Blood最新文献

{"title":"Large B-cell lymphoma imprints a dysfunctional immune phenotype that persists years after treatment.","authors":"Richard Pelzl,Giulia Benintende,Franziska Gsottberger,Julia Katharina Scholz,Matthias Ruebner,Hao Yao,Kerstin Wendland,Kai Rejeski,Heidi Altmann,Srdjan Petkovic,Lisa Mellenthin,Sabrina Kübel,Moritz Schmiedeberg,Paulina Klein,Agnese Petrera,Rebecca Baur,Sophie Eckstein,Sandra Hoepffner-Grundy,Christoph Röllig,Marion Subklewe,Hanna Huebner,Georg Schett,Andreas Mackensen,Luca Laurenti,Frederik Graw,Simon Völkl,Krystelle Nganou-Makamdop,Fabian Müller","doi":"10.1182/blood.2024027877","DOIUrl":"https://doi.org/10.1182/blood.2024027877","url":null,"abstract":"Immunotherapy has become standard of care in the treatment of diffuse large B-cell lymphoma (DLBCL). Changes in immunophenotypes observed at first diagnosis predict therapy outcome but little is known about the resolution of these alterations in remission. Comprehensive characterization of immune changes from fresh, peripheral whole blood revealed a functionally relevant increase of myeloid-derived suppressor cells, reduced naïve T-cells, and an increase of activated and terminally differentiated T-cells before treatment which aggravated after therapy. Suggesting causal relation, injection of lymphoma in mice induced similar changes in the murine T cells. Distinct immune imprints were found in breast cancer and AML survivors. Identified alterations persisted beyond five years of ongoing complete remission and in DLBCL correlated with increased pro-inflammatory markers such as IL-6, B2M, or sCD14. The chronic inflammation was associated with functionally blunted T-cell immunity against SARS-CoV-2-specific peptides and reduced responses correlated with reduced Tn-cells. Persisting inflammation was confirmed by deep sequencing and by cytokine profiles, together pointing towards a compensatory activation of innate immunity. The persisting, lymphoma-induced immune alterations in remission may explain long-term complications, have implications for vaccine strategies, and are likely relevant for immunotherapies.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"2 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Comprehensive Genetic Study of Classical Hodgkin Lymphoma Using Circulating Tumor DNA.","authors":"Maria Cristina Pirosa,Alessio Bruscaggin,Lodovico Terzi di Bergamo,Matin Salehi,Federico Jauk,Gabriela Forestieri,Simone Bocchetta,Deborah Piffaretti,Riccardo Moia,Vanessa Cristaldi,Martina di Trani,Georgia Alice Galimberti,Katia Pini,Valeria Spina,Claudia Giordano,Adalgisa Condoluci,Ilaria Romano,Salvatore Annunziata,Fabrizio Bergesio,Renzo Boldorini,Eugenio Borsatti,Pietro Bulian,Eleonora Calabretta,Stephane Chauvie,Francesco Corrado,Stefania Crisci,Marco Cuzzocrea,Rosaria De Filippi,Bernhard Gerber,Michał Kurlapski,Luigi Maria Larocca,Elisabetta Merlo,Andrea Rinaldi,Marcello Rodari,Grzegorz Romanowicz,Gian Mauro Sacchetti,Anastasios Stathis,Georg Stussi,Ilaria Zangrilli,Antonio Pinto,Luca Mazzucchelli,Valter Gattei,Jan Maciej Zaucha,Armando Santoro,Stefan Hohaus,Franco Cavalli,Alexandar Tzankov,Carmelo Carlo-Stella,Gianluca Gaidano,Luca Ceriani,Emanuele Zucca,Davide Rossi","doi":"10.1182/blood.2024027355","DOIUrl":"https://doi.org/10.1182/blood.2024027355","url":null,"abstract":"This study analyzed the genetics of classical Hodgkin lymphoma (cHL) by using circulating tumor DNA (ctDNA). Two genetic subtypes were identified, differing in genetic instability mechanisms: one subtype (64% of cases) showed a higher mutation load and a higher fraction of mutations associated with activation-induced cytidine deaminase and microsatellite instability signatures, while the other subtype (36% of cases) exhibited chromosomal instability with more somatic copy number alterations. Whole-genome duplication was more common in cHL compared to other B-cell tumors and emerged as a prognostic biomarker for patients undergoing ABVD-based therapy. Non-coding regulatory mutations, similar to those in diffuse large B-cell lymphoma, were highly prevalent in 86% of cHL. A recurrent somatic expression quantitative trait locus (seQTL) involving the BCL6 gene was found in 30% of cases. The seQTL of BCL6 aligned with accessible chromatin and increased H3K27 acetylation in cHL, disrupted PRDM1 binding, and co-occurred with BCL6 expression in cHL cells. Weak to strong expression of BCL6 was observed in 68% of cases and BCL6 expression associated with gene repression similarly in cHL and germinal center B cells. After BCL6 degradation, the core set of genes directly bound and regulated by BCL6 was derepressed in cHL and proliferation was impaired. The number and clonality of neoantigens was associated with tumor microenvironment type and response to checkpoint blockade. Finally, ctDNA analysis was suggested as a tool to distinguish ambiguous PET/CT-positive lesions post-treatment.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"113 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling the HLH immune synapse uncovers critical roles for IS termination, cytokine intensity, and target cell death.","authors":"Anastasia M Frank-Kamenetskii,Hannah Klinghoffer,Jemy Anna Varghese,Vinh Dang,Jeremy Morrissette,Joseph A Fraietta,Caroline Diorio,Janis K Burkhardt,Scott Canna","doi":"10.1182/blood.2024027179","DOIUrl":"https://doi.org/10.1182/blood.2024027179","url":null,"abstract":"Hemophagocytic Lymphohistiocytosis (HLH) is a life-threatening systemic hyperinflammatory syndrome arising in many contexts. Its underlying mechanisms are often unclear, but defective granule-mediated cytotoxicity (familial HLH) and excess IL-18 (Macrophage Activation Syndrome, MAS) provide clues. Mounting evidence suggests the causes of HLH converge on cytotoxic T lymphocyte (CTL) hyperactivation and overproduction of IFNγ. We refined an in vitro system to simultaneously quantify multiple parameters of the murine CTL immune synapse (IS). Even in haploinsufficiency, perforin deficiency prolonged IS duration and increased IFNγ/TNF production. Similarly, both target cell immortalization and inhibition of apoptotic caspases impaired IS termination and increased cytokine production. Strong CTL activation, through T-cell receptor or IL-18 signaling, also increased IFNγ secretion but accelerated target cell death. Impaired IS termination synergized with strong CTL activation in driving IFNγ production. Visually, both typical and Prf1-/- CTL-IS terminated with apoptotic contraction. We serendipitously observed many IL-18 exposed CTL-IS terminated by target cell ballooning. Both IL-18-activated CTL and IFNγ pretreatment caused up to half of target cells to die by RIPK1-dependent necroptosis. In vivo, RIPK1 inhibition ameliorated virus-triggered HLH in Il18tg more than Prf1-/- mice. By quantifying CTL-IS duration, cytokine production, and mode of cell death, we modeled multiple HLH contributors and their interactions, and identified three HLH mechanistic categories: impaired IS termination, intense CTL cytokine production, and inflammatory target cell death. Integrating the inputs and outcomes of a hyperinflammatory CTL-IS may provide a useful framework for understanding, predicting, or treating HLH in its many forms.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"10 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Multi-Omics Approach Reveals Novel Regulators of Plasma Factor V Levels: highlight on CLEC4M as a Clearance Receptor.","authors":"Gaëlle Munsch,Adarsh Mohapatra,Astrid van Hylckama Vlieg,Marcus E Kleber,Angel Martinez-Perez,Ngoc-Quynh Le,Kristian Dalsbø Hindberg,Philip J Dusart,Marine Germain,Florian Thibord,Jean-François Deleuze,Graciela E Delgado,Louisa Goumidi,Pierre Suchon,Noémie Saut,Juan Carlos Souto,Lynn Butler,Jose Manuel Soria,John-Bjarne Hansen,Winfried März,Frits R Rosendaal,Elisabetta Castoldi,Franck Peiretti,Maria Sabater-Lleal,David-Alexandre Tregouet,Pierre-Emmanuel Morange","doi":"10.1182/blood.2024027006","DOIUrl":"https://doi.org/10.1182/blood.2024027006","url":null,"abstract":"Coagulation factor V (FV) is a key protein in maintaining the hemostatic balance, with abnormal plasma levels associated with both thrombotic and hemorrhagic conditions. We propose a comprehensive bioinformatic analysis integrating large scale proteogenomics and transcriptomic data from original and public datasets. We identify a biological fingerprint of 26 new proteins and loci involved in the regulation of plasma FV levels. Furthermore, the mRNA expression levels of 10 of these components show strong correlation in liver. In addition, we provide experimental evidence for the involvement of one of the newly identified players (CLEC4M) in the clearance of FV. This work opens new avenues for a better understanding of the physiological processes involved in thrombotic and bleeding disorders.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"121 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How I approach hematopoietic stem cell transplantation for CML in a TKI world.","authors":"Yves Chalandon,Federico Simonetta,Stavroula Masouridi-Levrat","doi":"10.1182/blood.2024026512","DOIUrl":"https://doi.org/10.1182/blood.2024026512","url":null,"abstract":"Following the introduction of tyrosine kinase inhibitors (TKI), the number of patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) for chronic phase chronic myeloid leukemia (CP-CML) has dramatically decreased. Imatinib was the 1st TKI introduced into the clinical arena, predominantly utilized in the 1st line setting. In cases of insufficient response, resistance, or intolerance, CML patients can subsequently be treated with a 2nd, 3rdor 4th generation TKI. However, despite the approval of 1st, 2nd, 3rd, 4th generation TKI allo-HSCT still remains indicated for a minority of CML patients. Here, we discuss the indications in the era of TKI through different cases representing the clinical situations for which allo-HSCT remains the best option. We also propose our transplant strategy to decrease transplant-related morbidity, particularly graft-versus-host disease (GvHD), and mortality in the particular context of CML, a disease that is one of the most sensitive to immune cellular therapy, allowing the use of a combination of donor lymphocyte infusion (DLI) and TKI for post-transplant molecular progression.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"8 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How I Treat: Revisiting the myth of second remission in acute lymphoblastic leukemia in the era of immunotherapy.","authors":"Ibrahim Aldoss,Mary C Clark,Stephen J Forman","doi":"10.1182/blood.2024027267","DOIUrl":"https://doi.org/10.1182/blood.2024027267","url":null,"abstract":"In 2013, we published a perspective entitled, \"The myth of the second remission of acute leukemia,\" which underscored the dismal outcomes of relapsed acute leukemia in adults. We emphasized that only a minority of patients achieved second complete remission (CR2) after relapse and were subsequently eligible to receive a potentially curative allogeneic hematopoietic stem cell transplantation (HSCT). Hence, we urged the leukemia community not to delay HSCT in first complete remission (CR1) if indicated to avoid dire outcomes. Historically, poor outcomes resulted from suboptimal frontline therapy, inadequate risk stratification, and lack of effective agents to achieve CR2. In the past decade, remarkable progress has been made in the treatment paradigm of acute leukemia, most evidently in B-cell acute lymphoblastic leukemia. Key advancements include refinement of frontline treatment, incorporation of early immunotherapy, improved disease risk stratification based on molecular profiling and assessment of measurable residual disease, and discovery of highly effective salvage immunotherapies. These innovations have led to a high rate of cure by frontline therapy, precise selection for HSCT in CR1 for high-risk patients, and the reality of HSCT for patients in CR2. Here, we reexamine the myth of CR2 given the progress in the field.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"35 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lee HJ, Ramchandren R, Friedman J, et al. Brentuximab vedotin, nivolumab, doxorubicin, and dacarbazine for advanced-stage classical Hodgkin lymphoma. Blood. 2025;145(3):290-299.","authors":"","doi":"10.1182/blood.2025029278","DOIUrl":"https://doi.org/10.1182/blood.2025029278","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"117 1","pages":"2231"},"PeriodicalIF":20.3,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143921050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Seeking an escape door from the maze of cGVHD.","authors":"Yoshinobu Maeda","doi":"10.1182/blood.2025028581","DOIUrl":"https://doi.org/10.1182/blood.2025028581","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"106 1","pages":"2115-2116"},"PeriodicalIF":20.3,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143921052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Measurable residual disease and posttransplantation gilteritinib maintenance for patients with FLT3-ITD-mutated AML.","authors":"Mark J Levis, Mehdi Hamadani, Brent R Logan, Richard J Jones, Anurag K Singh, Mark R Litzow, John R Wingard, Esperanza B Papadopoulos, Alexander E Perl, Robert J Soiffer, Celalettin Ustun, Masumi Ueda Oshima, Geoffrey L Uy, Edmund K Waller, Sumithira Vasu, Melhem Solh, Asmita Mishra, Lori S Muffly, Hee-Je Kim, Matthias Stelljes, Yuho Najima, Masahiro Onozawa, Kirsty Thomson, Arnon Nagler, Andrew H Wei, Guido Marcucci, Caroline Chen, Nahla Hasabou, Matt Rosales, Jason Hill, Stanley C Gill, Rishita Nuthethi, Denise King, Adam Mendizabal, Steven M Devine, Mary M Horowitz, Yi-Bin Chen","doi":"10.1182/blood.2024025154","DOIUrl":"10.1182/blood.2024025154","url":null,"abstract":"<p><strong>Abstract: </strong>BMT CTN (Blood and Marrow Transplant Clinical Trials Network) 1506 (\"MORPHO\") was a randomized study of gilteritinib compared with placebo as maintenance therapy after hematopoietic cell transplantation (HCT) for patients with FLT3-ITD-mutated acute myeloid leukemia (AML). A key secondary end point was to determine the impact on survival of before and/or after HCT measurable residual disease (MRD), as determined using a highly sensitive assay for FLT3-ITD mutations. Generally, gilteritinib maintenance therapy was associated with improved relapse-free survival (RFS) for participants with detectable peri-HCT MRD, whereas no benefit was evident for those lacking detectable MRD. We conducted a post hoc analysis of the data and found that the level of MRD detected with this approach correlated remarkably with RFS and relapse risk, and that MRD detectable at any level negatively affected RFS. In the placebo arm, 42.2% of participants with detectable FLT3-ITD MRD relapsed compared with 13.4% of those without detectable MRD. We found that 14.8% of participants had multiple FLT3-ITD clones detected as MRD and had worse survival irrespective of treatment arm. Finally, we examined the kinetics of FLT3-ITD clonal relapse or eradication and found that participants on the placebo arm with detectable MRD relapsed rapidly after HCT, often within a few weeks. MRD-positive participants on the gilteritinib arm relapsed either with FLT3 wild-type clones (assessed by capillary electrophoresis), after cessation of gilteritinib with persistent MRD, or on progression of multiclonal disease. These data demonstrate the potential of FLT3-ITD MRD to guide therapy with gilteritinib for this subtype of AML. This trial was registered at www.clinicaltrials.gov as #NCT02997202.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2138-2148"},"PeriodicalIF":21.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142944581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GATA 2 much: stemness and resistance in AML chemotherapy.","authors":"Thomas Mercher,Marie-Laure Arcangeli","doi":"10.1182/blood.2024028200","DOIUrl":"https://doi.org/10.1182/blood.2024028200","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"117 1","pages":"2110-2112"},"PeriodicalIF":20.3,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143921057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}