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Sevuparin strongly reduces hepcidin expression in cells, mice, and healthy human volunteers Sevuparin在细胞、小鼠和健康人类志愿者中显著降低hepcidin的表达
IF 7.6 2区 医学
HemaSphere Pub Date : 2024-11-28 DOI: 10.1002/hem3.70035
Michela Asperti, Andrea Denardo, Magdalena Gryzik, Kristina E. M. Persson, Göran Westerberg, John Öhd, Maura Poli
{"title":"Sevuparin strongly reduces hepcidin expression in cells, mice, and healthy human volunteers","authors":"Michela Asperti,&nbsp;Andrea Denardo,&nbsp;Magdalena Gryzik,&nbsp;Kristina E. M. Persson,&nbsp;Göran Westerberg,&nbsp;John Öhd,&nbsp;Maura Poli","doi":"10.1002/hem3.70035","DOIUrl":"https://doi.org/10.1002/hem3.70035","url":null,"abstract":"<p>Hepcidin is an essential regulator of systemic iron availability mediating both iron uptake from the diet and its release from body stores. Abnormally high hepcidin levels resulting from inflammation in chronic diseases cause iron restriction with the onset of anemia. Restoring physiological levels of hepcidin could contribute to ameliorating anemia in these patients. Heparin derivatives are known to suppress hepcidin expression acting on the BMP/SMAD pathway. The novel heparin derivative sevuparin, modified to markedly reduce its anticoagulant activity, is proposed as a promising hepcidin antagonizing strategy. Sevuparin was tested for its anti-hepcidin properties <i>in vitro</i> in HepG2 cells, <i>in vivo</i> in mice, and in healthy volunteers. Sevuparin strongly suppressed basal, BMP6-, and IL6-dependent hepcidin expression in HepG2 cells in a dose- and time-dependent manner, modulating the essential BMP6/SMAD cascade. These effects were evident in C57BL/6J mice after intravenous injection of a single dose of sevuparin (20 mg/kg) with a 70% reduction of hepcidin mRNA. Remarkably, similar effects were observed in healthy volunteers following single subcutaneous doses at 3, 6, and 9 mg/kg with 40%–50% suppression at 3 and 6 mg/kg and 72% at 9 mg/kg. Moreover, sevuparin was able to reduce hepcidin upregulation in a mouse model of acute inflammation induced by LPS, also showing an amelioration of the inflammatory markers. Combined with its excellent safety profile, these data suggest a role for sevuparin in treating high-hepcidin disorders.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70035","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142748883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Prospective phase II study of allogeneic hematopoietic stem cell transplantation with targeted busulfan, fludarabine, and etoposide conditioning in pediatric acute lymphoblastic leukemia 靶向布苏凡、氟达拉滨和依托泊苷治疗小儿急性淋巴细胞白血病的异基因造血干细胞移植前瞻性II期研究
IF 7.6 2区 医学
HemaSphere Pub Date : 2024-11-28 DOI: 10.1002/hem3.70051
Kyung Taek Hong, Hyun Jin Park, Bo Kyung Kim, Jung Yoon Choi, Sang Hoon Song, SeungHwan Lee, Kyung-Sang Yu, In-Jin Jang, Hyoung Jin Kang
{"title":"Prospective phase II study of allogeneic hematopoietic stem cell transplantation with targeted busulfan, fludarabine, and etoposide conditioning in pediatric acute lymphoblastic leukemia","authors":"Kyung Taek Hong,&nbsp;Hyun Jin Park,&nbsp;Bo Kyung Kim,&nbsp;Jung Yoon Choi,&nbsp;Sang Hoon Song,&nbsp;SeungHwan Lee,&nbsp;Kyung-Sang Yu,&nbsp;In-Jin Jang,&nbsp;Hyoung Jin Kang","doi":"10.1002/hem3.70051","DOIUrl":"https://doi.org/10.1002/hem3.70051","url":null,"abstract":"&lt;p&gt;Allogeneic hematopoietic stem cell transplantation (HSCT) is an important treatment option for high-risk hematologic malignancies that harnesses the graft-versus-leukemia effect and employs a conditioning regimen to eradicate residual leukemic cells.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; High-risk acute lymphoblastic leukemia (ALL), including relapsed or refractory cases, remains a major indication for allogeneic HSCT in the pediatric population.&lt;span&gt;&lt;sup&gt;1-5&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Myeloablative conditioning regimens using total body irradiation (TBI) have demonstrated better outcomes than those of chemoconditioning in various pivotal prospective trials.&lt;span&gt;&lt;sup&gt;6-8&lt;/sup&gt;&lt;/span&gt; Most notably, the recently published FORUM trial demonstrated a superior overall survival (OS) rate and lower cumulative incidence (CI) of relapse and treatment-related mortality with 12 Gy TBI plus etoposide compared with those of chemoconditioning with fludarabine, thiotepa, and either busulfan or treosulfan in high-risk pediatric patients with ALL above 4 years of age.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; However, there remains an unmet need for chemoconditioning regimens for pediatric patients below 4 years of age. Additionally, concerns persist regarding the long-term complications of TBI with myeloablative dosing, particularly in the pediatric population, such as secondary malignancy and endocrinologic problems.&lt;span&gt;&lt;sup&gt;9-11&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Busulfan is a key chemotherapeutic drug for chemoconditioning; however, it exhibits variable pharmacokinetic profiles.&lt;span&gt;&lt;sup&gt;12&lt;/sup&gt;&lt;/span&gt; To optimize busulfan dosing and reduce unexpected toxicity or underdosing, our institution has implemented intensive pharmacokinetic monitoring of busulfan for chemoconditioning yielding favorable outcomes in HSCT for pediatric leukemia.&lt;span&gt;&lt;sup&gt;13, 14&lt;/sup&gt;&lt;/span&gt; In particular, our previous report on a chemoconditioning regimen utilizing targeted busulfan, fludarabine, and etoposide in high-risk pediatric patients with ALL showed promising outcomes.&lt;span&gt;&lt;sup&gt;15&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Herein, we present the findings of a prospective phase II trial (ClinicalTrials.gov: NCT02047578) evaluating the efficacy of targeted busulfan (the target busulfan area under the curve [AUC] between 74 and 76 mg × h/L), fludarabine (40 mg/m², once daily, 5 days), and etoposide (20 mg/kg, once daily, 3 days) conditioning regimens for allogeneic HSCT using matched sibling or unrelated donors in pediatric patients with high-risk ALL. The primary outcome of this study was the 1-year event-free survival (EFS) rate after HSCT, which was anticipated to exceed 80%. We estimated the sample size as a 20% increase in the 1-year EFS rate (to 80%) compared to historical data, with a type I error of 5% and a power of 80%. This study began in February 2014, and the final patient was enrolled in August 2021. The Institutional Review Board of our institution approved the study protocol (H-1210-066-434), and written informed consent was ob","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70051","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142748884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Kinetics of lymphocytosis in naïve chronic lymphocytic leukemia patients treated with covalent Bruton's tyrosine kinase inhibitors: An Italian multicenter real-life experience 用共价布鲁顿酪氨酸激酶抑制剂治疗naïve慢性淋巴细胞白血病患者的淋巴细胞增多动力学:意大利多中心现实生活经验
IF 7.6 2区 医学
HemaSphere Pub Date : 2024-11-28 DOI: 10.1002/hem3.144
Idanna Innocenti, Antonio Mosca, Annamaria Tomasso, Andrea Galitzia, Lydia Scarfò, Francesca Morelli, Eugenio Galli, Francesca Martini, Eugenio Sangiorgi, Roberta Laureana, Giulia Benintende, Veronica Mattiello, Sabrina Chiriu, Maria I. Del Principe, Giulia Zamprogna, Massimo Gentile, Enrica A. Martino, Emilia Cappello, Maria C. Montalbano, Giuliana Farina, Vanessa Innao, Luca Stirparo, Caterina Patti, Paolo Sportoletti, Alberto Fresa, Gioacchino Catania, Marta Coscia, Silvia Bellesi, Alessandra Tedeschi, Alessandro Sanna, Andrea Visentin, Francesco Autore, Raffaella Pasquale, Livio Trentin, Marzia Varettoni, Paolo Ghia, Roberta Murru, Luca Laurenti
{"title":"Kinetics of lymphocytosis in naïve chronic lymphocytic leukemia patients treated with covalent Bruton's tyrosine kinase inhibitors: An Italian multicenter real-life experience","authors":"Idanna Innocenti,&nbsp;Antonio Mosca,&nbsp;Annamaria Tomasso,&nbsp;Andrea Galitzia,&nbsp;Lydia Scarfò,&nbsp;Francesca Morelli,&nbsp;Eugenio Galli,&nbsp;Francesca Martini,&nbsp;Eugenio Sangiorgi,&nbsp;Roberta Laureana,&nbsp;Giulia Benintende,&nbsp;Veronica Mattiello,&nbsp;Sabrina Chiriu,&nbsp;Maria I. Del Principe,&nbsp;Giulia Zamprogna,&nbsp;Massimo Gentile,&nbsp;Enrica A. Martino,&nbsp;Emilia Cappello,&nbsp;Maria C. Montalbano,&nbsp;Giuliana Farina,&nbsp;Vanessa Innao,&nbsp;Luca Stirparo,&nbsp;Caterina Patti,&nbsp;Paolo Sportoletti,&nbsp;Alberto Fresa,&nbsp;Gioacchino Catania,&nbsp;Marta Coscia,&nbsp;Silvia Bellesi,&nbsp;Alessandra Tedeschi,&nbsp;Alessandro Sanna,&nbsp;Andrea Visentin,&nbsp;Francesco Autore,&nbsp;Raffaella Pasquale,&nbsp;Livio Trentin,&nbsp;Marzia Varettoni,&nbsp;Paolo Ghia,&nbsp;Roberta Murru,&nbsp;Luca Laurenti","doi":"10.1002/hem3.144","DOIUrl":"https://doi.org/10.1002/hem3.144","url":null,"abstract":"&lt;p&gt;Chronic lymphocytic leukemia (CLL) therapy has recently undergone a revolution with the introduction of a new class of drugs: covalent Bruton's tyrosine kinase inhibitors (cBTKi), paving the way for a chemotherapy-free approach.&lt;span&gt;&lt;sup&gt;1-4&lt;/sup&gt;&lt;/span&gt; Presently, cBTKi can be utilized in the first line of CLL management, thanks to the results of phase III clinical trials such as RESONATE-2 and ELEVATE-TN, which demonstrated the superiority of Ibrutinib over chemotherapy with chlorambucil&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; and acalabrutinib over chemoimmunotherapy with chlorambucil + obinutuzumab,&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; in terms of progression-free survival (PFS) in both cases. Ibrutinib exhibited better PFS, overall survival (OS), and overall response rate than the monoclonal anti-CD20 antibody ofatumumab in previously treated patients with CLL.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; Additionally, the ASCEND study, another phase III randomized clinical trial, demonstrated that acalabrutinib significantly improved PFS compared to a physician's choice of Idelalisib + rituximab or bendamustine + rituximab, in patients with relapsed/refractory CLL.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;BTK plays a pivotal role in B-cell receptor (BCR) signal transduction,&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt; stimulating important pathways such as NFKB&lt;span&gt;&lt;sup&gt;10, 11&lt;/sup&gt;&lt;/span&gt; and CXCR4.&lt;span&gt;&lt;sup&gt;12&lt;/sup&gt;&lt;/span&gt; Consequently, BTK is involved in B-cell survival, proliferation, and adhesion, while its activation promotes B-cell proliferation.&lt;span&gt;&lt;sup&gt;13&lt;/sup&gt;&lt;/span&gt; Paradoxically, ibrutinib has shown to increase absolute lymphocyte count (ALC) in the initial phase of treatment, regardless of previous lines of therapy. Ibrutinib-induced lymphocytosis may be explained by the redistribution of lymphocytes from neoplastic nodal compartments into the peripheral blood.&lt;span&gt;&lt;sup&gt;14&lt;/sup&gt;&lt;/span&gt; Furthermore, it was noted that Ibrutinib-induced lymphocytosis is transient in most patients, resolving within 8 months, but may rarely persist for over 12 months without impacting survival.&lt;span&gt;&lt;sup&gt;14&lt;/sup&gt;&lt;/span&gt; This evidence led to the introduction of a new criterion in the assessment of CLL therapy response: partial response with lymphocytosis (PR-L).&lt;span&gt;&lt;sup&gt;15&lt;/sup&gt;&lt;/span&gt; Subsequently, the kinetics of lymphocytosis in CLL treated with ibrutinib monotherapy showed that lymphocytosis occurred in the majority of patients treated in first line was higher in immunoglobulin variable heavy chain (IGHV) mutated settings and resolved in 95% of patients after a median of 18.4 months.&lt;span&gt;&lt;sup&gt;16&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Little is known about frequency and duration of lymphocytosis in patients treated with the second-generation cBTKi acalabrutinib. Therefore, the aim of this study is to outline the kinetics of lymphocytosis in CLL patients treated with acalabrutinib compared to ibrutinib.&lt;/p&gt;&lt;p&gt;We conducted a multicenter retrospective real-life study involving 17 Italian centers. The study was carried out according ","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.144","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Inflammatory pathways and anti-inflammatory therapies in sickle cell disease 镰状细胞病的炎症途径和抗炎治疗
IF 7.6 2区 医学
HemaSphere Pub Date : 2024-11-28 DOI: 10.1002/hem3.70032
Karina Tozatto-Maio, Felipe A. Rós, Ricardo Weinlich, Vanderson Rocha
{"title":"Inflammatory pathways and anti-inflammatory therapies in sickle cell disease","authors":"Karina Tozatto-Maio,&nbsp;Felipe A. Rós,&nbsp;Ricardo Weinlich,&nbsp;Vanderson Rocha","doi":"10.1002/hem3.70032","DOIUrl":"https://doi.org/10.1002/hem3.70032","url":null,"abstract":"<p>Sickle cell disease (SCD) is a monogenic disease, resulting from a single-point mutation, that presents a complex pathophysiology and high clinical heterogeneity. Inflammation stands as a prominent characteristic of SCD. Over the past few decades, the role of different cells and molecules in the regulation of the inflammatory process has been elucidated. In conjunction with the polymerization of hemoglobin S (HbS), intravascular hemolysis, which releases free heme, HbS, and hemoglobin-related damage-associated molecular patterns, initiates multiple inflammatory pathways that are not yet fully comprehended. These complex phenomena lead to a vicious cycle that perpetuates vaso-occlusion, hemolysis, and inflammation. To date, few inflammatory biomarkers can predict disease complications; conversely, there is a plethora of therapies that reduce inflammation in SCD, although clinical outcomes vary widely. Importantly, whether the clinical heterogeneity and complications are related to the degree of inflammation is not known. This review aims to further our understanding of the roles of main immune cells, and other inflammatory factors, as potential prognostic biomarkers for predicting clinical outcomes or identifying novel treatments for SCD.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70032","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Bortezomib before and after high-dose therapy in transplant-eligible patients with newly diagnosed multiple myeloma: Long-term overall survival after more than 10 years of follow-up from the phase III HOVON-65/GMMG-HD4 trial 对符合移植条件的新诊断多发性骨髓瘤患者进行大剂量治疗前后的硼替佐米治疗:HOVON-65/GMMG-HD4 III期试验10多年随访后的长期总生存率
IF 7.6 2区 医学
HemaSphere Pub Date : 2024-11-20 DOI: 10.1002/hem3.70052
Elias K. Mai, Axel Nogai, Henk M. Lokhorst, Bronno van der Holt, Sonja Zweegman, Katja C. Weisel, Sandra Croockewit, Anna Jauch, Jens Hillengass, Marian Stevens-Kroef, Marc S. Raab, Annemiek Broijl, Gerard M. J. Bos, Peter Brossart, Paula Ypma, Christine Hanoun, Uta Bertsch, Thomas Hielscher, Hans J. Salwender, Christoph Scheid, Hartmut Goldschmidt, Pieter Sonneveld
{"title":"Bortezomib before and after high-dose therapy in transplant-eligible patients with newly diagnosed multiple myeloma: Long-term overall survival after more than 10 years of follow-up from the phase III HOVON-65/GMMG-HD4 trial","authors":"Elias K. Mai,&nbsp;Axel Nogai,&nbsp;Henk M. Lokhorst,&nbsp;Bronno van der Holt,&nbsp;Sonja Zweegman,&nbsp;Katja C. Weisel,&nbsp;Sandra Croockewit,&nbsp;Anna Jauch,&nbsp;Jens Hillengass,&nbsp;Marian Stevens-Kroef,&nbsp;Marc S. Raab,&nbsp;Annemiek Broijl,&nbsp;Gerard M. J. Bos,&nbsp;Peter Brossart,&nbsp;Paula Ypma,&nbsp;Christine Hanoun,&nbsp;Uta Bertsch,&nbsp;Thomas Hielscher,&nbsp;Hans J. Salwender,&nbsp;Christoph Scheid,&nbsp;Hartmut Goldschmidt,&nbsp;Pieter Sonneveld","doi":"10.1002/hem3.70052","DOIUrl":"https://doi.org/10.1002/hem3.70052","url":null,"abstract":"&lt;p&gt;Life expectancy in patients with multiple myeloma (MM) has increased due to the availability of effective drugs such as proteasome inhibitors (PIs),&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; immunomodulatory drugs (IMiDs),&lt;span&gt;&lt;sup&gt;3-5&lt;/sup&gt;&lt;/span&gt; and more recently, monoclonal antibodies.&lt;span&gt;&lt;sup&gt;6-8&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;While the progression-free survival (PFS) rates and the depth of response increase with the use of modern multi-drug combinations, it is not clear whether these effects will translate into an improved long-term overall survival (OS). To draw such conclusions, long-term follow-up analyses from trials are needed as comparators for future trials. Here, we report on the long-term overall survival of the HOVON-65/GMMG-HD4 trial including the OS after more than 10 years, and the role of established prognostic factors.&lt;/p&gt;&lt;p&gt;The investigator-sponsored, open-label, randomized HOVON-65/GMMG-HD4 phase III trial was conducted by the Dutch-Belgian Cooperative Trial Group for Hematology Oncology (HOVON) and the German-speaking Myeloma Multicenter Group (GMMG) in 75 centers in the Netherlands, Belgium, and Germany from May 2005 to May 2008 and included 827 eligible patients. The trial was registered at www.trialregister.nl (until June 2022) and https://trialsearch.who.int/ as NTR213, at www.isrctn.com as ISRCTN64455289 and at www.clinicaltrialsregister.eu as EudraCT2004-000944-26. The ethics committees of the Erasmus University Medical Center, the University of Heidelberg, and all participating sites approved this trial. All patients gave written informed consent. The study was conducted in accordance with the European Clinical Trial Directive (2005) and the Declaration of Helsinki (1996).&lt;/p&gt;&lt;p&gt;Initial results of the trial have been published and include a detailed study protocol, inclusion and exclusion criteria, randomization procedures and toxicities,&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt; and results after a median follow-up of 96 months.&lt;span&gt;&lt;sup&gt;10&lt;/sup&gt;&lt;/span&gt; After that, only OS data were collected on which we here report the final long-term survival data.&lt;/p&gt;&lt;p&gt;The aim of the trial was to investigate the use of bortezomib (BTZ) in induction and maintenance compared to treatment with classical cytotoxic agents as induction and thalidomide maintenance in transplant-eligible patients regarding the primary endpoint PFS, while OS was a secondary endpoint. Patients were randomized 1:1 to receive either vincristine, adriamycin, and dexamethasone (VAD) as induction therapy, followed by high-dose chemotherapy with melphalan and autologous stem-cell transplantation (ASCT), followed by maintenance therapy with thalidomide (VAD arm). In the PAD arm, BTZ, adriamycin, and dexamethasone were used in induction, followed by ASCT and maintenance with BTZ. Patients were stratified by center and International Staging System (ISS, I vs. II vs. III). A single ASCT was planned in the HOVON group, whereas in the GMMG, a tandem ASCT was planned. Patients with an HLA-identical sib","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 11","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70052","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The incidence and clinical significance of monoclonal and oligoclonal protein bands in multiple myeloma patients after BCMA–CAR-T cell therapy: A retrospective study based on LEGEND-2 BCMA-CAR-T 细胞治疗后多发性骨髓瘤患者单克隆和寡克隆蛋白带的发生率和临床意义:基于 LEGEND-2 的回顾性研究
IF 7.6 2区 医学
HemaSphere Pub Date : 2024-11-19 DOI: 10.1002/hem3.70054
Rui Liu, Gongzhizi Gao, Hongli Chen, Ruijun Dong, Wanggang Zhang, Wanhong Zhao, Jie Liu, Jianli Wang, Bo Lei, Baiyan Wang, Jiali Liu, Xuezhu Xu, Zujie Lin, Ruoyu Yang, Yiwen Wang, Aili He, Fangxia Wang, Ju Bai
{"title":"The incidence and clinical significance of monoclonal and oligoclonal protein bands in multiple myeloma patients after BCMA–CAR-T cell therapy: A retrospective study based on LEGEND-2","authors":"Rui Liu,&nbsp;Gongzhizi Gao,&nbsp;Hongli Chen,&nbsp;Ruijun Dong,&nbsp;Wanggang Zhang,&nbsp;Wanhong Zhao,&nbsp;Jie Liu,&nbsp;Jianli Wang,&nbsp;Bo Lei,&nbsp;Baiyan Wang,&nbsp;Jiali Liu,&nbsp;Xuezhu Xu,&nbsp;Zujie Lin,&nbsp;Ruoyu Yang,&nbsp;Yiwen Wang,&nbsp;Aili He,&nbsp;Fangxia Wang,&nbsp;Ju Bai","doi":"10.1002/hem3.70054","DOIUrl":"https://doi.org/10.1002/hem3.70054","url":null,"abstract":"<p>The emergence of abnormal protein bands (APBs), also known as oligoclonal protein bands, has been documented in patients with multiple myeloma (MM) post hematopoietic stem cell transplantation. However, the incidence rate and clinical significance of APBs remain contentious. Few studies have explored the occurrence and prognostic implications of APBs in patients with MM treated with B-cell maturation antigen (BCMA)–specific chimeric antigen receptor (CAR)-T therapy. In this retrospective study, we examined the frequency, isotypes, and duration of APBs, as well as their correlation with MM disease characteristics, treatment response, clinical outcomes, and immune signature in patients with relapsed/refractory MM who had received LCAR-B38M therapy at the Xi'an site of the phase 1 LEGEND-2 trial. Among 47 patients assessed, 23 (48.9%) developed APBs following CAR-T therapy, with IgG being the most common isotype. The median onset and duration of APBs post-CAR-T infusion were 3.6 and 5.8 months, respectively. Patients with APBs demonstrated significantly improved response to LCAR-B38M therapy, along with longer overall and progression-free survival. Furthermore, those with APBs exhibited enhanced recovery rates of immunoglobulins and higher absolute counts of white blood cells, neutrophils, and lymphocytes post-CAR-T treatment compared to those without APBs. However, no significant differences were observed between the two groups in the percentages of various T-cell subsets and natural killer cells. Overall, the presence of APBs in patients with MM following CAR-T treatment was associated with deeper remission and a more favorable prognosis, suggesting a robust humoral response and subsequent immune reconstitution.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 11","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70054","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Monoclonal gammopathy of undetermined significance with multiple paraproteins: A population-based screening study 意义未定的单克隆丙种球蛋白病伴有多种副蛋白:基于人群的筛查研究
IF 7.6 2区 医学
HemaSphere Pub Date : 2024-11-19 DOI: 10.1002/hem3.70046
Sæmundur Rögnvaldsson, Jón Þ. Óskarsson, Sigrun Thorsteinsdóttir, Malin Hultcrantz, Robert Palmason, Ingigerdur S. Sverrisdottir, Elias Eythorsson, Thorir E. Long, Isleifur Olafsson, Ingunn Thorsteinsdottir, Brynjar Vidarsson, Pall T. Onundarson, Bjarni A. Agnarsson, Margret Sigurdardottir, Asbjorn Jonsson, Brian G. M. Durie, Stephen Harding, Ola Landgren, Thorvardur J. Love, Sigurdur Y. Kristinsson
{"title":"Monoclonal gammopathy of undetermined significance with multiple paraproteins: A population-based screening study","authors":"Sæmundur Rögnvaldsson,&nbsp;Jón Þ. Óskarsson,&nbsp;Sigrun Thorsteinsdóttir,&nbsp;Malin Hultcrantz,&nbsp;Robert Palmason,&nbsp;Ingigerdur S. Sverrisdottir,&nbsp;Elias Eythorsson,&nbsp;Thorir E. Long,&nbsp;Isleifur Olafsson,&nbsp;Ingunn Thorsteinsdottir,&nbsp;Brynjar Vidarsson,&nbsp;Pall T. Onundarson,&nbsp;Bjarni A. Agnarsson,&nbsp;Margret Sigurdardottir,&nbsp;Asbjorn Jonsson,&nbsp;Brian G. M. Durie,&nbsp;Stephen Harding,&nbsp;Ola Landgren,&nbsp;Thorvardur J. Love,&nbsp;Sigurdur Y. Kristinsson","doi":"10.1002/hem3.70046","DOIUrl":"https://doi.org/10.1002/hem3.70046","url":null,"abstract":"<p>Monoclonal gammopathy of undetermined significance (MGUS) is the precursor of multiple myeloma (MM) and related disorders. MGUS is characterized by asymptomatic paraproteinemia. In some cases, multiple paraproteins can be identified but the clinical implications of this phenomenon are poorly understood. In this study, we aim to inform the approach to this challenging MGUS subgroup by utilizing data from iStopMM, a population-based screening study and randomized trial of follow-up strategies. In total, 75,422 Icelanders over the age of 40 were screened for MGUS with 3389 (4.4%) having at least one paraprotein of whom 303 (9%) had multiple paraproteins. IgM paraproteins were more common in those with multiple paraproteins (49% vs. 27% of paraproteins, <i>p</i> &lt; 0.001), and IgM and non-IgM paraproteins frequently co-occurred (60% of cases). Two-thirds of these participants were randomized to active follow-up where only 31% of multiple paraproteins were persistent. Paraprotein concentrations were mostly independent, and although progression events were few, the progression rate was similar between those with multiple paraproteins and a single paraprotein. In a next-generation flow cytometry (NGF) sub-study, two phenotypically distinct aberrant plasma cell populations could be identified in some with multiple paraproteins. The findings suggest that multiple paraproteins often reflect independent ongoing disease processes that should be monitored independently but otherwise treated similarly to other MGUS cases. Specifically, the findings highlight the need for independent monitoring of IgM and non-IgM paraproteins in these individuals. The study provides novel insights into the management of this understudied MGUS subset.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 11","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70046","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A single-chain variable fragment-based bispecific T-cell activating antibody against CD117 enables T-cell mediated lysis of acute myeloid leukemia and hematopoietic stem and progenitor cells 基于单链可变片段的 CD117 双特异性 T 细胞激活抗体可实现 T 细胞介导的急性髓性白血病及造血干细胞和祖细胞裂解
IF 7.6 2区 医学
HemaSphere Pub Date : 2024-11-19 DOI: 10.1002/hem3.70055
Laura Volta, Renier Myburgh, Mara Hofstetter, Christian Koch, Jonathan D. Kiefer, Celeste Gobbi, Francesco Manfredi, Kathrin Zimmermann, Philipp Kaufmann, Serena Fazio, Christian Pellegrino, Norman F. Russkamp, Danielle Villars, Mattia Matasci, Monique Maurer, Jan Mueller, Florin Schneiter, Paul Büschl, Niclas Harrer, Jacqueline Mock, Stefan Balabanov, César Nombela-Arrieta, Timm Schroeder, Dario Neri, Markus G. Manz
{"title":"A single-chain variable fragment-based bispecific T-cell activating antibody against CD117 enables T-cell mediated lysis of acute myeloid leukemia and hematopoietic stem and progenitor cells","authors":"Laura Volta,&nbsp;Renier Myburgh,&nbsp;Mara Hofstetter,&nbsp;Christian Koch,&nbsp;Jonathan D. Kiefer,&nbsp;Celeste Gobbi,&nbsp;Francesco Manfredi,&nbsp;Kathrin Zimmermann,&nbsp;Philipp Kaufmann,&nbsp;Serena Fazio,&nbsp;Christian Pellegrino,&nbsp;Norman F. Russkamp,&nbsp;Danielle Villars,&nbsp;Mattia Matasci,&nbsp;Monique Maurer,&nbsp;Jan Mueller,&nbsp;Florin Schneiter,&nbsp;Paul Büschl,&nbsp;Niclas Harrer,&nbsp;Jacqueline Mock,&nbsp;Stefan Balabanov,&nbsp;César Nombela-Arrieta,&nbsp;Timm Schroeder,&nbsp;Dario Neri,&nbsp;Markus G. Manz","doi":"10.1002/hem3.70055","DOIUrl":"https://doi.org/10.1002/hem3.70055","url":null,"abstract":"<p>Acute myeloid leukemia (AML) derives from hematopoietic stem and progenitor cells (HSPCs). To date, no AML-exclusive, non-HSPC-expressed cell-surface target molecules for AML selective immunotherapy have been identified. Therefore, to still apply surface-directed immunotherapy in this disease setting, time-limited combined immune-targeting of AML cells and healthy HSPCs, followed by hematopoietic stem cell transplantation (HSCT), might be a viable therapeutic approach. To explore this, we generated a recombinant single-chain variable fragment-based bispecific T-cell engaging and activating antibody directed against CD3 on T-cells and CD117, the surface receptor for stem cell factor, expressed by both AML cells and healthy HSPCs. Bispecific CD117xCD3 targeting induced lysis of CD117-positive healthy human HSPCs, AML cell lines and patient-derived AML blasts in the presence of T-cells at subnanomolar concentrations in vitro. Furthermore, in immunocompromised mice, engrafted with human CD117-expressing leukemia cells and human T-cells, the bispecific molecule efficiently prevented leukemia growth in vivo. Additionally, in immunodeficient mice transplanted with healthy human HSPCs, the molecule decreased the number of CD117-positive cells in vivo. Therefore, bispecific CD117xCD3 targeting might be developed clinically in order to reduce CD117-expressing leukemia cells and HSPCs prior to HSCT.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 11","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70055","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
IL-11—An aging-related cytokine with opportunities for regulating hematopoiesis IL-11--一种与衰老有关的细胞因子,可调节造血功能。
IF 7.6 2区 医学
HemaSphere Pub Date : 2024-11-19 DOI: 10.1002/hem3.70050
David G. Kent
{"title":"IL-11—An aging-related cytokine with opportunities for regulating hematopoiesis","authors":"David G. Kent","doi":"10.1002/hem3.70050","DOIUrl":"10.1002/hem3.70050","url":null,"abstract":"&lt;p&gt;Cytokines have long been known as chemical messengers that act upon cells in the blood system to induce proliferation and response to disease. Studying them at scale in a tissue context has been challenging due to functional redundancy and pleiotropic effects, but they remain an area of active investigation for a wide range of groups, especially now that new approaches are emerging to studying cytokine signaling dynamics at the single molecule level.&lt;span&gt;&lt;sup&gt;1-3&lt;/sup&gt;&lt;/span&gt; This summer, a huge study on the proinflammatory cytokine Interleukin 11 (IL-11) emerged in &lt;i&gt;Nature&lt;/i&gt; magazine from the group of Stuart Cook—the paper &lt;i&gt;Inhibition of IL-11 signaling extends mammalian healthspan and lifespan&lt;/i&gt;&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; dropped into the hyperactive aging research community and caused quite a stir.&lt;/p&gt;&lt;p&gt;The headline statement: “Genetic deletion of &lt;i&gt;Il11&lt;/i&gt; extended the lives of mice of both sexes, by 24.9% on average” caught the research world's attention. This was impressively followed by a series of studies that involved treating mice with an anti-IL-11 antibody from middle age (75 weeks) until death where the researchers observed another impressive increase in lifespan (&gt;20%), strongly suggesting that early life events do not irrevocably sentence an organism to an early death. Simple in design and elegant in execution, the study details the genetic and pharmacological modulation of aging in both sexes. This positions the paper as one of the few that demonstrates a clear extension of lifespan through the removal of a single gene—one of the earliest examples of which is the &lt;i&gt;daf-2&lt;/i&gt; c.elegans mutants&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; that have an extended lifespan. The authors go on to detail a wide range of metabolic and pathway profiling and imply that the metabolic, proinflammatory, and profibrotic roles of IL-11 are the mechanistic drivers of aging through the ERK-mTORC1 and JAK/STAT signaling pathways. This also suggests that JAK inhibitors, metformin, rapamycin, and so forth might have antiaging and antifibrotic roles as well, but the authors note that some of these current therapies struggle with on- and off-target toxicities that an anti-IL-11 therapy might not have. Indeed, an early-stage clinical trial is already underway using anti-IL-11 for the treatment of fibro-inflammatory diseases.&lt;/p&gt;&lt;p&gt;IL-11 is no stranger to stem cell and hematopoiesis research. It is one of a handful of critical molecules that interact with the glycoprotein 130 (gp130) family for signal transduction, in the good company of leukemia inhibitory factor (LIF) and interleukin 6 (IL-6) among others. These molecules have long been studied in stem cell systems (e.g., LIF in mouse embryonic stem cells and ciliary neurotrophic factor [CNTF] in neural stem cells) and have also been among the key regulators of hematopoietic stem cell (HSC) self-renewal in the form of IL-6 and IL-11. Early studies highlighted IL-11's partnership with the stem cell factor (S","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 11","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11574441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Preclinical evaluation of the CD38-targeting engineered toxin body MT-0169 against multiple myeloma 针对多发性骨髓瘤的 CD38 靶向工程毒素体 MT-0169 的临床前评估。
IF 7.6 2区 医学
HemaSphere Pub Date : 2024-11-14 DOI: 10.1002/hem3.70039
Wassilis S. C. Bruins, Rosa Rentenaar, John Newcomb, Wenrou Zheng, Ruud W. J. Ruiter, Thomas Baardemans, Eric Poma, Chris Moore, Garrett L. Robinson, Anya Lublinsky, Yuhong Zhang, Sakeena Syed, Michael Milhollen, Ajeeta B. Dash, Niels W. C. J. van de Donk, Richard W. J. Groen, Sonja Zweegman, Tuna Mutis
{"title":"Preclinical evaluation of the CD38-targeting engineered toxin body MT-0169 against multiple myeloma","authors":"Wassilis S. C. Bruins,&nbsp;Rosa Rentenaar,&nbsp;John Newcomb,&nbsp;Wenrou Zheng,&nbsp;Ruud W. J. Ruiter,&nbsp;Thomas Baardemans,&nbsp;Eric Poma,&nbsp;Chris Moore,&nbsp;Garrett L. Robinson,&nbsp;Anya Lublinsky,&nbsp;Yuhong Zhang,&nbsp;Sakeena Syed,&nbsp;Michael Milhollen,&nbsp;Ajeeta B. Dash,&nbsp;Niels W. C. J. van de Donk,&nbsp;Richard W. J. Groen,&nbsp;Sonja Zweegman,&nbsp;Tuna Mutis","doi":"10.1002/hem3.70039","DOIUrl":"10.1002/hem3.70039","url":null,"abstract":"<p>Despite significant progress in the treatment of multiple myeloma (MM), relapsed/refractory patients urgently require more effective therapies. We here describe the discovery, mechanism of action, and preclinical anti-MM activity of engineered toxin body MT-0169, a next-generation immunotoxin comprising a CD38-specific antibody fragment linked to a de-immunized Shiga-like toxin A subunit (SLTA) payload. We show that specific binding of MT-0169 to CD38 on MM cell lines triggers rapid internalization of SLTA, causing cell death via irreversible ribosome inhibition, protein synthesis blockade, and caspase 3/7 activation. In co-culture experiments, bone marrow mesenchymal stromal cells did not induce drug resistance against MT-0169. In the preclinical setting, MT-0169 effectively lysed primary MM cells from newly diagnosed and heavily pretreated MM patients, including those refractory to daratumumab, with minimal toxicity against nonmalignant hematopoietic cells. MM cell lysis showed a significant correlation with their CD38 expression levels but not with cytogenetic risk, tumor load, or number of prior lines of therapy. Finally, MT-0169 showed efficient in vivo anti-MM activity in various mouse xenograft models, including one in which MM cells are grown in a humanized bone marrow-like niche. These findings support clinical investigation of MT-0169 in relapsed/refractory MM patients, including those refractory to CD38-targeting immunotherapies.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 11","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561653/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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