
| | - Xuzhang Lu
- Department of Hematology, Affiliated Changzhou Second Hospital of Nanjing Medical University, Changzhou, 213004, China
- Jiangsu Cooperative Lymphoma Group (JCLG), Nanjing, China
| | - Bingzong Li
- Department of Hematology, the Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
- Jiangsu Cooperative Lymphoma Group (JCLG), Nanjing, China
| | - Chunling Wang
- Department of Hematology, The First People's Hospital of Huai'an, Huai'an, 223399, China
- Jiangsu Cooperative Lymphoma Group (JCLG), Nanjing, China
| | - Haiwen Ni
- Department of Hematology, The Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, 210004, China
- Jiangsu Cooperative Lymphoma Group (JCLG), Nanjing, China
| | - Jun Qian
- Department of Hematology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, 212002, China
- Jiangsu Cooperative Lymphoma Group (JCLG), Nanjing, China
| | - Jinning Shi
- Department of Hematology, the Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, 211199, China
- Jiangsu Cooperative Lymphoma Group (JCLG), Nanjing, China
| | - Maozhong Xu
- Department of Hematology, The Affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin, 214433, China
- Jiangsu Cooperative Lymphoma Group (JCLG), Nanjing, China
| | - Guangqi Wu
- Department of Hematology, The First People's Hospital of Suqian, Suqian, 223812, China
- Jiangsu Cooperative Lymphoma Group (JCLG), Nanjing, China
| | - Yunping Zhang
- Department of Hematology, The Affiliated Yixing Hospital of Jiangsu University, Yixing, 214206, China
- Jiangsu Cooperative Lymphoma Group (JCLG), Nanjing, China
| | - Qiudan Shen
- Department of Hematology, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, 215008, China
- Jiangsu Cooperative Lymphoma Group (JCLG), Nanjing, China
| | - Zhi Wang
- Department of Hematology, Wuxi Second People's Hospital, Wuxi, 214001, China
- Jiangsu Cooperative Lymphoma Group (JCLG), Nanjing, China
| | - Jianfeng Zhu
- Department of Hematology, The People's Hospital of Taizhou, Taizhou, 225399, China
- Jiangsu Cooperative Lymphoma Group (JCLG), Nanjing, China
| | - Zhen Cheng
- Department of Hematology, Taicang Hospital Affiliated to Soochow University, Taicang, 215488, China
- Jiangsu Cooperative Lymphoma Group (JCLG), Nanjing, China
| | - Wanchuan Zhuang
- Department of Hematology, The Second People's Hospital of Lianyungang, Lianyungang, 222002, China
- Jiangsu Cooperative Lymphoma Group (JCLG), Nanjing, China
| | - Guoqiang Lin
- Department of Hematology, Huai'an Hospital Affiliated to Xuzhou Medical College and Huai'an Second People's Hospital, Huai'an, 223022, China
- Jiangsu Cooperative Lymphoma Group (JCLG), Nanjing, China
| | - Yongjun Hu
- Department of Hematology, Huaiyin Hospital of Huai'an, Huai'an, 223399, China
- Jiangsu Cooperative Lymphoma Group (JCLG), Nanjing, China
| | - Qiurong Shan
- Department of Hematology, Shuyang Traditional Chinese Medicine Hospital, Shuyang, 223614, China
- Jiangsu Cooperative Lymphoma Group (JCLG), Nanjing, China
| | - Yifei Chen
- Department of Hematology, Jiangdu People's Hospital of Yangzhou, Yangzhou, 225202, China
- Jiangsu Cooperative Lymphoma Group (JCLG), Nanjing, China
| | - Hongchun Qiu
- Department of Hematology, The Third People's Hospital of Kunshan, Kunshan, 215316, China
- Jiangsu Cooperative Lymphoma Group (JCLG), Nanjing, China
| | - Jianyong Li
- Department of Hematology, Lymphoma Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
- Jiangsu Cooperative Lymphoma Group (JCLG), Nanjing, China.
| | - Wenyu Shi
- Department of Oncology, Affiliated Hospital of Nantong University, Nantong, 226001, China.
- Department of Hematology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu, China.
- Jiangsu Cooperative Lymphoma Group (JCLG), Nanjing, China.
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21
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Fallin T, Thacker E, Sahra S, Siegrist EA, White BP, Summers K, Shibib D, Sassine J. CNS Aspergillosis and Cryptococcosis with Cytomegalovirus Pneumonia in a Patient with Chronic Lymphocytic Leukemia Treated with Acalabrutinib. J Pharm Pract 2024; 37:1391-1395. [PMID: 38621678 DOI: 10.1177/08971900241247660] [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: 04/17/2024]
Abstract
Bruton's tyrosine kinase inhibitors (BTKis) are the preferred treatment for chronic lymphocytic leukemia (CLL). Despite their therapeutic benefits, these targeted agents have been associated with an increased risk of invasive infections. We describe a 68-year-old male who developed multiple bacterial, fungal and viral infections while on treatment with acalabrutinib. To our knowledge, this is the first reported case of concomitant CNS infections with Cryptococcus neoformans and Aspergillus fumigatus, along with cytomegalovirus (CMV) and herpes simplex virus type 1 (HSV-1) pneumonia while on acalabrutinib. This case adds to the scarce literature of fungal and bacterial infections associated with acalabrutinib, raising the suspicion that infection risk is a medication class effect for BTKis.
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Affiliation(s)
- Taylor Fallin
- Department of Pharmacy, Clinical and Administrative Sciences, OU Health, University of Oklahoma College of Pharmacy, Oklahoma City, OK, USA
| | - Erica Thacker
- Department of Pharmacy, Clinical and Administrative Sciences, OU Health, University of Oklahoma College of Pharmacy, Oklahoma City, OK, USA
| | - Syeda Sahra
- Infectious Diseases Section, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Emily A Siegrist
- Department of Pharmacy, Clinical Infectious Diseases, OU Health, Oklahoma City, OK, USA
| | - Bryan P White
- Department of Pharmacy, Clinical Infectious Diseases, OU Health, Oklahoma City, OK, USA
| | - Katherine Summers
- Department of Pharmacy, Critical Care, OU Health, Oklahoma City, OK, USA
| | - Dena Shibib
- Department of Pathology, Microbiology and Virology Laboratories, OU Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Joseph Sassine
- Infectious Diseases Section, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
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22
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Zheng J, Liu S, Yang J, Zheng S, Sun B. Per- and polyfluoroalkyl substances (PFAS) and cancer: Detection methodologies, epidemiological insights, potential carcinogenic mechanisms, and future perspectives. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 953:176158. [PMID: 39255941 DOI: 10.1016/j.scitotenv.2024.176158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Revised: 08/01/2024] [Accepted: 09/07/2024] [Indexed: 09/12/2024]
Abstract
Per- and polyfluoroalkyl substances (PFAS), known as "forever chemicals," are synthetic chemicals which have been used since the 1940s. Given their remarkable thermostability and chemical stability, PFAS have been widely utilized in commercial products, including textiles, surfactants, food packages, nonstick coatings, and fire-fighting foams. Thus, PFAS are widely distributed worldwide and have been detected in human urine, blood, breast milk, tissues and other substances. Growing concerns over the risks of PFAS, including their toxicity and carcinogenicity, have attracted people's attention. Recent reviews have predominantly emphasized advancements in the detection, adsorption, and degradation of PFAS through their chemical structures and toxic properties; however, further examination of the literature is needed to determine the link between PFAS exposure and cancer risk. Here, we introduced different PFAS detection methods based on sensors and liquid chromatography-mass spectrometry (LC-MS). Then, we discussed epidemiological investigations on PFAS levels and cancer risks in recent years, as well as the mechanisms underlying the carcinogenesis. Finally, we proposed the "4C principles" for ongoing exploration and refinement in this field. This review highlights PFAS-cancer associations to fill knowledge gaps and provide evidence-based strategies for future research.
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Affiliation(s)
- Jie Zheng
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520, USA
| | - Sheng Liu
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT 06510, USA
| | - Junjie Yang
- Department of Chemistry, Washington University, St. Louis, MO 63130, USA
| | - Shujian Zheng
- Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
| | - Boshi Sun
- Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China; Division of Surgical Oncology, Department of Surgery, Yale School of Medicine, New Haven, CT 06510, USA.
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23
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Derigs P, Schubert ML, Dreger P, Schmitt A, Yousefian S, Haas S, Röthemeier C, Neuber B, Hückelhoven-Krauss A, Brüggemann M, Bernhard H, Kobbe G, Lindemann A, Rummel M, Michels B, Korell F, Ho AD, Müller-Tidow C, Schmitt M. Third-generation anti-CD19 CAR T cells for relapsed/refractory chronic lymphocytic leukemia: a phase 1/2 study. Leukemia 2024; 38:2419-2428. [PMID: 39192036 PMCID: PMC11519001 DOI: 10.1038/s41375-024-02392-7] [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: 06/23/2024] [Revised: 08/15/2024] [Accepted: 08/19/2024] [Indexed: 08/29/2024]
Abstract
Third-generation chimeric antigen receptor T cells (CARTs) for relapsed or refractory (r/r) chronic lymphocytic leukemia (CLL) may improve efficacy compared to second-generation CARTs due to their enhanced CAR design. We performed the first phase 1/2 investigator-initiated trial evaluating escalating doses of third-generation CARTs (HD-CAR-1) targeting CD19 in patients with r/r CLL and B-cell lymphoma. CLL eligibility criteria were failure to two therapy lines including at least one pathway inhibitor and/or allogeneic hematopoietic cell transplantation. Nine heavily pretreated patients received HD-CAR-1 at dose levels ranging from 1 × 106 to 200 × 106 CART/m2. In-house HD-CAR-1 manufacturing was successful for all patients. While neurotoxicity was absent, one case of grade 3 cytokine release syndrome was observed. By day 90, six patients (67%) attained a CR, five of these (83%) with undetectable MRD. With a median follow-up of 27 months, 2-year PFS and OS were 30% and 69%, respectively. HD-CAR-1 products of responders contained significantly more CD4 + T cells compared to non-responders. In non-responders, a strong enrichment of effector memory-like CD8 + T cells with high expression of CD39 and/or CD197 was observed. HD-CAR-1 demonstrated encouraging efficacy and exceptionally low treatment-specific toxicity, presenting new treatment options for patients with r/r CLL. Trial registration: #NCT03676504.
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MESH Headings
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell/therapy
- Leukemia, Lymphocytic, Chronic, B-Cell/immunology
- Male
- Immunotherapy, Adoptive/methods
- Immunotherapy, Adoptive/adverse effects
- Antigens, CD19/immunology
- Middle Aged
- Female
- Aged
- Receptors, Chimeric Antigen/immunology
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/immunology
- Neoplasm Recurrence, Local/therapy
- Adult
- Follow-Up Studies
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Affiliation(s)
- Patrick Derigs
- Internal Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany.
| | - Maria-Luisa Schubert
- Internal Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany
| | - Peter Dreger
- Internal Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany
| | - Anita Schmitt
- Internal Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany
| | - Schayan Yousefian
- Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine, Berlin, Germany
| | - Simon Haas
- Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine, Berlin, Germany
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ)/National Center for Tumor Diseases (NCT), Heidelberg, Germany
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany
- Precision Healthcare University Research Institute, Queen Mary University of London, London, UK
| | - Caroline Röthemeier
- Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine, Berlin, Germany
| | - Brigitte Neuber
- Internal Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany
| | - Angela Hückelhoven-Krauss
- Internal Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany
| | - Monika Brüggemann
- Department of Internal Medicine II, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Helga Bernhard
- Department of Internal Medicine V, Klinikum Darmstadt, Darmstadt, Germany
| | - Guido Kobbe
- Department of Hematology, Oncology and Clinical Immunology, University Hospital Düsseldorf, Düsseldorf, Germany
| | | | - Mathias Rummel
- Department of Internal Medicine IV, University Hospital Giessen, Giessen, Germany
| | - Birgit Michels
- Internal Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany
| | - Felix Korell
- Internal Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany
| | - Anthony D Ho
- Internal Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ)/National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Carsten Müller-Tidow
- Internal Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ)/National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Michael Schmitt
- Internal Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany
- German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ)/National Center for Tumor Diseases (NCT), Heidelberg, Germany
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24
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Zhang R, Khare P, Banerjee P, Ivan C, Schneider S, Barbaglio F, Clise-Dwyer K, Jensen VB, Thompson E, Mendoza M, Chiorazzi N, Chen SS, Yan XJJ, Jain N, Ghia P, Caligaris-Cappio F, Mendonsa R, Kasimsetty S, Swoboda R, Bayraktar R, Wierda W, Gandhi V, Calin GA, Keating MJ, Bertilaccio MTS. The DLEU2/miR-15a/miR-16-1 cluster shapes the immune microenvironment of chronic lymphocytic leukemia. Blood Cancer J 2024; 14:168. [PMID: 39438453 PMCID: PMC11496494 DOI: 10.1038/s41408-024-01142-3] [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: 06/19/2024] [Revised: 09/03/2024] [Accepted: 09/05/2024] [Indexed: 10/25/2024] Open
Abstract
The development and progression of chronic lymphocytic leukemia (CLL) depend on genetic abnormalities and on the immunosuppressive microenvironment. We have explored the possibility that genetic drivers might be responsible for the immune cell dysregulation that shapes the protumor microenvironment. We performed a transcriptome analysis of coding and non-coding RNAs (ncRNAs) during leukemia progression in the Rag2-/-γc-/- MEC1-based xenotransplantation model. The DLEU2/miR-16 locus was found downmodulated in monocytes/macrophages of leukemic mice. To validate the role of this cluster in the tumor immune microenvironment, we generated a mouse model that simultaneously mimics the overexpression of hTCL1 and the germline deletion of the minimal deleted region (MDR) encoding the DLEU2/miR-15a/miR-16-1 cluster. This model provides an innovative and faster CLL system where monocyte differentiation and macrophage polarization are exacerbated, and T-cells are dysfunctional. MDR deletion inversely correlates with the levels of predicted target proteins including BCL2 and PD1/PD-L1 on murine CLL cells and immune cells. The inverse correlation of miR-15a/miR-16-1 with target proteins has been confirmed on patient-derived immune cells. Forced expression of miR-16-1 interferes with monocyte differentiation into tumor-associated macrophages, indicating that selected ncRNAs drive the protumor phenotype of non-malignant immune cells.
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MESH Headings
- MicroRNAs/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Leukemia, Lymphocytic, Chronic, B-Cell/immunology
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- Animals
- Mice
- Tumor Microenvironment/immunology
- Humans
- RNA, Long Noncoding/genetics
- Tumor Suppressor Proteins/genetics
- Multigene Family
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Affiliation(s)
- Ronghua Zhang
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Priyanka Khare
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Priyanka Banerjee
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Bryan, TX, USA
| | - Cristina Ivan
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Caris Life Sciences, Irving, TX, USA
| | - Sarah Schneider
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- The University of Texas MD Anderson Cancer Center, UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Federica Barbaglio
- Division of Experimental Oncology, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Karen Clise-Dwyer
- Department of Hematopoietic Biology and Malignancy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Vanessa Behrana Jensen
- Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Erika Thompson
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Marisela Mendoza
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Nicholas Chiorazzi
- Karches Center for Oncology Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA
- Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Uniondale, NY, USA
- Departments of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Uniondale, NY, USA
- Northwell Health Cancer Institute, Lake Success, NY, USA
| | - Shih-Shih Chen
- Karches Center for Oncology Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA
| | - Xiao-Jie Joy Yan
- Karches Center for Oncology Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA
| | - Nitin Jain
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Paolo Ghia
- B cell neoplasia Unit, Division of Experimental Oncology, IRCCS Ospedale San Raffaele, Milan, Italy
- Università Vita-Salute San Raffaele, Milan, Italy
| | - Federico Caligaris-Cappio
- Division of Experimental Oncology, IRCCS Ospedale San Raffaele, Milan, Italy
- AIRC (Associazione Italiana per la Ricerca sul Cancro), 20123, Milan, Italy
| | | | | | | | - Recep Bayraktar
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - William Wierda
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Varsha Gandhi
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - George A Calin
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Michael J Keating
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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25
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Lu X, Gao L, Qian SJ, Dai LMJ, Zhou ZY, Qiu TL, Xia Y, Miao Y, Qin SC, Fan L, Xu W, Li JY, Zhu HY. [Single-center study of COVID-19 in patients with chronic lymphocytic leukemia]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2024; 45:923-930. [PMID: 39622756 PMCID: PMC11579760 DOI: 10.3760/cma.j.cn121090-20240621-00230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Indexed: 12/06/2024]
Abstract
Objective: To investigate the vaccination status, characteristics and prognosis of patients suffering from a combination of COVID-19 and chronic lymphocytic anemia (CLL) in China. Methods: Clinical data of 328 patients with chronic lymphocytic leukemia (CLL) who were first diagnosed with COVID-19 and treated in the Department of Hematology of Jiangsu Provincial People's Hospital between November 2022 and February 2023 were retrospectively analyzed. Univariate and multivariate analysis of data of patients with severe/critical COVID-19 were conducted by applying the binary logistic regression model. Results: The median age of the CLL patients was 60 (24-87) years. 23.5% (77/328) of these patients suffered from severe/critical COVID-19 infection. Univariate analysis of the data demonstrated that a combination of factors including age >67 years (OR=2.15, 95% CI 1.24- 3.73, P=0.006), diabetes (OR=2.09, 95% CI 1.05-4.20, P=0.037), chronic hepatitis B (OR=2.91, 95% CI 1.30-6.51, P=0.010), CLL progressive (OR=3.79, 95% CI 1.57-9.15, P=0.003) and CD20 antibody-based treatments within three months prior to the COVID-19 infection (OR=2.79, 95% CI 1.35-5.77, P=0.006) were the risk factors for severe/critical COVID-19. According to the multivariate analysis, CLL progressive (OR=2.98, 95% CI 1.10-8.10, P=0.033) was an independent risk factor for severe/critical COVID-19 and administration of the BTK (Bruton tyrosine kinase) inhibitor monotherapy might exert a protective effect and influence a positive outcome of the COVID-19 infection (OR=0.38, 95% CI 0.16-0.90, P=0.028). Among the 242 patients who were followed up until October 2023, 9.1% (22/242) had multiple subsequent COVID-19 infections (≥3), and 2.1% (5/242) had persistent COVID-19 infections (patients with persistent positive test for the SARS-CoV-2 antigen testing until missing follow-up for any reason). The peak value of the anti-SARS-CoV-2-IgG titres was observed between three and four months post symptom onset (median: 3.511 S/CO vs 1.047 S/CO, P<0.05). The levels of immunoglobulin A gradually decreased following infection with COVID-19, and its trough levels were attained between two to four weeks post infection (median: 0.30 g/L vs 0.74 g/L, P<0.05). According to this study the mortality of patients suffering from a combination of COVID-19 infection and CLL was 2.7% (9/328), and the main reason for their death was respiratory failure and heart failure. Conclusions: A low rate of COVID-19 vaccination and a high rate of severe/critical COVID-19 infection was observed in the CLL patients. CLL progressive was associated with severe/critical COVID-19. Anti-CD20-based treatments received within the past three months might be a risk factor for exacerbation of COVID-19 infection, whereas a monotherapy with BTK inhibitors exert a protective effect and improve outcome of COVID-19 infection.
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Affiliation(s)
- X Lu
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China
| | - L Gao
- Department of Hematology, The Affiliate Suqian First People's Hospital of Nanjing Medical University, Suqian Branch of Jiangsu Provincial People's Hospital, Suqian 223999, China
| | - S J Qian
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China
| | - L M J Dai
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China
| | - Z Y Zhou
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China
| | - T L Qiu
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China
| | - Y Xia
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China
| | - Y Miao
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China
| | - S C Qin
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China
| | - L Fan
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China
| | - W Xu
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China
| | - J Y Li
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China
| | - H Y Zhu
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China Department of Hematology, The Affiliate Suqian First People's Hospital of Nanjing Medical University, Suqian Branch of Jiangsu Provincial People's Hospital, Suqian 223999, China
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26
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Baratè C, Scortechini I, Ciofini S, Picardi P, Angeletti I, Loscocco F, Sanna A, Isidori A, Sportoletti P. Management of infections for patient treated with ibrutinib in clinical practice. Front Oncol 2024; 14:1428464. [PMID: 39319061 PMCID: PMC11420164 DOI: 10.3389/fonc.2024.1428464] [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: 05/06/2024] [Accepted: 08/23/2024] [Indexed: 09/26/2024] Open
Abstract
Ibrutinib, a highly effective inhibitor of the Bruton tyrosine kinase, has significantly transformed the therapeutic approach in chronic lymphocytic leukemia (CLL). Despite these advancements, the disease continues to be characterized by immune dysfunction and increased susceptibility to infections, with mortality rates from infections showing no significant improvement over the past few decades. Therefore, timely prevention, recognition, and treatment of infections remains an important aspect of the standard management of a patient with CLL. A panel of hematologists with expertise in CLL met to discuss existing literature and clinical insights for the management of infectious in CLL undergoing ibrutinib treatment. Despite not being a fully comprehensive review on the topic, this work provides a set of practical recommendations that can serve as a guide to healthcare professionals who manage these patients in their daily clinical practice.
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Affiliation(s)
- Claudia Baratè
- Oncology Department, Hematology and Bone Marrow Transplant Unit, Pisa, Italy
| | - Ilaria Scortechini
- Clinic of Hematology, Azienda Ospedaliero Universitaria delle Marche, Ancona, Italy
| | - Sara Ciofini
- Department of Cell Therapies, Hematology Unit, Senese Hospital and University, Siena, Italy
| | - Paola Picardi
- Hematology and Cellular Therapy, Mazzoni Hospital, Ascoli Piceno, Italy
| | | | - Federica Loscocco
- Hematology and Stem Cell Transplant Center, Azienda Sanitaria Territoriale (AST) Pesaro and Urbino, Pesaro, Italy
| | - Alessandro Sanna
- Hematology Unit, Azienda Ospedaliera Universitaria (AOU) Careggi, Florence, Italy
| | - Alessandro Isidori
- Hematology and Stem Cell Transplant Center, Azienda Sanitaria Territoriale (AST) Pesaro and Urbino, Pesaro, Italy
| | - Paolo Sportoletti
- Department of Medicine and Surgery, Institute of Hematology and Center for Hemato-Oncology Research (CREO), University of Perugia, Santa Maria della Misericordia Hospital, Perugia, Italy
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27
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van Bruggen JAC, Peters FS, Mes M, Rietveld JM, Cerretani E, Cretenet G, van Kampen R, Jongejan A, Moerland PD, Melenhorst JJ, van der Windt GJW, Eldering E, Kater AP. T-cell dysfunction in CLL is mediated through expression of Siglec-10 ligands CD24 and CD52 on CLL cells. Blood Adv 2024; 8:4633-4646. [PMID: 39042920 PMCID: PMC11401197 DOI: 10.1182/bloodadvances.2023011934] [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: 10/16/2023] [Revised: 07/09/2024] [Accepted: 07/11/2024] [Indexed: 07/25/2024] Open
Abstract
ABSTRACT Autologous T-cell-based therapies, such as chimeric antigen receptor (CAR) T-cell therapy, exhibit low success rates in chronic lymphocytic leukemia (CLL) and correlate with a dysfunctional T-cell phenotype observed in patients. Despite various proposed mechanisms of T-cell dysfunction in CLL, the specific CLL-derived factors responsible remain unidentified. This study aimed to investigate the mechanisms through which CLL cells suppress CAR T-cell activation and function. We found that CLL-derived T cells get activated, albeit in a delayed fashion, and specifically that restimulation of CAR T cells in the presence of CLL cells causes impaired cytokine production and reduced proliferation. Notably, coculture of T cells with CD40-activated CLL cells did not lead to T-cell dysfunction, and this required direct cell contact between the CD40-stimulated CLL cells and T cells. Inhibition of kinases involved in the CD40 signaling cascade revealed that the Spare Respiratory Capacity (SRC) kinase inhibitor dasatinib prevented rescue of T-cell function independent of CD40-mediated increased levels of costimulatory and adhesion ligands on CLL cells. Transcriptome profiling of CD40-stimulated CLL cells with or without dasatinib identified widespread differential gene expression. Selecting for surface receptor genes revealed CD40-mediated downregulation of the Sialic acid-binding Ig-like lectin 10 (Siglec-10) ligands CD24 and CD52, which was prevented by dasatinib, suggesting a role for these ligands in functional T-cell suppression in CLL. Indeed, blocking CD24 and/or CD52 markedly reduced CAR T-cell dysfunction upon coculture with resting CLL cells. These results demonstrated that T cells derived from CLL patients can be reinvigorated by manipulating CLL-T-cell interactions. Targeting CD24- and CD52-mediated CLL-T-cell interaction could be a promising therapeutic strategy to enhance T-cell function in CLL.
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MESH Headings
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell/metabolism
- Leukemia, Lymphocytic, Chronic, B-Cell/immunology
- Leukemia, Lymphocytic, Chronic, B-Cell/therapy
- CD52 Antigen/metabolism
- T-Lymphocytes/metabolism
- T-Lymphocytes/immunology
- CD24 Antigen/metabolism
- Lymphocyte Activation/immunology
- Ligands
- Receptors, Chimeric Antigen/metabolism
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Affiliation(s)
- Jaco A. C. van Bruggen
- Department of Hematology, Cancer Center Amsterdam, Lymphoma and Myeloma Center Amsterdam, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Fleur S. Peters
- Department of Hematology, Cancer Center Amsterdam, Lymphoma and Myeloma Center Amsterdam, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Morris Mes
- Department of Hematology, Cancer Center Amsterdam, Lymphoma and Myeloma Center Amsterdam, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Joanne M. Rietveld
- Department of Hematology, Cancer Center Amsterdam, Lymphoma and Myeloma Center Amsterdam, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Elisa Cerretani
- Department of Hematology, Cancer Center Amsterdam, Lymphoma and Myeloma Center Amsterdam, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Gaspard Cretenet
- Department of Hematology, Cancer Center Amsterdam, Lymphoma and Myeloma Center Amsterdam, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | | | - Aldo Jongejan
- Department of Epidemiology and Data Science, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Perry D. Moerland
- Department of Epidemiology and Data Science, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - J. Joseph Melenhorst
- Cleveland Clinic, Lerner Research Institute, Center for Immunotherapy & Precision Immuno-Oncology, Cleveland, OH
| | - Gerritje J. W. van der Windt
- Department of Hematology, Cancer Center Amsterdam, Lymphoma and Myeloma Center Amsterdam, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Eric Eldering
- Department of Hematology, Cancer Center Amsterdam, Lymphoma and Myeloma Center Amsterdam, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Arnon P. Kater
- Department of Hematology, Cancer Center Amsterdam, Lymphoma and Myeloma Center Amsterdam, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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28
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Kater AP, Eichhorst BF, Owen CJ, Jaeger U, Chyla B, Lefebure M, Millen R, Jiang Y, Thadani‐Mulero M, Boyer M, Seymour JF. Long-term immune changes in patients with relapsed/refractory chronic lymphocytic leukemia following treatment with venetoclax plus rituximab. Hemasphere 2024; 8:e146. [PMID: 39193190 PMCID: PMC11347997 DOI: 10.1002/hem3.146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 04/22/2024] [Accepted: 06/04/2024] [Indexed: 08/29/2024] Open
Abstract
Immune dysregulation is a hallmark of chronic lymphocytic leukemia (CLL). Anti-CD20 antibodies (e.g., rituximab [R]) can be combined with venetoclax (Ven) to treat CLL. However, anti-CD20 antibodies can increase hypogammaglobulinemia risk, while the effects of Ven on immune dysregulation are still uncertain. We report long-term immune changes in VenR- and bendamustine-R (BR)-treated patients with relapsed/refractory CLL in the MURANO trial (NCT02005471). Patients were randomized to fixed-duration VenR (2 years Ven; VenR for the first 6 months) or BR (6 months). Immune cell levels were evaluated at the end of combination treatment (EOCT), end of treatment (EOT; VenR arm only), and 12 and 24 months post-EOCT. Overall, 130/194 VenR- and 134/195 BR-treated patients completed treatment without progressive disease. In patients who completed VenR combination therapy, median immunoglobulin (Ig)G and IgM levels decreased from baseline to EOT (p ≤ 0.01 and p ≤ 0.0001, respectively); by 24 months, post-EOT IgG had returned to baseline level and IgM had increased from baseline (p ≤ 0.001). Median IgA levels increased from baseline to 12 (p ≤ 0.0001) and 24 months post-EOT (p ≤ 0.0001). In BR-treated patients, changes in IgG, IgA, and IgM levels across the assessed time points were not significant, and by 24 months, post-EOCT IgG, IgA, and IgM were above baseline levels. Grade ≥3 infection rates on treatment were low. Overall, immune recovery was observed with VenR and BR, with stabilization of Ig levels after treatment. Post-treatment infection rates were generally low, making these very tolerable therapies for CLL.
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Affiliation(s)
- Arnon P. Kater
- Department of Hematology, Cancer Center Amsterdam, LYMMCARE, Amsterdam University Medical CentersUniversity of AmsterdamAmsterdamThe Netherlands
| | - Barbara F. Eichhorst
- Department of Internal Medicine and Center of Integrated Oncology Aachen, Bonn, Cologne, Dusseldorf (CIO ABCD), Faculty of Medicine and University Hospital CologneUniversity of CologneCologneGermany
| | - Carolyn J. Owen
- Departments of Medicine and OncologyUniversity of CalgaryCalgaryAlbertaCanada
| | - Ulrich Jaeger
- Clinical Department of Hematology and HemostaseologyMedical University of ViennaViennaAustria
| | | | | | | | | | | | | | - John F. Seymour
- Peter MacCallum Cancer CentreRoyal Melbourne Hospital and University of MelbourneMelbourneAustralia
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Dasanu CA, Mann SK, Baidya M, Mdluli XP, Stapleton AE, Codreanu I. Evaluation of infectious morbidity due to BTK inhibitors in indolent B-cell lymphomas: latest research findings and systematic analysis. Expert Opin Pharmacother 2024; 25:1525-1540. [PMID: 39109526 DOI: 10.1080/14656566.2024.2390121] [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: 05/22/2024] [Accepted: 08/05/2024] [Indexed: 08/28/2024]
Abstract
INTRODUCTION Randomized clinical trials (RCTs) have suggested that BTK inhibitors (BTKis) might increase infectious disease (ID) risk. Systematic analysis of this topic as derived from RCTs and clinical practice is needed. AREAS COVERED An extensive Medline, Embase, and Cochrane search of peer-reviewed sources reporting on ID morbidity in patients on BTKis was performed (1 January 2014 - 31 December 2023). Contribution of intrinsic immune defects in indolent B-cell lymphomas to this morbidity was carefully considered. EXPERT OPINION Patients with indolent B-cell lymphomas display a wide range of innate and adaptive immune defects. In addition, BTKi use is linked with an increased signal of upper respiratory tract infections (URTIs) and pneumonias, mainly grade 1-2. These agents also increase the risk of rare invasive fungal infections (IFIs), mainly due to Cryptococcus and Aspergillus spp. with a peak within several months after the start of therapy. More than half of these IFIs are fatal. Research suggests a similar ID risk across 1st, 2nd and 3rd generations of BTKis, all causing B-cell dysfunction due to BTK inhibition, along with off-target functional neutrophil/macrophage alterations. Expanding the knowledge base on ID morbidity in patients on BTKis would facilitate timely diagnosis and treatment, and improve clinical outcomes.
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Affiliation(s)
- Constantin A Dasanu
- Lucy Curci Cancer Center, Eisenhower Health, Rancho Mirage, CA, USA
- Department of Medical Oncology and Hematology, UC San Diego Health System, San Diego, CA, USA
| | - Samar K Mann
- Department of Graduate Medical Education, Oakland William Beaumont School of Medicine, Rochester, MI, USA
| | - Melvin Baidya
- Lucy Curci Cancer Center, Eisenhower Health, Rancho Mirage, CA, USA
| | - Xolani P Mdluli
- Department of Infectious Diseases, Eisenhower Health, Rancho Mirage, CA, USA
| | - Ann E Stapleton
- Department of Infectious Diseases, Eisenhower Health, Rancho Mirage, CA, USA
| | - Ion Codreanu
- Translational Imaging Center, Houston Methodist Research Institute, Houston, TX, USA
- Department of Radiology, Nicolae Testemitanu State University of Medicine and Pharmacy, Chisinau, Republic of Moldova
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Chen Y, Yuan L, Lu X, Wang X, Zhang Q, Wang X, Zhao X. Efficacy of venetoclax and rituximab in the treatment of concurrent acute myeloid leukemia and untreated chronic lymphocytic leukemia: A case report and literature review. Oncol Lett 2024; 28:393. [PMID: 38966581 PMCID: PMC11223026 DOI: 10.3892/ol.2024.14526] [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: 09/18/2023] [Accepted: 02/09/2024] [Indexed: 07/06/2024] Open
Abstract
To date, few cases of concurrent acute myeloid leukemia (AML) and untreated chronic lymphocytic leukemia (CLL) have been reported. Due to the complexity of the pathogenesis and the absence of a uniform treatment regimen, the associated prognosis remains poor. The present study reports the case of a 58-year-old male with asymptomatic leukocytosis, who was previously healthy with no malignancies. Flow cytometry analysis revealed protocytosis, monocytosis and monoclonal B lymphocytosis in a bone marrow specimen. Results of a gene rearrangement assay demonstrated positive immunoglobulin heavy-chain variable region gene status in monoclonal B lymphocytes. Thus, the patient was diagnosed with AML with maturation (AML-M2) that co-existed with untreated CLL. The normative daunorubicin (40 mg/m2 on days 1-3) and cytarabine (80 mg/m2 on days 1-7) regimen combined with venetoclax (400 mg on days 1-7) and rituximab (375 mg/m2 on day 0) was used as induction chemotherapy. The patient achieved morphological complete remission in both AML and CLL following the first course of chemotherapy. In addition, the present study retrospectively analyzed the data of 22 patients with concurrent AML and untreated CLL, and the results demonstrated that the median age at the time of AML diagnosis was 69 years (range, 52-86 years). Moreover, the male:female ratio was 6.33:1 and AML-M2 was the most frequent subtype at diagnosis. The presence of a complex karyotype was associated with the poorest prognosis, and patients who received venetoclax often exhibited an improved prognosis. In conclusion, the combination of venetoclax and rituximab improves the prognosis of patients with concurrent AML and untreated CLL.
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Affiliation(s)
- Yafang Chen
- Department of Hematology, Oncology Center, Tianjin Union Medical Center of Nankai University, Tianjin 300121, P.R. China
| | - Linyu Yuan
- Department of Hematology, Oncology Center, Tianjin Union Medical Center of Nankai University, Tianjin 300121, P.R. China
| | - Xinxiao Lu
- Department of Hematology, Oncology Center, Tianjin Union Medical Center of Nankai University, Tianjin 300121, P.R. China
| | - Xue Wang
- Department of Hematology, Oncology Center, Tianjin Union Medical Center of Nankai University, Tianjin 300121, P.R. China
| | - Qiuqiu Zhang
- Department of Hematology, Oncology Center, Tianjin Union Medical Center of Nankai University, Tianjin 300121, P.R. China
| | - Xiaofang Wang
- Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, P.R. China
- Tianjin's Clinical Research Center for Cancer, Tianjin Medical University, Ministry of Education, Tianjin 300060, P.R. China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin 300060, P.R. China
| | - Xingli Zhao
- Department of Hematology, Oncology Center, Tianjin Union Medical Center of Nankai University, Tianjin 300121, P.R. China
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Lee BJ, Vittayawacharin P, Griffin SP, Doh J, Nam HH, Jeyakumar D, Blodget E, Kongtim P, Ciurea SO. Persistent Impairment in Immune Reconstitution and Worse Survival Outcomes in Allogeneic Stem Cell Transplantation Patients with Early Coronavirus Disease 2019 Infection. Transplant Cell Ther 2024; 30:816.e1-816.e10. [PMID: 38710303 DOI: 10.1016/j.jtct.2024.04.021] [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: 02/19/2024] [Revised: 04/12/2024] [Accepted: 04/30/2024] [Indexed: 05/08/2024]
Abstract
Patients undergoing allogenic hematopoietic stem cell transplantation (HSCT) are at an increased risk of mortality due to transplantation-related complications in the first year post-transplantation, owing in part to the profound immune dysregulation with T cell and B cell lymphopenia and functional impairment. Although several large studies have reported higher mortality rates from Coronavirus disease 2019 (COVID-19) in HSCT recipients, to date no study has focused on the impact of early COVID-19 infection on immune reconstitution post-transplantation and the correlation with transplantation outcomes. We retrospectively analyzed 61 consecutive adult patients who underwent their first allogeneic HSCT at our institution. Thirteen patients (21.3%) experienced early COVID-19 infection, with a median time to diagnosis of 100 days post-transplantation. In multivariable analysis, patients with early COVID-19 infection had significantly worse overall survival (adjusted hazard ratio [aHR], 4.06; 95% confidence interval [CI], 1.26 to 13.05; P = .019) and progression-free survival (aHR, 6.68; 95% CI, 2.11 to 21.11; P = .001). This was attributed mainly to higher nonrelapse mortality (NRM) among early COVID-19 patients (P = .042). Allogeneic HSCT recipients with early COVID-19 infection had significant delays in absolute lymphocyte count (95% CI, -703.69 to -56.79; P = .021), CD3+CD4+ cell (95% CI, -105.35 to -11.59; P = .042), CD3+CD8+ cell (95% CI, -324.55 to -57.13; P = .038), and CD3-CD56+ cell (95% CI, -193.51 to -47.31; P = .014) recovery compared to those without early COVID-19 infection. Our findings suggest that patients with early COVID-19 infection after allogeneic HSCT have higher NRM and worse survival, at least in part due to impaired immune reconstitution post-transplantation.
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Affiliation(s)
- Benjamin J Lee
- Department of Pharmacy, Chao Family Comprehensive Cancer Center, University of California Irvine Health, Orange, California, USA; Department of Clinical Pharmacy Practice, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, California
| | - Pongthep Vittayawacharin
- Division of Hematology-Oncology, Department of Medicine, Hematopoietic Stem Cell Transplantation and Cellular Therapy Program, Chao Family Comprehensive Cancer Center, University of California Irvine Health, Orange, California; Division of Hematology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Shawn P Griffin
- Department of Pharmacy, Chao Family Comprehensive Cancer Center, University of California Irvine Health, Orange, California, USA; Department of Clinical Pharmacy Practice, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, California
| | - Jean Doh
- Department of Pharmacy, Chao Family Comprehensive Cancer Center, University of California Irvine Health, Orange, California, USA; Department of Clinical Pharmacy Practice, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine, California
| | - Hannah H Nam
- Division of Infectious Diseases, Department of Medicine, University of California Irvine Health, Orange, California
| | - Deepa Jeyakumar
- Division of Hematology-Oncology, Department of Medicine, Hematopoietic Stem Cell Transplantation and Cellular Therapy Program, Chao Family Comprehensive Cancer Center, University of California Irvine Health, Orange, California
| | - Emily Blodget
- Division of Infectious Diseases, Department of Medicine, University of California Irvine Health, Orange, California
| | - Piyanuch Kongtim
- Division of Hematology-Oncology, Department of Medicine, Hematopoietic Stem Cell Transplantation and Cellular Therapy Program, Chao Family Comprehensive Cancer Center, University of California Irvine Health, Orange, California
| | - Stefan O Ciurea
- Division of Hematology-Oncology, Department of Medicine, Hematopoietic Stem Cell Transplantation and Cellular Therapy Program, Chao Family Comprehensive Cancer Center, University of California Irvine Health, Orange, California.
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Baggio D, Chung E, Wellard C, Waters N, Cushion T, Chong G, Cochrane T, Cull G, Giri P, Hamad N, Johnston A, Lee D, Murali A, Morgan S, Mulligan S, Talaulikar D, Ratnasingam S, Wood E, Hawkes E, Opat S. Australians with chronic lymphocytic leukaemia continue to have high rates of second primary malignancies in the modern era. Intern Med J 2024; 54:1223-1227. [PMID: 38973146 DOI: 10.1111/imj.16445] [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: 11/15/2023] [Accepted: 05/26/2024] [Indexed: 07/09/2024]
Abstract
Population-based studies have demonstrated a high risk of second cancers, especially of the skin, among patients with chronic lymphocytic leukaemia (CLL). We describe age-standardised incidence ratios (SIRs) of second primary malignancies (SPM) in Australian patients with relapsed/refractory CLL treated with at least two lines of therapy, including ibrutinib. From December 2014 to November 2017, 156 patients were identified from 13 sites enrolled in the Australasian Lymphoma and Related Diseases Registry, and 111 had follow-up data on rates of SPM. At 38.4 months from ibrutinib therapy commencement, 25% experienced any SPM. SIR for melanoma and all cancers (excluding nonmelanomatous skin cancers) were 15.8 (95% confidence interval (CI): 7.0-35.3) and 4.6 (95% CI: 3.1-6.9) respectively. These data highlight the importance of primary preventive interventions and surveillance, particularly as survival from CLL continues to improve.
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Affiliation(s)
- Diva Baggio
- Olivia Newton-John Cancer Research and Wellness Centre, Austin Health, Melbourne, Victoria, Australia
- Monash University, Melbourne, Victoria, Australia
| | - Eliza Chung
- Monash University, Melbourne, Victoria, Australia
| | | | - Neil Waters
- Monash University, Melbourne, Victoria, Australia
| | - Tania Cushion
- Olivia Newton-John Cancer Research and Wellness Centre, Austin Health, Melbourne, Victoria, Australia
| | - Geoffrey Chong
- Ballarat Regional Integrated Cancer Centre, Ballarat, Victoria, Australia
| | - Tara Cochrane
- Gold Coast University Hospital, Gold Coast, Queensland, Australia
| | - Gavin Cull
- Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
| | - Pratyush Giri
- Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Nada Hamad
- St Vincent's Health, Sydney, New South Wales, Australia
| | - Anna Johnston
- Royal Hobart Hospital, Hobart, Tasmania, Australia
- University of Tasmania, Hobart, Tasmania, Australia
| | - Denise Lee
- Eastern Health, Melbourne, Victoria, Australia
| | - Aarya Murali
- Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | | | | | - Dipti Talaulikar
- Canberra Health Services, Australian National University, Canberra, Australian Capital Territory, Australia
| | | | - Erica Wood
- Monash University, Melbourne, Victoria, Australia
| | - Eliza Hawkes
- Olivia Newton-John Cancer Research and Wellness Centre, Austin Health, Melbourne, Victoria, Australia
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Galitzia A, Maccaferri M, Mauro FR, Murru R, Marasca R. Chronic Lymphocytic Leukemia: Management of Adverse Events in the Era of Targeted Agents. Cancers (Basel) 2024; 16:1996. [PMID: 38893115 PMCID: PMC11171383 DOI: 10.3390/cancers16111996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 05/20/2024] [Accepted: 05/22/2024] [Indexed: 06/21/2024] Open
Abstract
The treatment landscape for CLL has undergone a profound transformation with the advent of targeted agents (TAs) like Bruton's Tyrosine Kinase inhibitors (BTKis) and BCL-2 inhibitors (BCL-2is). These agents target crucial cellular pathways in CLL, offering superior efficacy over traditional chemo-immunotherapy, which has led to improved progression-free and overall survival rates. This advancement promises enhanced disease control and potentially normal life expectancy for many patients. However, the journey is not without challenges, as these TAs are associated with a range of adverse events (AEs) that can impact treatment efficacy and patient quality of life. This review focuses on detailing the various AEs related to TA management in CLL, evaluating their frequency and clinical impact. The aim is to present a comprehensive guide to the effective management of these AEs, ensuring optimal tolerability and efficacy of TAs. By reviewing the existing literature and consolidating findings, we provide insights into AE management, which is crucial for maximizing patient outcomes in CLL therapy.
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Affiliation(s)
- Andrea Galitzia
- Hematology and Stem Cell Transplantation Unit, Ospedale San Francesco, 08100 Nuoro, Italy;
| | - Monica Maccaferri
- Hematology Unit, Department of Oncology and Hematology, A.O.U of Modena, Policlinico, 41125 Modena, Italy; (M.M.); (R.M.)
| | - Francesca Romana Mauro
- Hematology, Department of Translational and Precision Medicine, Sapienza University, 00185 Rome, Italy;
| | - Roberta Murru
- Hematology and Stem Cell Transplantation Unit, Ospedale Oncologico A. Businco, ARNAS G. Brotzu, 09134 Cagliari, Italy
| | - Roberto Marasca
- Hematology Unit, Department of Oncology and Hematology, A.O.U of Modena, Policlinico, 41125 Modena, Italy; (M.M.); (R.M.)
- Department of Medical and Surgical Sciences, Section of Hematology, University of Modena and Reggio Emilia, 41121 Modena, Italy
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34
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Bernstein JA, Maurer M, Saini SS. BTK signaling-a crucial link in the pathophysiology of chronic spontaneous urticaria. J Allergy Clin Immunol 2024; 153:1229-1240. [PMID: 38141832 DOI: 10.1016/j.jaci.2023.12.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 12/18/2023] [Accepted: 12/18/2023] [Indexed: 12/25/2023]
Abstract
Chronic spontaneous urticaria (CSU) is an inflammatory skin disorder that manifests with itchy wheals, angioedema, or both for more than 6 weeks. Mast cells and basophils are the key pathogenic drivers of CSU; their activation results in histamine and cytokine release with subsequent dermal inflammation. Two overlapping mechanisms of mast cell and basophil activation have been proposed in CSU: type I autoimmunity, also called autoallergy, which is mediated via IgE against various autoallergens, and type IIb autoimmunity, which is mediated predominantly via IgG directed against the IgE receptor FcεRI or FcεRI-bound IgE. Both mechanisms involve cross-linking of FcεRI and activation of downstream signaling pathways, and they may co-occur in the same patient. In addition, B-cell receptor signaling has been postulated to play a key role in CSU by generating autoreactive B cells and autoantibody production. A cornerstone of FcεRI and B-cell receptor signaling is Bruton tyrosine kinase (BTK), making BTK inhibition a clear therapeutic target in CSU. The potential application of early-generation BTK inhibitors, including ibrutinib, in allergic and autoimmune diseases is limited owing to their unfavorable benefit-risk profile. However, novel BTK inhibitors with improved selectivity and safety profiles have been developed and are under clinical investigation in autoimmune diseases, including CSU. In phase 2 trials, the BTK inhibitors remibrutinib and fenebrutinib have demonstrated rapid and sustained improvements in CSU disease activity. With phase 3 studies of remibrutinib ongoing, it is hoped that BTK inhibitors will present an effective, well-tolerated option for patients with antihistamine-refractory CSU, a phenotype that presents a considerable clinical challenge.
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Affiliation(s)
- Jonathan A Bernstein
- Department of Internal Medicine, Allergy and Immunology Section, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Marcus Maurer
- Institute of Allergology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology, Berlin, Germany
| | - Sarbjit S Saini
- Johns Hopkins Asthma and Allergy Center, Division of Allergy and Clinical Immunology, The Johns Hopkins University School of Medicine, Baltimore, Md.
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Murru R, Galitzia A, Barabino L, Presicci R, La Nasa G, Caocci G. Prediction of severe infections in chronic lymphocytic leukemia: a simple risk score to stratify patients at diagnosis. Ann Hematol 2024; 103:1655-1664. [PMID: 38236391 PMCID: PMC11009768 DOI: 10.1007/s00277-024-05625-y] [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: 09/12/2023] [Accepted: 01/11/2024] [Indexed: 01/19/2024]
Abstract
Chronic Lymphocytic Leukemia (CLL) is well-known for increasing susceptibility to infections. Factors such as immune dysregulation, IGHV status, hypogammaglobulinemia, and patient comorbidity and treatment, contribute to higher infection rates and mortality. However, the impact of hypogammaglobulinemia on infection rates is controversial. We aimed to identify clinical and biological parameters linked to the risk of severe infectious events. Additionally, we set up a straightforward risk infection score to stratify CLL patients at diagnosis, thereby enabling the development of suitable infection prevention strategies. We retrospectively evaluated 210 unselected CLL patients diagnosed between 1988 and 2018. This evaluation encompassed demographics, Binet stage, immunoglobulin (Ig) levels, treatment history, comorbidities, and IGHV mutational status at diagnosis. The frequency and severity of infectious events were recorded. Analysis revealed that age, IGHV mutational status, Binet stage, and hypogammaglobulinemia were statistically associated with the Time to First Infection (TTFI) in univariate and multivariate analyses. Using hazard ratios from the multivariate analysis, we finally devised a risk scoring system that integrated age, IGHV mutational status, immunoglobulin levels, and Binet stage to stratify patients at diagnosis based on their specific infection risk. In our cohort, disease progression and infections were the leading cause of death. These findings pointed out the clinical need for a screening process strategic for defining infectious risk at the time of CLL diagnosis, with a significant enhancement in the clinical management of these patients.
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Affiliation(s)
- Roberta Murru
- Hematology and Stem Cell Transplantation Unit, Ospedale Oncologico A. Businco, ARNAS G. Brotzu, Cagliari, Italy
| | - Andrea Galitzia
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Luca Barabino
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Roberta Presicci
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Giorgio La Nasa
- Hematology and Stem Cell Transplantation Unit, Ospedale Oncologico A. Businco, ARNAS G. Brotzu, Cagliari, Italy
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Giovanni Caocci
- Hematology and Stem Cell Transplantation Unit, Ospedale Oncologico A. Businco, ARNAS G. Brotzu, Cagliari, Italy.
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.
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Francis ER, Vu J, Perez CO, Sun C. Vaccinations in patients with chronic lymphocytic leukemia. Semin Hematol 2024; 61:131-138. [PMID: 38302313 PMCID: PMC11162341 DOI: 10.1053/j.seminhematol.2024.01.003] [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: 11/17/2023] [Revised: 12/04/2023] [Accepted: 01/02/2024] [Indexed: 02/03/2024]
Abstract
Chronic lymphocytic leukemia (CLL) is characterized by immune dysfunction resulting in heightened susceptibility to infections and elevated rates of morbidity and mortality. A key strategy to mitigate infection-related complications has been immunization against common pathogens. However, the immunocompromised status of CLL patients poses challenges in eliciting an adequate humoral and cellular immune response to vaccination. Most CLL-directed therapy disproportionately impairs humoral immunity. Vaccine responsiveness also depends on the phase and type of immune response triggered by immunization. In this review, we discuss the immune dysfunction, vaccine responsiveness, and considerations for optimizing vaccine response in patients with CLL.
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Affiliation(s)
| | - Jennifer Vu
- Rosalind Franklin University of Medicine and Science, Chicago Medical School
| | | | - Clare Sun
- National Institutes of Health, National Heart, Lung, and Blood Institute.
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Tsilingiris D, Vallianou NG, Spyrou N, Kounatidis D, Christodoulatos GS, Karampela I, Dalamaga M. Obesity and Leukemia: Biological Mechanisms, Perspectives, and Challenges. Curr Obes Rep 2024; 13:1-34. [PMID: 38159164 PMCID: PMC10933194 DOI: 10.1007/s13679-023-00542-z] [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] [Accepted: 11/06/2023] [Indexed: 01/03/2024]
Abstract
PURPOSE OF REVIEW To examine the epidemiological data on obesity and leukemia; evaluate the effect of obesity on leukemia outcomes in childhood acute lymphoblastic leukemia (ALL) survivors; assess the potential mechanisms through which obesity may increase the risk of leukemia; and provide the effects of obesity management on leukemia. Preventive (diet, physical exercise, obesity pharmacotherapy, bariatric surgery) measures, repurposing drugs, candidate therapeutic agents targeting oncogenic pathways of obesity and insulin resistance in leukemia as well as challenges of the COVID-19 pandemic are also discussed. RECENT FINDINGS Obesity has been implicated in the development of 13 cancers, such as breast, endometrial, colon, renal, esophageal cancers, and multiple myeloma. Leukemia is estimated to account for approximately 2.5% and 3.1% of all new cancer incidence and mortality, respectively, while it represents the most frequent cancer in children younger than 5 years. Current evidence indicates that obesity may have an impact on the risk of leukemia. Increased birthweight may be associated with the development of childhood leukemia. Obesity is also associated with worse outcomes and increased mortality in leukemic patients. However, there are several limitations and challenges in meta-analyses and epidemiological studies. In addition, weight gain may occur in a substantial number of childhood ALL survivors while the majority of studies have documented an increased risk of relapse and mortality among patients with childhood ALL and obesity. The main pathophysiological pathways linking obesity to leukemia include bone marrow adipose tissue; hormones such as insulin and the insulin-like growth factor system as well as sex hormones; pro-inflammatory cytokines, such as IL-6 and TNF-α; adipocytokines, such as adiponectin, leptin, resistin, and visfatin; dyslipidemia and lipid signaling; chronic low-grade inflammation and oxidative stress; and other emerging mechanisms. Obesity represents a risk factor for leukemia, being among the only known risk factors that could be prevented or modified through weight loss, healthy diet, and physical exercise. Pharmacological interventions, repurposing drugs used for cardiometabolic comorbidities, and bariatric surgery may be recommended for leukemia and obesity-related cancer prevention.
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Affiliation(s)
- Dimitrios Tsilingiris
- First Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, Dragana, 68100, Alexandroupolis, Greece
| | - Natalia G Vallianou
- Department of Internal Medicine, Evangelismos General Hospital, 45-47 Ipsilantou str, 10676, Athens, Greece
| | - Nikolaos Spyrou
- Tisch Cancer Institute Icahn School of Medicine at Mount Sinai, 1190 One Gustave L. Levy Place, New York, NY, 10029, USA
| | - Dimitris Kounatidis
- Department of Internal Medicine, Evangelismos General Hospital, 45-47 Ipsilantou str, 10676, Athens, Greece
| | | | - Irene Karampela
- 2nd Department of Critical Care, Medical School, University of Athens, Attikon General University Hospital, 1 Rimini Str, 12462, Athens, Greece
| | - Maria Dalamaga
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias str, 11527, Athens, Greece.
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Ntsethe A, Mkhwanazi ZA, Dludla PV, Nkambule BB. B Cell Subsets and Immune Checkpoint Expression in Patients with Chronic Lymphocytic Leukemia. Curr Issues Mol Biol 2024; 46:1731-1740. [PMID: 38534728 DOI: 10.3390/cimb46030112] [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: 01/10/2024] [Revised: 02/12/2024] [Accepted: 02/22/2024] [Indexed: 03/28/2024] Open
Abstract
Chronic lymphocytic leukemia (CLL) is characterized by dysfunctional B cells. Immune checkpoint molecules such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death-1 (PD-1) are upregulated in patients with CLL and may correlate with prognostic markers such as beta-2 microglobulin (B2M). The aim of this study was to evaluate the levels of immune checkpoints on B cell subsets and to further correlate them with B2M levels in patients with CLL. We recruited 21 patients with CLL and 12 controls. B cell subsets and the levels of immune checkpoint expression were determined using conventional multi-color flow cytometry. Basal levels of B2M in patients with CLL were measured using an enzyme-linked immunosorbent assay. Patients with CLL had increased levels of activated B cells when compared to the control group, p < 0.001. The expression of PD-1 and CTLA-4 were increased on activated B cells and memory B cells, p < 0.05. There were no associations between B2M levels and the measured immune checkpoints on B cell subsets, after adjusting for sex and age. In our cohort, the patients with CLL expressed elevated levels of PD-1 and CTLA-4 immune checkpoints on activated and memory B cell subsets. However, there was no correlation between these immune checkpoint expressions and B2M levels.
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Affiliation(s)
- Aviwe Ntsethe
- School of Laboratory Medicine and Medical Sciences (SLMMS), University of KwaZulu-Natal, Durban 4000, South Africa
| | - Zekhethelo Alondwe Mkhwanazi
- School of Laboratory Medicine and Medical Sciences (SLMMS), University of KwaZulu-Natal, Durban 4000, South Africa
| | - Phiwayinkosi Vusi Dludla
- Cochrane South Africa, South African Medical Research Council, Tygerberg 7505, South Africa
- Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa 3886, South Africa
| | - Bongani Brian Nkambule
- School of Laboratory Medicine and Medical Sciences (SLMMS), University of KwaZulu-Natal, Durban 4000, South Africa
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Boncompagni G, Tatangelo V, Lopresti L, Ulivieri C, Capitani N, Tangredi C, Finetti F, Marotta G, Frezzato F, Visentin A, Ciofini S, Gozzetti A, Bocchia M, Calzada-Fraile D, Martin Cofreces NB, Trentin L, Patrussi L, Baldari CT. Leukemic cell-secreted interleukin-9 suppresses cytotoxic T cell-mediated killing in chronic lymphocytic leukemia. Cell Death Dis 2024; 15:144. [PMID: 38360867 PMCID: PMC10869739 DOI: 10.1038/s41419-024-06528-6] [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: 05/16/2023] [Revised: 12/19/2023] [Accepted: 02/01/2024] [Indexed: 02/17/2024]
Abstract
The tumor microenvironment (TME) plays a central role in the pathogenesis of chronic lymphocytic leukemia (CLL), contributing to disease progression and chemoresistance. Leukemic cells shape the TME into a pro-survival and immunosuppressive niche through contact-dependent and contact-independent interactions with the cellular components of the TME. Immune synapse (IS) formation is defective in CLL. Here we asked whether soluble factors released by CLL cells contribute to their protection from cytotoxic T cell (CTL)-mediated killing by interfering with this process. We found that healthy CTLs cultured in media conditioned by leukemic cells from CLL patients or Eμ-TCL1 mice upregulate the exhaustion marker PD-1 and become unable to form functional ISs and kill target cells. These defects were more pronounced when media were conditioned by leukemic cells lacking p66Shc, a proapoptotic adapter whose deficiency has been implicated in disease aggressiveness both in CLL and in the Eμ-TCL1 mouse model. Multiplex ELISA assays showed that leukemic cells from Eμ-TCL1 mice secrete abnormally elevated amounts of CCL22, CCL24, IL-9 and IL-10, which are further upregulated in the absence of p66Shc. Among these, IL-9 and IL-10 were also overexpressed in leukemic cells from CLL patients, where they inversely correlated with residual p66Shc. Using neutralizing antibodies or the recombinant cytokines we show that IL-9, but not IL-10, mediates both the enhancement in PD-1 expression and the suppression of effector functions in healthy CTLs. Our results demonstrate that IL-9 secreted by leukemic cells negatively modulates the anti-tumor immune abilities of CTLs, highlighting a new suppressive mechanism and a novel potential therapeutical target in CLL.
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Affiliation(s)
| | | | | | | | - Nagaja Capitani
- Department of Life Sciences, University of Siena, Siena, Italy
| | | | | | - Giuseppe Marotta
- Stem Cell Transplant and Cellular Therapy Unit, University Hospital, Siena, Italy
| | - Federica Frezzato
- Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy
- Venetian Institute of Molecular Medicine, Padua, Italy
| | - Andrea Visentin
- Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy
- Venetian Institute of Molecular Medicine, Padua, Italy
| | - Sara Ciofini
- Department of Medical Science, Surgery and Neuroscience, University of Siena, Siena, Italy
| | - Alessandro Gozzetti
- Department of Medical Science, Surgery and Neuroscience, University of Siena, Siena, Italy
| | - Monica Bocchia
- Department of Medical Science, Surgery and Neuroscience, University of Siena, Siena, Italy
| | - Diego Calzada-Fraile
- Immunology Unit from Hospital Universitario de la Princesa, Universidad Autónoma de Madrid and Instituto de investigación Sanitaria La Princesa (IIS-IP), Madrid, Spain
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029, Madrid, Spain
| | - Noa B Martin Cofreces
- Immunology Unit from Hospital Universitario de la Princesa, Universidad Autónoma de Madrid and Instituto de investigación Sanitaria La Princesa (IIS-IP), Madrid, Spain
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029, Madrid, Spain
- Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Livio Trentin
- Department of Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy
- Venetian Institute of Molecular Medicine, Padua, Italy
| | - Laura Patrussi
- Department of Life Sciences, University of Siena, Siena, Italy.
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40
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Moss P. Ibrutinib reversal of immune exhaustion in CLL. Blood 2024; 143:5-7. [PMID: 38175677 DOI: 10.1182/blood.2023022243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2024] Open
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Andreescu M, Andreescu B. Immune Evasion Through Human Leukocyte Antigen Implications and Its Impact on Targeted Therapy. Cureus 2024; 16:e52737. [PMID: 38384647 PMCID: PMC10880808 DOI: 10.7759/cureus.52737] [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] [Accepted: 01/22/2024] [Indexed: 02/23/2024] Open
Abstract
The malfunctioning of human leukocyte antigen (HLA) class I antigens has a substantial negative impact on the effectiveness of leukemia treatment, particularly in the development of immunotherapies that rely on T-cell activation. HLA-G, a molecule that suppresses the immune response, plays a role in repressing the activation and proliferation of T cells, natural killer cells, and antigen-presenting cells. The expression of HLA-G is associated with various pathological conditions. Tumor cells exploit the immune evasion capabilities of HLA, allowing them to evade detection and elimination by the immune system. Understanding and modifying the HLA molecules is crucial for the advancement of innovative immunotherapies targeting chronic lymphocytic leukemia. Numerous mechanisms have been investigated to elucidate how HLA facilitates tumor evasion in patients with chronic lymphocytic leukemia and other malignancies. These mechanisms include inhibiting immune cell cytolysis, altering cytokine production levels, promoting immune cell programmed cell death, and impairing chemotaxis. This review provides a comprehensive overview of immune evasion mediated by HLA and its implications for targeted therapy.
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Affiliation(s)
- Mihaela Andreescu
- Faculty of Medicine, Titu Maiorescu University, Bucharest, ROU
- Hematology, Colentina Clinical Hospital, Bucharest, ROU
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42
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Crassini K, Gibson J. Pathogenesis and management of immune dysfunction secondary to B cell haematological malignancies. Intern Med J 2024; 54:16-25. [PMID: 38066723 DOI: 10.1111/imj.16279] [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: 02/18/2023] [Accepted: 10/15/2023] [Indexed: 01/26/2024]
Abstract
Malignancies of the B-lymphocyte lineage are among the most diagnosed haematological malignancies in clinical practice. In our community, multiple myeloma (MM) and its precursor condition monoclonal gammopathy of undetermined significance are the commonest, accounting for ~12% of diagnoses, followed by chronic lymphocytic leukaemia (CLL) and its precursor condition monoclonal B lymphocytosis, ~9%. Along with diffuse large B cell lymphoma, follicular lymphoma and marginal zone lymphoma, these conditions comprise around a third of all haematological malignancies diagnosed. Infection remains an important cause of mortality and morbidity in the management of patients with these conditions. This is in part treatment-related but also reflective of disease-related immune dysfunction. Infectious complications account for up to 50% of early mortality in patients with myeloma and up to 50% of all mortality in patients with CLL. A variety of strategies are available to decrease the morbidity and mortality of infectious complications; however, practices vary between countries and often between treating physicians. Treatment options have evolved significantly over the last decade, with the introduction of monoclonal antibodies, small molecule inhibitors, second- and third-generation immunomodulatory agents and CAR-T cell therapy. Much of the data that inform clinical practice in infection management predates current therapeutic approaches. This is in part because of the rapid development of new therapies but also reflective of the long natural history of many of these diseases and the need for prolonged periods of observation. In this article, we review the aspects of disease and treatment that contribute to immune dysfunction in MM, CLL and B-cell non-Hodgkin lymphoma and review the current strategies used to manage immune dysfunction and infection.
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Affiliation(s)
- Kyle Crassini
- MNCCI, Coffs Harbour Health Campus, Coffs Harbour, New South Wales, Australia
| | - John Gibson
- Department of Haematology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
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43
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Welch BM, Manso BA, Gwin KA, Lothert PK, Parikh SA, Kay NE, Medina KL. Comparison of the blood immune repertoire with clinical features in chronic lymphocytic leukemia patients treated with chemoimmunotherapy or ibrutinib. Front Oncol 2023; 13:1302038. [PMID: 38111528 PMCID: PMC10725910 DOI: 10.3389/fonc.2023.1302038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 11/20/2023] [Indexed: 12/20/2023] Open
Abstract
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD19+ CD5+ clonal B lymphocytes in the blood, bone marrow, and peripheral lymphoid organs. Treatment options for patients range from historical chemoimmunotherapy (CIT) to small molecule inhibitors targeting pro-survival pathways in leukemic B cells, such as the Bruton's tyrosine kinase inhibitor ibrutinib (IBR). Using biobanked blood samples obtained pre-therapy and at standard response evaluation timepoints, we performed an in-depth evaluation of the blood innate and adaptive immune compartments between pentostatin-based CIT and IBR and looked for correlations with clinical sequelae. CD4+ conventional T cells and CD8+ cytotoxic T cells responded similarly to CIT and IBR, although exhaustion status differed. Both treatments dramatically increased the prevalence and functional status of monocyte, dendritic cell, and natural killer cell subsets. As expected, both regimens reduced clonal B cell levels however, we observed no substantial recovery of normal B cells. Although improvements in most immune subsets were observed with CIT and IBR at response evaluation, both patient groups remained susceptible to infections and secondary malignancies during the study.
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Affiliation(s)
- Baustin M. Welch
- Department of Immunology, Mayo Clinic, Rochester, MN, United States
- Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, United States
| | - Bryce A. Manso
- Department of Immunology, Mayo Clinic, Rochester, MN, United States
- Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, United States
- Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA, United States
| | - Kimberly A. Gwin
- Department of Immunology, Mayo Clinic, Rochester, MN, United States
| | - Petra K. Lothert
- Department of Immunology, Mayo Clinic, Rochester, MN, United States
- Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, United States
| | - Sameer A. Parikh
- Division of Hematology, Mayo Clinic, Rochester, MN, United States
| | - Neil E. Kay
- Department of Immunology, Mayo Clinic, Rochester, MN, United States
- Division of Hematology, Mayo Clinic, Rochester, MN, United States
| | - Kay L. Medina
- Department of Immunology, Mayo Clinic, Rochester, MN, United States
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44
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Visentin A, Chatzikonstantinou T, Scarfò L, Kapetanakis A, Demosthenous C, Karakatsoulis G, Minga E, Chamou D, Allsup D, Cabrero AA, Andres M, Antic D, Baile M, Baliakas P, Besikli-Dimou S, Bron D, Chatzileontiadou S, Cordoba R, Correa JG, Cuéllar-García C, De Paoli L, De Paolis MR, Delgado J, Dimou M, Donaldson D, Catherwood M, Doubek M, Efstathopoulou M, Eichhorst B, Elashwah S, Enrico A, Espinet B, Farina L, Ferrari A, Foglietta M, Frederiksen H, Fürstenau M, García-Marco JA, García-Serra R, Collado R, Gentile M, Gimeno E, Glenthøj A, da Silva MG, Hakobyan YK, Herishanu Y, Hernández-Rivas JÁ, Herold T, Innocenti I, Itchaki G, Jaksic O, Janssens A, Kalashnikova ОB, Kalicińska E, Kater AP, Kersting S, Labrador J, Lad D, Laurenti L, Levin MD, Lista E, Lopez-Garcia A, Malerba L, Marasca R, Marchetti M, Marquet J, Mattsson M, Mauro FR, Morawska M, Motta M, Munir T, Murru R, Niemann CU, Rodrigues RN, Olivieri J, Orsucci L, Papaioannou M, Pavlovsky MA, Piskunova I, Popov VM, Quaglia FM, Quaresmini G, Qvist K, Rigolin GM, Ruchlemer R, Šimkovič M, Špaček M, Sportoletti P, Stanca O, Tadmor T, Capasso A, Del Poeta G, Gutwein O, Karlsson LK, Milosevic I, Mirás F, Reda G, Saghumyan G, Shrestha A, Te Raa D, et alVisentin A, Chatzikonstantinou T, Scarfò L, Kapetanakis A, Demosthenous C, Karakatsoulis G, Minga E, Chamou D, Allsup D, Cabrero AA, Andres M, Antic D, Baile M, Baliakas P, Besikli-Dimou S, Bron D, Chatzileontiadou S, Cordoba R, Correa JG, Cuéllar-García C, De Paoli L, De Paolis MR, Delgado J, Dimou M, Donaldson D, Catherwood M, Doubek M, Efstathopoulou M, Eichhorst B, Elashwah S, Enrico A, Espinet B, Farina L, Ferrari A, Foglietta M, Frederiksen H, Fürstenau M, García-Marco JA, García-Serra R, Collado R, Gentile M, Gimeno E, Glenthøj A, da Silva MG, Hakobyan YK, Herishanu Y, Hernández-Rivas JÁ, Herold T, Innocenti I, Itchaki G, Jaksic O, Janssens A, Kalashnikova ОB, Kalicińska E, Kater AP, Kersting S, Labrador J, Lad D, Laurenti L, Levin MD, Lista E, Lopez-Garcia A, Malerba L, Marasca R, Marchetti M, Marquet J, Mattsson M, Mauro FR, Morawska M, Motta M, Munir T, Murru R, Niemann CU, Rodrigues RN, Olivieri J, Orsucci L, Papaioannou M, Pavlovsky MA, Piskunova I, Popov VM, Quaglia FM, Quaresmini G, Qvist K, Rigolin GM, Ruchlemer R, Šimkovič M, Špaček M, Sportoletti P, Stanca O, Tadmor T, Capasso A, Del Poeta G, Gutwein O, Karlsson LK, Milosevic I, Mirás F, Reda G, Saghumyan G, Shrestha A, Te Raa D, Tonino SH, Van Der Spek E, van Gelder M, van Kampen R, Wasik-Szczepanek E, Wróbel T, Segundo LYS, Yassin M, Pocali B, Vandenberghe E, Iyengar S, Varettoni M, Vitale C, Coscia M, Rambaldi A, Montserrat E, Cuneo A, Stavroyianni N, Trentin L, Stamatopoulos K, Ghia P. The evolving landscape of COVID-19 and post-COVID condition in patients with chronic lymphocytic leukemia: A study by ERIC, the European research initiative on CLL. Am J Hematol 2023; 98:1856-1868. [PMID: 37772428 DOI: 10.1002/ajh.27093] [Show More Authors] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 08/18/2023] [Accepted: 08/23/2023] [Indexed: 09/30/2023]
Abstract
In this retrospective international multicenter study, we describe the clinical characteristics and outcomes of patients with chronic lymphocytic leukemia (CLL) and related disorders (small lymphocytic lymphoma and high-count monoclonal B lymphocytosis) infected by SARS-CoV-2, including the development of post-COVID condition. Data from 1540 patients with CLL infected by SARS-CoV-2 from January 2020 to May 2022 were included in the analysis and assigned to four phases based on cases disposition and SARS-CoV-2 variants emergence. Post-COVID condition was defined according to the WHO criteria. Patients infected during the most recent phases of the pandemic, though carrying a higher comorbidity burden, were less often hospitalized, rarely needed intensive care unit admission, or died compared to patients infected during the initial phases. The 4-month overall survival (OS) improved through the phases, from 68% to 83%, p = .0015. Age, comorbidity, CLL-directed treatment, but not vaccination status, emerged as risk factors for mortality. Among survivors, 6.65% patients had a reinfection, usually milder than the initial one, and 16.5% developed post-COVID condition. The latter was characterized by fatigue, dyspnea, lasting cough, and impaired concentration. Infection severity was the only risk factor for developing post-COVID. The median time to resolution of the post-COVID condition was 4.7 months. OS in patients with CLL improved during the different phases of the pandemic, likely due to the improvement of prophylactic and therapeutic measures against SARS-CoV-2 as well as the emergence of milder variants. However, mortality remained relevant and a significant number of patients developed post-COVID conditions, warranting further investigations.
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Affiliation(s)
- Andrea Visentin
- Hematology and Clinical Immunology Unit, Department of Medicine, University of Padova, Padova, Italy
| | | | - Lydia Scarfò
- Università Vita-Salute San Raffaele and IRCC Ospedale San Raffaele, Milan, Italy
| | - Anargyros Kapetanakis
- Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece
| | | | - Georgios Karakatsoulis
- Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece
- Department of Mathematics, University of Ioannina, Ioannina, Greece
| | - Eva Minga
- Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece
| | - Dimitra Chamou
- Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece
| | - David Allsup
- Centre for Biomedicine, Hull York Medical School, Hull, UK
| | - Alejandro Alonso Cabrero
- Spanish Society of Hematology and Hemotherapy (SEHH: Sociedad Española de Hematología y hemoterapia), Madrid, Spain
- Hematology Department, Hospital Universitario de La Princesa, Madrid, Spain
| | - Martin Andres
- Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Darko Antic
- University Clinical Center of Serbia, Belgrade, Serbia
- School of Medicine, University of Belgrade, Belgrade, Serbia
| | - Mónica Baile
- Hospital Clinico Universitario de Salamanca (CAUSA/IBSAL), Salamanca, Spain
| | - Panagiotis Baliakas
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
- Department of Clinical Genetics, Uppsala University Hospital, Uppsala, Sweden
| | | | | | - Sofia Chatzileontiadou
- Hematology Unit, 1st Dept of Internal Medicine, AUTH, AHEPA Hospital, Thessaloniki, Greece
| | - Raul Cordoba
- Department of Hematology, Health Research Institute IIS-FJD, Fundacion Jimenez Diaz University Hospital, Madrid, Spain
| | | | | | - Lorenzo De Paoli
- Division of Hematology, Department of Translational Medicine, Università del Piemonte Orientale Amedeo Avogadro, Azienda Ospedaliero-Universitaria Maggiore della Carità Novara, Novara, Italy
| | | | | | - Maria Dimou
- 1st Internal Medicine Department, Propaedeutic, Hematology Clinical Trial Unit, National and Kapodistrian University of Athens, Athens, Greece
| | | | | | - Michael Doubek
- Department of Internal Medicine-Hematology and Oncology, University Hospital, Brno, Czech Republic
- Faculty of Medicine, Department of Medical Genetics and Genomics, Masaryk University, Brno, Czech Republic
| | - Maria Efstathopoulou
- Department of Haematology, Athens Medical Center-Psychikon Branch, Athens, Greece
| | - Barbara Eichhorst
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Salma Elashwah
- Medical Oncology Unit, Faculty of Medicine, Oncology Center Mansoura University (OCMU), Mansoura, Egypt
| | | | | | - Lucia Farina
- Hematology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Angela Ferrari
- Hematology Unit, Azienda Unità Sanitaria Locale-IRCCS, Reggio Emilia, Italy
| | | | | | - Moritz Fürstenau
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), University Hospital Cologne, University of Cologne, Cologne, Germany
| | - José A García-Marco
- Hematology Department, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain
| | - Rocío García-Serra
- Department of Hematology, Hospital General Universitario, Valencia, Spain
- Fundaci_on de Investigaci_on del Hospital General Universitario, Valencia, Spain
| | - Rosa Collado
- Department of Hematology, Hospital General Universitario, Valencia, Spain
| | - Massimo Gentile
- Hematology Unit, Azienda Ospedaliera Annunziata, Cosenza, Italy
- Department of Pharmacy, Health and Nutritional Science, University of Calabria, Rende, Italy
| | - Eva Gimeno
- Department of Hematology, Hospital del Mar, Barcelona, Spain
| | - Andreas Glenthøj
- Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | | | | | - Yair Herishanu
- Department of Hematology, Tel Aviv Sourasky Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | | | - Tobias Herold
- Department of Medicine III, Laboratory for Leukemia Diagnostics, University Hospital, Munich, Germany
| | - Idanna Innocenti
- Hematology Unit, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Gilad Itchaki
- Meir Medical Center, Kfar-Saba, Israel
- The Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Ozren Jaksic
- Department of Hematology, University Hospital Dubrava, Zagreb, Croatia
| | - Ann Janssens
- Department of Hematology, Universitaire Ziekenhuizen Leuven, Leuven, Belgium
| | - Оlga B Kalashnikova
- Federal State Budgetary Educational Institution of Higher Education Academician I.P. Pavlov First St. Petersburg State Medical University of the Ministry of Healthcare of Russian Federation, St. Petersburg, Russia
| | - Elżbieta Kalicińska
- Department and Clinic of Hematology, Blood Neoplasms and Bone Marrow Transplantation Wroclaw Medical University, Wroclaw, Poland
| | - Arnon P Kater
- Department of Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Sabina Kersting
- Department of Hematology, Haga Teaching Hospital, The Hague, The Netherlands
| | - Jorge Labrador
- Hematology Department, Unit Research, Complejo Asistencial Universitario de Burgos, Burgos, Spain
| | - Deepesh Lad
- Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Luca Laurenti
- Hematology Unit, Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Mark-David Levin
- Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, the Netherlands
| | - Enrico Lista
- Department of Hematology, Santa Chiara Hospital, Trento, Italy
| | - Alberto Lopez-Garcia
- Department of Hematology, Health Research Institute IIS-FJD, Fundacion Jimenez Diaz University Hospital, Madrid, Spain
| | - Lara Malerba
- Hematology and Stem Cell Transplant Center, Marche Nord Hospital, Pesaro, Italy
| | - Roberto Marasca
- Department of Medical Sciences, Section of Hematology, University of Modena and Reggio E., Modena, Italy
| | - Monia Marchetti
- Hematology Unit and BM Transplant Center, AO SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
| | - Juan Marquet
- Hematology Department, Ram_on y Cajal University Hospital, Madrid, Spain
| | - Mattias Mattsson
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
- Department of Hematology, Uppsala University Hospital, Uppsala, Sweden
| | - Francesca R Mauro
- Hematology Unit, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy
| | - Marta Morawska
- Experimental Hematooncology Department, Medical University of Lublin, Lublin, Poland
- Hematology Department, St. John's Cancer Center, Lublin, Poland
| | - Marina Motta
- S.C. Ematologia, ASST Spedali Civili Brescia, Brescia, Italy
| | - Talha Munir
- Consultant Haematologist, St James's Hospital, Leeds, UK
| | - Roberta Murru
- Hematology and Stem Cell Transplantation Unit, Ospedale Oncologico A. Businco, ARNAS "G. Brotzu", Cagliari, Italy
| | - Carsten U Niemann
- Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | | | - Jacopo Olivieri
- Hematology Clinic, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy
| | - Lorella Orsucci
- S.C. Ematologia, Città della Salute e della Scienza di Torino, Turin, Italy
| | - Maria Papaioannou
- Hematology Unit, 1st Dept of Internal Medicine, AUTH, AHEPA Hospital, Thessaloniki, Greece
| | | | - Inga Piskunova
- Consultative Hematology Department with a Day Hospital for Intensive High-Dose Chemotherapy, National Research Center for Hematology, Moscow, Russia
| | - Viola Maria Popov
- HematologyDepartment, Colentina Clinical Hospital, Bucharest, Romania
| | | | - Giulia Quaresmini
- Department of Oncology and Hematology, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII Bergamo, Bergamo, Italy
| | - Kristian Qvist
- Hematologic Section, Department of Internal Medicine, Hospital Union West, Herning, Denmark
| | | | - Rosa Ruchlemer
- Department of Hematology, Shaare-Zedek Medical Center, Affiliated with the Hebrew University Medical School, Jerusalem, Israel
| | - Martin Šimkovič
- Faculty of Medicine in Hradec Králové, 4th Department of Internal Medicine-Haematology, University Hospital and Charles University in Prague, Hradec Kralove, Czech Republic
| | - Martin Špaček
- First Faculty of Medicine, 1st Department of Medicine-Hematology, Charles University and General Hospital in Prague, Prague, Czech Republic
| | - Paolo Sportoletti
- Department of Medicine and Surgery, Institute of Hematology and Center for Hemato-Oncological Research, University of Perugia, Perugia, Italy
| | - Oana Stanca
- Hematology Department, Coltea Clinical Hospital, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
| | - Tamar Tadmor
- Division of Hematology, Bnai-Zion Medical Center, Haifa, Israel
| | | | - Giovanni Del Poeta
- Department of Biomedicine and Prevention Hematology, University Tor Vergata, Rome, Italy
| | - Odit Gutwein
- Department of Hematology, Shamir Medical Center, Zerifin, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | | | - Ivana Milosevic
- Faculty of Medicine, Clinical Centre of Vojvodina, University of Novi Sad, Novi Sad, Serbia
| | - Fatima Mirás
- Hematology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Gianluigi Reda
- Hematology Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico of Milan, Milan, Italy
| | | | - Amit Shrestha
- Hematology Unit, Nepal Cancer Hospital & Research Centre, Lalitpur, Nepal
| | - Doreen Te Raa
- Department of Hematology, Gelderse Vallei Ede, Ede, the Netherlands
| | - Sanne H Tonino
- Department of Hematology, Lymmcare, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Ellen Van Der Spek
- Department of Internal Medicine, Rijnstate Hospital, Arnhem, the Netherlands
| | - Michel van Gelder
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands
| | | | - Ewa Wasik-Szczepanek
- Department of Hematooncology and Bone Marrow Transplantation, Medical University in Lublin, Lublin, Poland
| | - Tomasz Wróbel
- Department and Clinic of Hematology, Blood Neoplasms and Bone Marrow Transplantation Wroclaw Medical University, Wroclaw, Poland
| | - Lucrecia Yáñez San Segundo
- Hematology Department, University Hospital and Research Institute of Marqués de Valdecilla (IDIVAL), Santander, Spain
| | - Mohamed Yassin
- Hematology Section, Department of Medical Oncology, National Center for Cancer Care and Research, Doha, Qatar
| | | | | | - Sunil Iyengar
- Haemato-oncology Unit, The Royal Marsden Hospital, UK
| | - Marzia Varettoni
- Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Candida Vitale
- Division of Hematology, Department of Molecular Biotechnology and Health Sciences, A.O.U. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Marta Coscia
- Division of Hematology, Department of Molecular Biotechnology and Health Sciences, A.O.U. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Alessandro Rambaldi
- Department of Medicine and Surgery, Institute of Hematology and Center for Hemato-Oncological Research, University of Perugia, Perugia, Italy
| | | | | | - Niki Stavroyianni
- Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece
| | - Livio Trentin
- Hematology and Clinical Immunology Unit, Department of Medicine, University of Padova, Padova, Italy
| | - Kostas Stamatopoulos
- Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece
| | - Paolo Ghia
- Università Vita-Salute San Raffaele and IRCC Ospedale San Raffaele, Milan, Italy
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Vitale C, Griggio V, Perutelli F, Coscia M. CAR-modified Cellular Therapies in Chronic Lymphocytic Leukemia: Is the Uphill Road Getting Less Steep? Hemasphere 2023; 7:e988. [PMID: 38044959 PMCID: PMC10691795 DOI: 10.1097/hs9.0000000000000988] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 10/23/2023] [Indexed: 12/05/2023] Open
Abstract
The clinical development of chimeric antigen receptor (CAR) T-cell therapy has been more challenging for chronic lymphocytic leukemia (CLL) compared to other settings. One of the main reasons is the CLL-associated state of immune dysfunction that specifically involves patient-derived T cells. Here, we provide an overview of the clinical results obtained with CAR T-cell therapy in CLL, describing the identified immunologic reasons for the inferior efficacy. Novel CAR T-cell formulations, such as lisocabtagene maraleucel, administered alone or in combination with the Bruton tyrosine kinase inhibitor ibrutinib, are currently under investigation. These approaches are based on the rationale that improving the quality of the T-cell source and of the CAR T-cell product may deliver a more functional therapeutic weapon. Further strategies to boost the efficacy of CAR T cells should rely not only on the production of CAR T cells with an improved cellular composition but also on additional changes. Such alterations could include (1) the coadministration of immunomodulatory agents capable of counteracting CLL-related immunological alterations, (2) the design of improved CAR constructs (such as third- and fourth-generation CARs), (3) the incorporation into the manufacturing process of immunomodulatory compounds overcoming the T-cell defects, and (4) the use of allogeneic CAR T cells or alternative CAR-modified cellular vectors. These strategies may allow to develop more effective CAR-modified cellular therapies capable of counteracting the more aggressive and still incurable forms of CLL.
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Affiliation(s)
- Candida Vitale
- University Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino, Italy
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy
| | - Valentina Griggio
- University Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino, Italy
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy
| | - Francesca Perutelli
- University Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino, Italy
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy
| | - Marta Coscia
- University Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino, Italy
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy
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Chatzikonstantinou T, Scarfò L, Karakatsoulis G, Minga E, Chamou D, Iacoboni G, Kotaskova J, Demosthenous C, Smolej L, Mulligan S, Alcoceba M, Al-Shemari S, Aurran-Schleinitz T, Bacchiarri F, Bellido M, Bijou F, Calleja A, Medina A, Khan MA, Cassin R, Chatzileontiadou S, Collado R, Christian A, Davis Z, Dimou M, Donaldson D, Santos GD, Dreta B, Efstathopoulou M, El-Ashwah S, Enrico A, Fresa A, Galimberti S, Galitzia A, García-Serra R, Gimeno E, González-Gascón-y-Marín I, Gozzetti A, Guarente V, Guieze R, Gogia A, Gupta R, Harrop S, Hatzimichael E, Herishanu Y, Hernández-Rivas JÁ, Inchiappa L, Jaksic O, Janssen S, Kalicińska E, Laribi K, Karakus V, Kater AP, Kho B, Kislova M, Konstantinou E, Koren-Michowitz M, Kotsianidis I, Kreitman RJ, Labrador J, Lad D, Levin MD, Levy I, Longval T, Lopez-Garcia A, Marquet J, Martin-Rodríguez L, Maynadié M, Maslejova S, Mayor-Bastida C, Mihaljevic B, Milosevic I, Miras F, Moia R, Morawska M, Murru R, Nath UK, Navarro-Bailón A, Oliveira AC, Olivieri J, Oscier D, Panovska-Stavridis I, Papaioannou M, Papajík T, Kubova Z, Phumphukhieo P, Pierie C, Puiggros A, Rani L, Reda G, Rigolin GM, Ruchlemer R, Daniel de Deus Santos M, Schipani M, Schiwitza A, Shen Y, Simkovic M, Smirnova S, Abdelrahman Soliman DS, Spacek M, et alChatzikonstantinou T, Scarfò L, Karakatsoulis G, Minga E, Chamou D, Iacoboni G, Kotaskova J, Demosthenous C, Smolej L, Mulligan S, Alcoceba M, Al-Shemari S, Aurran-Schleinitz T, Bacchiarri F, Bellido M, Bijou F, Calleja A, Medina A, Khan MA, Cassin R, Chatzileontiadou S, Collado R, Christian A, Davis Z, Dimou M, Donaldson D, Santos GD, Dreta B, Efstathopoulou M, El-Ashwah S, Enrico A, Fresa A, Galimberti S, Galitzia A, García-Serra R, Gimeno E, González-Gascón-y-Marín I, Gozzetti A, Guarente V, Guieze R, Gogia A, Gupta R, Harrop S, Hatzimichael E, Herishanu Y, Hernández-Rivas JÁ, Inchiappa L, Jaksic O, Janssen S, Kalicińska E, Laribi K, Karakus V, Kater AP, Kho B, Kislova M, Konstantinou E, Koren-Michowitz M, Kotsianidis I, Kreitman RJ, Labrador J, Lad D, Levin MD, Levy I, Longval T, Lopez-Garcia A, Marquet J, Martin-Rodríguez L, Maynadié M, Maslejova S, Mayor-Bastida C, Mihaljevic B, Milosevic I, Miras F, Moia R, Morawska M, Murru R, Nath UK, Navarro-Bailón A, Oliveira AC, Olivieri J, Oscier D, Panovska-Stavridis I, Papaioannou M, Papajík T, Kubova Z, Phumphukhieo P, Pierie C, Puiggros A, Rani L, Reda G, Rigolin GM, Ruchlemer R, Daniel de Deus Santos M, Schipani M, Schiwitza A, Shen Y, Simkovic M, Smirnova S, Abdelrahman Soliman DS, Spacek M, Tadmor T, Tomic K, Tse E, Vassilakopoulos T, Visentin A, Vitale C, von Tresckow J, Vrachiolias G, Vukovic V, Walewska R, Wasik-Szczepanek E, Xu Z, Yagci M, Yañez L, Yassin M, Zuchnicka J, Angelopoulou M, Antic D, Biderman B, Catherwood M, Claus R, Coscia M, Cuneo A, Demirkan F, Espinet B, Gaidano G, Kalashnikova OB, Laurenti L, Nikitin E, Pangalis GA, Panagiotidis P, Popov VM, Pospisilova S, Sportoletti P, Stavroyianni N, Tam C, Trentin L, Chatzidimitriou A, Bosch F, Doubek M, Ghia P, Stamatopoulos K. Other malignancies in the history of CLL: an international multicenter study conducted by ERIC, the European Research Initiative on CLL, in HARMONY. EClinicalMedicine 2023; 65:102307. [PMID: 38033506 PMCID: PMC10685149 DOI: 10.1016/j.eclinm.2023.102307] [Show More Authors] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 10/19/2023] [Accepted: 10/25/2023] [Indexed: 12/02/2023] Open
Abstract
Background Patients with chronic lymphocytic leukemia (CLL) have a higher risk of developing other malignancies (OMs) compared to the general population. However, the impact of CLL-related risk factors and CLL-directed treatment is still unclear and represents the focus of this work. Methods We conducted a retrospective international multicenter study to assess the incidence of OMs and detect potential risk factors in 19,705 patients with CLL, small lymphocytic lymphoma, or high-count CLL-like monoclonal B-cell lymphocytosis, diagnosed between 2000 and 2016. Data collection took place between October 2020 and March 2022. Findings In 129,254 years of follow-up after CLL diagnosis, 3513 OMs were diagnosed (27.2 OMs/1000 person-years). The most common hematological OMs were Richter transformation, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Non-melanoma skin (NMSC) and prostate cancers were the most common solid tumors (STs).The only predictor for MDS and AML development was treatment with fludarabine and cyclophosphamide with/without rituximab (FC ± R) (OR = 3.7; 95% CI = 2.79-4.91; p < 0.001). STs were more frequent in males and patients with unmutated immunoglobulin heavy variable genes (OR = 1.77; 95% CI = 1.49-2.11; p < 0.001/OR = 1.89; 95% CI = 1.6-2.24; p < 0.001).CLL-directed treatment was associated with non-melanoma skin and prostate cancers (OR = 1.8; 95% CI = 1.36-2.41; p < 0.001/OR = 2.11; 95% CI = 1.12-3.97; p = 0.021). In contrast, breast cancers were more frequent in untreated patients (OR = 0.17; 95% CI = 0.08-0.33; p < 0.001).Patients with CLL and an OM had inferior overall survival (OS) than those without. AML and MDS conferred the worst OS (p < 0.001). Interpretation OMs in CLL impact on OS. Treatment for CLL increased the risk for AML/MDS, prostate cancer, and NMSC. FCR was associated with increased risk for AML/MDS. Funding AbbVie, and EU/EFPIAInnovative Medicines Initiative Joint Undertaking HARMONY grant n° 116026.
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Affiliation(s)
| | - Lydia Scarfò
- Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan, Italy
| | - Georgios Karakatsoulis
- Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece
- Department of Mathematics, University of Ioannina, Ioannina, Greece
| | - Eva Minga
- Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece
| | - Dimitra Chamou
- Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece
| | - Gloria Iacoboni
- Department of Haematology, University Hospital Vall d'Hebron, Autonomous University, Barcelona, Spain
| | - Jana Kotaskova
- Central European Institute of Technology (CEITEC), Masaryk University, Brno, Czech Republic
- Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | | | - Lukas Smolej
- 4th Department of Internal Medicine-Haematology, University Hospital and Faculty of Medicine, Hradec Králové, Czech Republic
| | | | - Miguel Alcoceba
- Department of Haematology, University Hospital of Salamanca (HUS-IBSAL), CIBERONC (CB16/12/00233) and Cancer Research Centre (CIC-IBMCC, USAL-CSIC), Salamanca, Spain
| | - Salem Al-Shemari
- Faculty of Medicine, Department of Medicine, Kuwait University, Kuwait City, Kuwait
| | | | | | - Mar Bellido
- Hematology Department, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | | | - Anne Calleja
- Department of Hemato-Oncology, Institut Paoli Calmettes, Marseille, France
| | | | - Mehreen Ali Khan
- Department of Hematology and Stem Cell Transplant, Armed Forces Bone Marrow Transplant Center/National Institute of Blood and Marrow Transplant, Rawalpindi, Pakistan
| | - Ramona Cassin
- Hematology Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milan, Milan, Italy
| | - Sofia Chatzileontiadou
- Hematology Unit, 1st Dept of Internal Medicine, AUTH, AHEPA Hospital, Thessaloniki, Greece
| | - Rosa Collado
- Servicio de Hematología, Consorcio Hospital General Universitario de Valencia, Fundación de Investigación Hospital General Universitario de Valencia, Valencia, Spain
| | - Amy Christian
- Department of Haematology, Royal Bournemouth Hospital, Bournemouth, United Kingdom
| | - Zadie Davis
- Department of Haematology, Royal Bournemouth Hospital, Bournemouth, United Kingdom
| | - Maria Dimou
- Department of Hematology and Bone Marrow Transplantation Unit, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece
| | - David Donaldson
- Clinical Haematology, Belfast City Hospital, Belfast, United Kingdom
| | | | - Barbara Dreta
- Division of Hematology, Department of Internal Medicine, University Hospital Center Zagreb, Zagreb, Croatia
| | - Maria Efstathopoulou
- Department of Haematology, Athens Medical Center-Psychikon Branch, Athens, Greece
| | | | | | - Alberto Fresa
- Sezione di Ematologia, Dipartimento di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, Rome, Italy
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Sara Galimberti
- Section of Hematology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Andrea Galitzia
- Hematology and Stem Cell Transplantation Unit, Ospedale Oncologico A. Businco, ARNAS "G. Brotzu", Cagliari, Italy
| | - Rocío García-Serra
- Servicio de Hematología, Consorcio Hospital General Universitario de Valencia, Fundación de Investigación Hospital General Universitario de Valencia, Valencia, Spain
| | - Eva Gimeno
- Department of Hematology, Hospital del Mar, Barcelona, Spain
| | | | | | - Valerio Guarente
- Institute of Hematology and Center for Hemato-Oncology Research, University of Perugia and Santa Maria della Misericordia Hospital, Perugia, Italy
| | - Romain Guieze
- Department of Hematology and Cell Therapy, Estaing University Hospital, Clermont-Ferrand, France
| | - Ajay Gogia
- Laboratory Oncology Unit, Dr. B.R.A. IRCH, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Ritu Gupta
- Laboratory Oncology Unit, Dr. B.R.A. IRCH, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Sean Harrop
- Peter MacCallum Cancer Centre, St Vincent's Hospital, University of Melbourne, Melbourne, VIC 3000, Australia
| | - Eleftheria Hatzimichael
- Faculty of Medicine, Department of Haematology, School of Health Sciences, University of Ioannina, Stavros Niarchos Avenue, Ioannina 45110, Greece
| | - Yair Herishanu
- Department of Hematology, Tel Aviv Sourasky Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | | | - Luca Inchiappa
- Department of Hemato-Oncology, Institut Paoli Calmettes, Marseille, France
| | - Ozren Jaksic
- Department of Hematology, University Hospital Dubrava, Zagreb, Croatia
| | - Susanne Janssen
- Dept of Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Elżbieta Kalicińska
- Department and Clinic of Hematology, Blood Neoplasms and Bone Marrow Transplantation Wroclaw Medical University, Wroclaw, Poland
| | - Kamel Laribi
- Department of Hematology, Centre Hospitalier Le Mans, Le Mans, France
| | | | - Arnon P. Kater
- Dept of Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Bonnie Kho
- Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong, China
| | - Maria Kislova
- Department of Hematology, Oncology, and Chemotherapy, S. P. Botkin's City Hospital, Moscow, Russia
| | | | - Maya Koren-Michowitz
- Department of Hematology, Shamir Medical Center, Zerifin, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel
| | - Ioannis Kotsianidis
- Department of Hematology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
| | - Robert J. Kreitman
- Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jorge Labrador
- Department of Hematology, Hospital Universitario de Burgos, Burgos, Spain
| | - Deepesh Lad
- Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Mark-David Levin
- Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, the Netherlands
| | - Ilana Levy
- Hematology, Bnai-Zion Medical Center, Haifa, Israel
| | - Thomas Longval
- Service d'Hématologie Oncologie, Centre Hospitalier de Versailles, Le Chesnay, France
| | - Alberto Lopez-Garcia
- Fundacion Jimenez Diaz University Hospital, Health Research Institute IIS-FJD, Madrid, Spain
| | - Juan Marquet
- Hematology Department, Ramón y Cajal University Hospital, Madrid, Spain
| | - Lucia Martin-Rodríguez
- Department of Haematology, University Hospital Vall d'Hebron, Autonomous University, Barcelona, Spain
| | - Marc Maynadié
- Biological Haematology Department, Dijon Bourgogne University Hospital, Haematological Malignancies Registry, LNC UMR 1231, Dijon 21000, France
| | - Stanislava Maslejova
- Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | | | - Biljana Mihaljevic
- Clinic for Hematology, University Clinical Center of Serbia, Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Ivana Milosevic
- Faculty of Medicine, Clinical Centre of Vojvodina, University of Novi Sad, Novi Sad, Serbia
| | - Fatima Miras
- Hematology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Riccardo Moia
- Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
| | - Marta Morawska
- Experimental Hematooncology Department, Medical University of Lublin, Lublin, Poland
- Hematology Department, St. John's Cancer Center, Lublin, Poland
| | - Roberta Murru
- Hematology and Stem Cell Transplantation Unit, Ospedale Oncologico A. Businco, ARNAS "G. Brotzu", Cagliari, Italy
| | - Uttam Kumar Nath
- Department of Medical Oncology & Hematology, All India Institute of Medical Sciences, Rishikesh, India
| | - Almudena Navarro-Bailón
- Department of Haematology, University Hospital of Salamanca (HUS-IBSAL), CIBERONC (CB16/12/00233) and Cancer Research Centre (CIC-IBMCC, USAL-CSIC), Salamanca, Spain
| | - Ana C. Oliveira
- Department of Clinical Hematology, ICO, Hospital Duran i Reynals, IDIBELL, Barcelona, Spain
| | | | - David Oscier
- Department of Haematology, Royal Bournemouth Hospital, Bournemouth, United Kingdom
| | - Irina Panovska-Stavridis
- Medical Faculty, University Clinic of Hematology, University Ss. Cyril and Methodius, Skopje, North Macedonia
| | - Maria Papaioannou
- Hematology Unit, 1st Dept of Internal Medicine, AUTH, AHEPA Hospital, Thessaloniki, Greece
| | - Tomas Papajík
- Faculty of Medicine and Dentistry, Department of Hemato-Oncology, Palacký University and University Hospital Olomouc, Olomouc, Czech Republic
| | - Zuzana Kubova
- Faculty of Medicine and Dentistry, Department of Hemato-Oncology, Palacký University and University Hospital Olomouc, Olomouc, Czech Republic
| | | | - Cheyenne Pierie
- Dept of Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Anna Puiggros
- Molecular Cytogenetics Laboratory, Pathology Department, Hospital del Mar and Translational Research on Hematological Neoplasms Group, Hospital del Mar Research Institute (IMIM), Barcelona, Spain
| | - Lata Rani
- Laboratory Oncology Unit, Dr. B.R.A. IRCH, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Gianluigi Reda
- Hematology Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milan, Milan, Italy
| | | | - Rosa Ruchlemer
- Department of Hematology, Shaare-Zedek Medical Center, Affiliated with the Hebrew University Medical School, Jerusalem, Israel
| | | | - Mattia Schipani
- Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
| | - Annett Schiwitza
- Hematology and Oncology, Faculty of Medicine, University of Augsburg, Stenglinstrasse 2, Augsburg 86156, Germany
| | - Yandong Shen
- Royal North Shore Hospital, Sydney, NSW, Australia
| | - Martin Simkovic
- 4th Department of Internal Medicine-Haematology, University Hospital and Faculty of Medicine, Hradec Králové, Czech Republic
| | - Svetlana Smirnova
- Consultative Hematology Department with a Day Hospital for Intensive High-Dose Chemotherapy, National Medical Research Center for Hematology, Moscow, Russia
| | | | - Martin Spacek
- First Faculty of Medicine, 1st Department of Medicine - Hematology, Charles University and General Hospital in Prague, Czech Republic
| | - Tamar Tadmor
- Hematology, Bnai-Zion Medical Center, Haifa, Israel
| | - Kristina Tomic
- Clinic for Hematology, University Clinical Center of Serbia, Belgrade, Serbia
| | - Eric Tse
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
| | | | - Andrea Visentin
- Hematology and Clinical Immunology Unit, Department of Medicine, University of Padova, Padova, Italy
| | - Candida Vitale
- Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino and Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Julia von Tresckow
- Clinic for Hematology and Stem Cell Transplantation, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - George Vrachiolias
- Department of Hematology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
| | - Vojin Vukovic
- Clinic for Hematology, University Clinical Center of Serbia, Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Renata Walewska
- Department of Haematology, Royal Bournemouth Hospital, Bournemouth, United Kingdom
| | - Ewa Wasik-Szczepanek
- Dept. Hematooncology and Bone Marrow Transplantation, Medical University in Lublin, Lublin, Poland
| | - Zhenshu Xu
- Fujian Provincial Key Laboratory of Hematology, Fujian Institute of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, China
| | - Munci Yagci
- Gazi University Medical Faculty, Ankara, Turkey
| | - Lucrecia Yañez
- Department of Hematology, University Hospital Marqués de Valdecilla, Santander, Spain
- Department of Hematological Malignancies and Stem Cell Transplantation, Research Institute of Marques de Valdecilla (IDIVAL), Santander, Spain
| | - Mohamed Yassin
- Hematology Section, Department of Medical Oncology, National Center for Cancer Care and Research, Doha, Qatar
| | - Jana Zuchnicka
- Department of Haematooncology, University Hospital Ostrava, Ostrava, Czech Republic
| | - Maria Angelopoulou
- Haematology, University of Athens, Laikon General Hospital, Athens, Greece
| | - Darko Antic
- Clinic for Hematology, University Clinical Center of Serbia, Belgrade, Serbia
- Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Bella Biderman
- Department of Molecular Hematology, National Medical Research Center for Hematology, Moscow, Russia
| | - Mark Catherwood
- Clinical Haematology, Belfast City Hospital, Belfast, United Kingdom
| | - Rainer Claus
- Pathology, Faculty of Medicine, University of Augsburg, Stenglinstrasse 2, Augsburg 86156, Germany
- Faculty of Medicine, Comprehensive Cancer Center Augsburg, University of Augsburg, Stenglinstrasse 2, Augsburg 86156, Germany
| | - Marta Coscia
- Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino and Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | | | - Fatih Demirkan
- Division of Hematology, Dokuz Eylul University, Izmir, Turkey
| | - Blanca Espinet
- Molecular Cytogenetics Laboratory, Pathology Department, Hospital del Mar and Translational Research on Hematological Neoplasms Group, Hospital del Mar Research Institute (IMIM), Barcelona, Spain
| | - Gianluca Gaidano
- Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
| | - Olga B. Kalashnikova
- Federal State Budgetary Educational Institution of Higher Education Academician I.P. Pavlov First St. Petersburg State Medical University of the Ministry of Healthcare of Russian Federation, St. Petersburg, Russia
| | - Luca Laurenti
- Sezione di Ematologia, Dipartimento di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, Rome, Italy
- Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Eugene Nikitin
- Department of Hematology, Oncology, and Chemotherapy, S. P. Botkin's City Hospital, Moscow, Russia
| | | | - Panagiotis Panagiotidis
- Department of Hematology and Bone Marrow Transplantation Unit, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece
| | - Viola Maria Popov
- Hematology Department, Colentina Clinical Hospital, Bucharest, Romania
| | - Sarka Pospisilova
- Central European Institute of Technology (CEITEC), Masaryk University, Brno, Czech Republic
- Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Paolo Sportoletti
- Institute of Hematology and Center for Hemato-Oncology Research, University of Perugia and Santa Maria della Misericordia Hospital, Perugia, Italy
| | - Niki Stavroyianni
- Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece
| | - Constantine Tam
- Peter MacCallum Cancer Centre, St Vincent's Hospital, University of Melbourne, Melbourne, VIC 3000, Australia
| | - Livio Trentin
- Hematology and Clinical Immunology Unit, Department of Medicine, University of Padova, Padova, Italy
| | | | - Francesc Bosch
- Department of Haematology, University Hospital Vall d'Hebron, Autonomous University, Barcelona, Spain
| | - Michael Doubek
- Central European Institute of Technology (CEITEC), Masaryk University, Brno, Czech Republic
- Department of Internal Medicine - Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Paolo Ghia
- Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan, Italy
| | - Kostas Stamatopoulos
- Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece
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Doukas PG, St. Pierre F, Karmali R, Mi X, Boyer J, Nieves M, Ison MG, Winter JN, Gordon LI, Ma S. Humoral Immunity After COVID-19 Vaccination in Chronic Lymphocytic Leukemia and Other Indolent Lymphomas: A Single-Center Observational Study. Oncologist 2023; 28:e930-e941. [PMID: 37141401 PMCID: PMC10546828 DOI: 10.1093/oncolo/oyad121] [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: 11/03/2022] [Accepted: 04/06/2023] [Indexed: 05/06/2023] Open
Abstract
BACKGROUND Chronic lymphocytic leukemia (CLL) and other non-Hodgkin's lymphomas (NHLs) lead to broad immunosuppression, conferring a greater risk for morbidity and mortality from SARS-CoV-2. Our study analyzed antibody (Ab) seropositivity from SARS-CoV-2 vaccination in patients with these cancers. METHODS In the final analysis, 240 patients were involved, and seropositivity was defined as a positive total or spike protein Ab. RESULTS Seropositivity was 50% in CLL, 68% in WM, and 70% in the remaining NHLs. Moderna vaccination led to higher seropositivity compared to Pfizer vaccination across all cancers (64% vs. 49%; P = .022) and specifically CLL patients (59% vs. 43%; P = .029). This difference was not explainable by differences in treatment status or prior anti-CD20 monoclonal Ab therapy. In CLL patients, current or prior cancer therapy led to lower seropositivity compared to treatment-naïve patients (36% vs. 68%; P = .000019). CLL patients treated with Bruton's tyrosine kinase (BTK) inhibitors had better seropositivity after receiving the Moderna vaccination compared to Pfizer (50% vs. 23%; P = .015). Across all cancers, anti-CD20 agents within 1 year led to a lower Ab response compared to greater than one year (13% vs. 40%; P = .022), a difference which persisted after booster vaccination. CONCLUSION Antibody response is lower in patients with indolent lymphomas compared to the general population. Lower Ab seropositivity was found in patients with a history of anti-leukemic agent therapy or those immunized with Pfizer vaccine. This data suggests that Moderna vaccination may confer a greater degree of immunity against SARS-CoV-2 in patients with indolent lymphomas.
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Affiliation(s)
- Peter G Doukas
- Department of Medicine, Northwestern Feinberg School of Medicine, Chicago, IL, USA
| | - Frederique St. Pierre
- Division of Hematology and Oncology, Northwestern Feinberg School of Medicine, Chicago, IL, USA
| | - Reem Karmali
- Division of Hematology and Oncology, Northwestern Feinberg School of Medicine, Chicago, IL, USA
| | - Xinlei Mi
- Department of Preventive Medicine and Biostatistics, Northwestern Feinberg School of Medicine, Chicago, IL, USA
| | - Jennifer Boyer
- Division of Hematology and Oncology, Northwestern Feinberg School of Medicine, Chicago, IL, USA
| | - Mariana Nieves
- Division of Hematology and Oncology, Northwestern Feinberg School of Medicine, Chicago, IL, USA
| | - Michael G Ison
- Divisions of Infectious Diseases and Organ Transplantation, Northwestern Feinberg School of Medicine, Chicago, IL, USA
| | - Jane N Winter
- Division of Hematology and Oncology, Northwestern Feinberg School of Medicine, Chicago, IL, USA
| | - Leo I Gordon
- Division of Hematology and Oncology, Northwestern Feinberg School of Medicine, Chicago, IL, USA
| | - Shuo Ma
- Division of Hematology and Oncology, Northwestern Feinberg School of Medicine, Chicago, IL, USA
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Brady MT, Laniewski N, Strawderman M, Chu CC, Kanagaiah P, Sangster MY, Topham DJ, Friedberg JW, Zent CS. Long-term results of vaccination with adjuvanted recombinant varicella zoster glycoprotein E during initial Bruton tyrosine kinase inhibitors therapy for chronic lymphocytic leukemia or lymphoplasmacytic lymphoma. Am J Hematol 2023; 98:E288-E290. [PMID: 37483138 DOI: 10.1002/ajh.27038] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/06/2023] [Accepted: 07/09/2023] [Indexed: 07/25/2023]
Affiliation(s)
- Michael T Brady
- Wilmot Cancer Institute and Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA
| | - Nathan Laniewski
- David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA
| | - Myla Strawderman
- Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, New York, USA
| | - Charles C Chu
- Wilmot Cancer Institute and Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA
| | - Preshetha Kanagaiah
- David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA
| | - Mark Y Sangster
- David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA
| | - David J Topham
- David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA
| | - Jonathan W Friedberg
- Wilmot Cancer Institute and Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA
| | - Clive S Zent
- Wilmot Cancer Institute and Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA
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49
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Fisher JG, Doyle ADP, Graham LV, Sonar S, Sale B, Henderson I, Del Rio L, Johnson PWM, Landesman Y, Cragg MS, Forconi F, Walker CJ, Khakoo SI, Blunt MD. XPO1 inhibition sensitises CLL cells to NK cell mediated cytotoxicity and overcomes HLA-E expression. Leukemia 2023; 37:2036-2049. [PMID: 37528310 PMCID: PMC10539165 DOI: 10.1038/s41375-023-01984-z] [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: 03/09/2023] [Revised: 07/03/2023] [Accepted: 07/21/2023] [Indexed: 08/03/2023]
Abstract
The first-in-class inhibitor of exportin-1 (XPO1) selinexor is currently under clinical investigation in combination with the BTK inhibitor ibrutinib for patients with chronic lymphocytic leukaemia (CLL) or non-Hodgkin lymphoma. Selinexor induces apoptosis of tumour cells through nuclear retention of tumour suppressor proteins and has also recently been described to modulate natural killer (NK) cell and T cell cytotoxicity against lymphoma cells. Here, we demonstrate that XPO1 inhibition enhances NK cell effector function against primary CLL cells via downregulation of HLA-E and upregulation of TRAIL death receptors DR4 and DR5. Furthermore, selinexor potentiates NK cell activation against CLL cells in combination with several approved treatments; acalabrutinib, rituximab and obinutuzumab. We further demonstrate that lymph node associated signals (IL-4 + CD40L) inhibit NK cell activation against CLL cells via upregulation of HLA-E, and that inhibition of XPO1 can overcome this protective effect. These findings allow for the design of more efficacious combination strategies to harness NK cell effector functions against CLL.
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Affiliation(s)
- Jack G Fisher
- School of Clinical and Experimental Sciences, University of Southampton, Southampton, UK
| | - Amber D P Doyle
- School of Clinical and Experimental Sciences, University of Southampton, Southampton, UK
| | - Lara V Graham
- School of Clinical and Experimental Sciences, University of Southampton, Southampton, UK
| | - Shreyanshi Sonar
- School of Clinical and Experimental Sciences, University of Southampton, Southampton, UK
| | - Ben Sale
- School of Cancer Sciences, University of Southampton, Southampton, UK
| | - Isla Henderson
- School of Cancer Sciences, University of Southampton, Southampton, UK
| | - Luis Del Rio
- School of Cancer Sciences, University of Southampton, Southampton, UK
| | - Peter W M Johnson
- School of Cancer Sciences, University of Southampton, Southampton, UK
| | | | - Mark S Cragg
- School of Cancer Sciences, University of Southampton, Southampton, UK
- Antibody and Vaccine Group, Centre for Cancer Immunology, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Francesco Forconi
- School of Cancer Sciences, University of Southampton, Southampton, UK
- Haematology Department, Cancer Care Directorate, University Hospital Southampton NHS Trust, Southampton, UK
| | | | - Salim I Khakoo
- School of Clinical and Experimental Sciences, University of Southampton, Southampton, UK
| | - Matthew D Blunt
- School of Clinical and Experimental Sciences, University of Southampton, Southampton, UK.
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50
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Moreno C, Solman IG, Tam CS, Grigg A, Scarfò L, Kipps TJ, Srinivasan S, Mali RS, Zhou C, Dean JP, Szafer-Glusman E, Choi M. Immune restoration with ibrutinib plus venetoclax in first-line chronic lymphocytic leukemia: the phase 2 CAPTIVATE study. Blood Adv 2023; 7:5294-5303. [PMID: 37315225 PMCID: PMC10506056 DOI: 10.1182/bloodadvances.2023010236] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 05/16/2023] [Accepted: 06/05/2023] [Indexed: 06/16/2023] Open
Abstract
We evaluated immune cell subsets in patients with chronic lymphocytic leukemia (CLL) who received first-line therapy with 3 cycles of ibrutinib then 13 cycles of ibrutinib plus venetoclax in the minimal residual disease (MRD) cohort of the CAPTIVATE study (NCT02910583). Patients with Confirmed undetectable MRD (uMRD) were randomly assigned to placebo or ibrutinib groups; patients without Confirmed uMRD were randomly assigned to ibrutinib or ibrutinib plus venetoclax groups. We compared immune cell subsets in samples collected at 7 time points with age-matched healthy donors. CLL cells decreased within 3 cycles after venetoclax initiation; from cycle 16 onward, levels were similar to healthy donor levels (HDL; ≤0.8 cells per μL) in patients with Confirmed uMRD and slightly above HDL in patients without Confirmed uMRD. By 4 months after cycle 16, normal B cells had recovered to HDL in patients randomly assigned to placebo. Regardless of randomized treatment, abnormal counts of T cells, classical monocytes, and conventional dendritic cells recovered to HDL within 6 months (median change from baseline -49%, +101%, and +91%, respectively); plasmacytoid dendritic cells recovered by cycle 20 (+598%). Infections generally decreased over time regardless of randomized treatment and were numerically lowest in patients randomly assigned to placebo within 12 months after cycle 16. Sustained elimination of CLL cells and recovery of normal B cells were confirmed in samples from patients treated with fixed-duration ibrutinib plus venetoclax in the GLOW study (NCT03462719). These results demonstrate promising evidence of restoration of normal blood immune composition with ibrutinib plus venetoclax.
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Affiliation(s)
- Carol Moreno
- Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Josep Carreras Leukaemia Research Institute, Barcelona, Spain
| | | | - Constantine S. Tam
- Department of Hematology, Alfred Hospital and Monash University, Melbourne, VIC, Australia
| | | | - Lydia Scarfò
- Division of Experimental Oncology, Università Vita Salute San Raffaele and Istituto di Ricovero e Cura a Carattere Scientifico Ospedale San Raffaele, Milan, Italy
| | - Thomas J. Kipps
- Moores Cancer Center, University of California San Diego, La Jolla, CA
| | | | | | - Cathy Zhou
- Pharmacyclics LLC, an AbbVie Company, South San Francisco, CA
| | - James P. Dean
- Pharmacyclics LLC, an AbbVie Company, South San Francisco, CA
| | | | - Michael Choi
- University of California San Diego, La Jolla, CA
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