HemaSphere最新文献

{"title":"Interferon gamma-mediated prevention of tumor progression in a mouse model of multiple myeloma","authors":"Zoltán Kellermayer,&nbsp;Sabrin Tahri,&nbsp;Madelon M. E. de Jong,&nbsp;Natalie Papazian,&nbsp;Cathelijne Fokkema,&nbsp;Elodie C. G. Stoetman,&nbsp;Remco Hoogenboezem,&nbsp;Gregory van Beek,&nbsp;Mathijs A. Sanders,&nbsp;Louis Boon,&nbsp;Chelsea Den Hollander,&nbsp;Annemiek Broijl,&nbsp;Pieter Sonneveld,&nbsp;Tom Cupedo","doi":"10.1002/hem3.70047","DOIUrl":"https://doi.org/10.1002/hem3.70047","url":null,"abstract":"<p>Malignant plasma cells in multiple myeloma patients reside in the bone marrow and continuously interact with local immune cells. Progression and therapy response are influenced by this immune environment, highlighting the need for a detailed understanding of endogenous immune responses to malignant plasma cells. Here we used the 5TGM1 murine transfer model of multiple myeloma to dissect early immune responses to myeloma cells. We modeled stable and progressive disease by transferring 5TGM1 murine myeloma cells into C57Bl/6 mice and KaLwRij mice, respectively. We used flow cytometry and single-cell and bulk transcriptomic analyses to characterize differential immune responses in stable and progressive disease. Transfer of 5TGM1 cells in C57Bl/6 mice led to stable disease with low tumor burden in a subset of animals. Stable disease was associated with sustained activation and expansion of NK cells, ILC1, and CD8⁺ T cells, a response that was lost upon disease progression. Single-cell RNA-sequencing of immune cells and bulk RNA sequencing of immune and mesenchymal stromal cells implicated the activation of interferon responses as a central immune pathway during stable disease. Experimentally, neutralization of IFNγ significantly increased myeloma development and progression in C57Bl/6 mice, testifying to the importance of this pathway in early disease control. In conclusion, we provide a framework for studying immune responses to multiple myeloma progression in immunocompetent and genetically modifiable mice and highlight the importance of bone marrow immunity in tumor control.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70047","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142762104","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}

{"title":"Dual specific STAT3/5 degraders effectively block acute myeloid leukemia and natural killer/T cell lymphoma","authors":"Daniel Pölöske,&nbsp;Helena Sorger,&nbsp;Anna Schönbichler,&nbsp;Elvin D. de Araujo,&nbsp;Heidi A. Neubauer,&nbsp;Anna Orlova,&nbsp;Sanna H. Timonen,&nbsp;Diaaeldin I. Abdallah,&nbsp;Aleksandr Ianevski,&nbsp;Heikki Kuusanmäki,&nbsp;Marta Surbek,&nbsp;Elisabeth Heyes,&nbsp;Thomas Eder,&nbsp;Christina Wagner,&nbsp;Tobias Suske,&nbsp;Martin L. Metzelder,&nbsp;Michael Bergmann,&nbsp;Maik Dahlhoff,&nbsp;Florian Grebien,&nbsp;Roman Fleck,&nbsp;Christine Pirker,&nbsp;Walter Berger,&nbsp;Emir Hadzijusufovic,&nbsp;Wolfgang R. Sperr,&nbsp;Lukas Kenner,&nbsp;Peter Valent,&nbsp;Tero Aittokallio,&nbsp;Marco Herling,&nbsp;Satu Mustjoki,&nbsp;Patrick T. Gunning,&nbsp;Richard Moriggl","doi":"10.1002/hem3.70001","DOIUrl":"https://doi.org/10.1002/hem3.70001","url":null,"abstract":"<p>The transcription factors STAT3, STAT5A, and STAT5B steer hematopoiesis and immunity, but their enhanced expression and activation promote acute myeloid leukemia (AML) or natural killer/T cell lymphoma (NKCL). Current therapeutic strategies focus on blocking upstream tyrosine kinases to inhibit STAT3/5, but these kinase blockers are not selective against STAT3/5 activation and frequent resistance causes relapse, emphasizing the need for targeted drugs. We evaluated the efficacy of JPX-0700 and JPX-0750 as dual STAT3/5 binding inhibitors promoting protein degradation. JPX-0700/−0750 decreased the mRNA and protein levels of STAT3/5 targets involved in cancer survival, metabolism, and cell cycle progression, exhibiting nanomolar to low micromolar efficacy. They induced cell death and growth arrest in both AML/NKCL cell lines and primary AML patient blasts. We found that both AML/NKCL cells hijack STAT3/5 signaling through either upstream activating mutations in kinases, activating mutations in STAT3, mutational loss of negative STAT regulators, or genetic gains in anti-apoptotic, pro-proliferative, or epigenetic-modifying STAT3/5 targets. This emphasizes a vicious cycle for proliferation and survival through STAT3/5. Both JPX-0700/−0750 treatment reduced leukemic cell growth in human AML or NKCL xenograft mouse models significantly, being well tolerated by mice. Synergistic cell death was induced upon combinatorial use with approved chemotherapeutics in AML/NKCL cells.</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/hem3.70001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749325","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}

{"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}

{"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}

{"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}

{"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}

{"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}

{"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}

{"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}

{"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}