Blood最新文献

{"title":"How I treat challenging transfusion cases in sickle cell disease.","authors":"Stella T Chou, Jeanne E Hendrickson","doi":"10.1182/blood.2023023648","DOIUrl":"10.1182/blood.2023023648","url":null,"abstract":"<p><strong>Abstract: </strong>Transfusion of red blood cells (RBCs) can be lifesaving for individuals living with sickle cell disease (SCD). However, alloimmunization after transfusion is more common with patients with SCD than in other patient populations, resulting in morbidity and mortality. Management of complications related to RBC alloantibodies, including delayed hemolytic transfusion reactions (DHTRs) and identifying compatible RBCs for future transfusions, remains a challenge for hematologists and transfusion medicine providers. Although transfusion guidelines from organizations, including the American Society for Hematology provide general recommendations, individual cases remain challenging. Antibody evanescence and the lack of widespread RBC alloantibody data sharing across hospitals pose unique challenges, as do RH variants in both transfusion recipients and blood donors. Further, as potentially curative therapies require RBC transfusions to lower the hemoglobin S before cellular therapy collections and infusions, patients who are highly alloimmunized may be deemed ineligible. The cases described are representative of clinical dilemmas the authors have encountered, and the approaches are as evidence-based as the literature and the authors' experiences allow. A future desired state is one in which RBC alloantibody data are efficiently shared across institutions, Rh alloimmunization can be mitigated, better treatments exist for DHTRs, and a label of difficult to transfuse does not prevent desired therapies.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2257-2265"},"PeriodicalIF":21.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140903703","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":"IAP dependency of T-cell prolymphocytic leukemia identified by high-throughput drug screening.","authors":"Marcel Fabian Pohly, Kerstin Putzker, Sebastian Scheinost, Lena Ben Taarit, Tatjana Walther, Sandra Kummer, Tobias Wertheimer, Minqi Lin, Thi Huong Lan Do, Kristina Handler, Jan Michler, Jarno Kivioja, Karsten Bach, Samanta Kisele, James Kim, Sascha Dietrich, Beat Bornhauser, Wendy Wei-Lynn Wong, Burkhard Becher, Andreas Moor, Joe Lewis, Xenia Ficht, Junyan Lu, Wolfgang Huber, Thorsten Zenz","doi":"10.1182/blood.2024027171","DOIUrl":"10.1182/blood.2024027171","url":null,"abstract":"<p><strong>Abstract: </strong>T-cell prolymphocytic leukemia (T-PLL) is an aggressive lymphoid malignancy with limited treatment options. To discover new treatment targets for T-PLL, we performed high-throughput drug sensitivity screening on 30 primary patient samples ex vivo. After screening >2800 unique compounds, we found T-PLL to be more resistant to most drug classes, including chemotherapeutics, than other blood cancers. Furthermore, we discovered previously unreported vulnerabilities of T-PLL. T-PLL cells exhibited a particular sensitivity to drugs targeting autophagy (thapsigargin and bafilomycin A1), nuclear export (selinexor), and inhibitor of apoptosis proteins (IAPs; birinapant), sensitivities that were also shared by other T-cell malignancies. Through bulk and single-cell RNA sequencing, we found these compounds to activate the Toll-like receptor (bafilomycin A1), p53 (selinexor), and tumor necrosis factor α (TNF-α)/NF-κB signaling pathways (birinapant) in T-PLL cells. Focusing on birinapant for its potential in drug repurposing, we uncovered that IAP inhibitor-induced cell death was primarily necroptotic and dependent on TNF-α. Through spectral flow cytometry, we confirmed the absence of cleaved caspase-3 in IAP inhibitor-treated T-PLL cells and show that IAP inhibition reduces the proliferation of T-PLL cells stimulated ex vivo, while showing only a limited effect on nonmalignant T-cells. In summary, our study maps the drug sensitivity of T-PLL across a broad range of targets and identifies new therapeutic approaches for T-PLL by targeting IAPs, exportin 1, and autophagy, highlighting potential candidates for drug repurposing and novel treatment strategies.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2336-2352"},"PeriodicalIF":21.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051779","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":"Low rates of chronic graft-versus-host disease with ruxolitinib maintenance following allogeneic HCT.","authors":"Zachariah DeFilipp, Haesook T Kim, Laura W Knight, Suzanne M O'Connor, Shilton E Dhaver, Meghan White, Bhagirathbhai Dholaria, Mark A Schroeder, Sumithira Vasu, Sameem Abedin, Jooho Chung, Areej El-Jawahri, Matthew J Frigault, Steven McAfee, Richard A Newcomb, Paul V O'Donnell, Thomas R Spitzer, Yi-Bin Chen, Gabriela S Hobbs","doi":"10.1182/blood.2024028005","DOIUrl":"10.1182/blood.2024028005","url":null,"abstract":"<p><strong>Abstract: </strong>Despite recent advances in graft-versus-host disease (GVHD) prophylaxis, novel approaches to effective prevention of chronic GVHD (cGVHD) remain of high importance. In this prospective, multicenter, phase 2 trial, ruxolitinib, an oral inhibitor of Janus kinase (JAK) 1 and 2, was administered as maintenance therapy after reduced-intensity allogeneic hematopoietic cell transplantation (HCT). GVHD prophylaxis consisted of tacrolimus and methotrexate. Ruxolitinib began between day +30 to 100 and was administered continuously in 28-day cycles for up to 24 cycles. Seventy-eight participants were enrolled before HCT; 63 participants received the intervention. The median start date of ruxolitinib after HCT was day +45. The most common grade ≥3 adverse events were neutropenia, thrombocytopenia, and anemia. Seven participants experienced grade ≥3 infectious events. GVHD-free, relapse-free survival at 1 year after HCT, the primary end point, was 70%. Grade 3 to 4 acute GVHD at 6 months was 4.8%, and moderate-severe cGVHD at 2 years was 16%. cGVHD requiring systemic therapy was 9.5% at 1 year and 13% at 2 years. Overall survival and progression-free survival at 2 years were 76% and 68%, respectively. Prolonged administration of ruxolitinib following HCT is associated with low rates of clinically significant cGVHD. The incorporation of JAK inhibition into GVHD prevention approaches warrants further investigation. This trial was registered at www.clinicaltrials.gov as #NCT03286530.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2312-2316"},"PeriodicalIF":21.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662431","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":"Three-year follow-up analysis of first-line axicabtagene ciloleucel for high-risk large B-cell lymphoma: the ZUMA-12 study.","authors":"Julio C Chavez, Michael Dickinson, Javier Munoz, Matthew L Ulrickson, Catherine Thieblemont, Olalekan O Oluwole, Alex F Herrera, Chaitra S Ujjani, Yi Lin, Peter A Riedell, Natasha Kekre, Sven de Vos, Jacob Wulff, Chad M Williams, Joshua Winters, Ioana Kloos, Hairong Xu, Sattva S Neelapu","doi":"10.1182/blood.2024027347","DOIUrl":"10.1182/blood.2024027347","url":null,"abstract":"<p><p>ZUMA-12 is a multicenter phase 2 study evaluating axicabtagene ciloleucel (axi-cel) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy as part of first-line treatment for high-risk large B-cell lymphoma (LBCL). In the primary efficacy analysis (n = 37; median follow-up, 15.9 months), axi-cel demonstrated a high rate of complete responses (CR; 78%) and a safety profile consistent with prior experience. Here, we assessed updated outcomes from ZUMA-12 in 40 treated patients after ≥3 years of follow-up. Eligible adults underwent leukapheresis, lymphodepleting chemotherapy, and  axi-cel infusion (2 × 106 CAR T cells/kg). Investigator-assessed CR, objective response, survival, safety, and CAR T-cell expansion were assessed. The CR rate among response-evaluable patients (n = 37) increased after the primary analysis to 86% (95% confidence interval [CI], 71%-95%), with a 92% objective response rate. After a median follow-up of 47.0 months (range, 37.1-57.8 months), 36-month estimates (95% CI) of duration of response and event-free, progression-free, and overall survival were 81.8% (63.9%-91.4%), 73.0% (55.6%-84.4%), 75.1% (57.5%-86.2%), and 81.1% (64.4%-90.5%), respectively. In total, 4 patients had new malignancies, 2 occurring after the data cutoff of the primary analysis; none were axi-cel-related. Eight patients died on study, 2 of whom died from nonrelapse mortality causes. After long-term follow-up, axi-cel demonstrated a high durable response rate, with no new safety signals after the primary analysis, suggestive of an effective first-line therapy with curative intent in high-risk LBCL. Further assessments are needed to determine its benefit vs standard of care. This trial was registered at clinicaltrials.gov, as NCT03761056.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2303-2311"},"PeriodicalIF":21.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405562","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":"CARs in pole position: ready for the race?","authors":"Guillaume Manson,Roch Houot","doi":"10.1182/blood.2025028354","DOIUrl":"https://doi.org/10.1182/blood.2025028354","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"40 1","pages":"2235-2236"},"PeriodicalIF":20.3,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991971","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":"Expanding the universe of T-PLL targets.","authors":"Marwan Kwok,Tatjana Stankovic","doi":"10.1182/blood.2025028353","DOIUrl":"https://doi.org/10.1182/blood.2025028353","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"28 1","pages":"2239-2241"},"PeriodicalIF":20.3,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143992025","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":"Adult T-cell leukemia/lymphoma coexistent with immune dysregulation-associated EBV+ lymphoproliferative disorder.","authors":"Xuan Wang,Hongmei Yi","doi":"10.1182/blood.2025028361","DOIUrl":"https://doi.org/10.1182/blood.2025028361","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"55 1","pages":"2396"},"PeriodicalIF":20.3,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143992032","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 new severe congenital neutropenia syndrome associated with autosomal recessive COPZ1 mutations.","authors":"Natalia Borbaran Bravo, Ekaterina Deordieva, Larissa Doll, Mohammad ElGamacy, Benjamin Dannenmann, Joana Azevedo, Alberto Iannuzzo, Selket Delafontaine, Moritz Lehners, Marius Kolodziej, Birte Hernandez Alvarez, Anna-Sophia Hellmuth, Malte Ritter, Betül Findik, Viktoria Zakharova, Sandro Bräuning, Sergey Kandabarau, Claudia Lengerke, Robert Feil, Isabelle Meyts, Jérôme Delon, Markus Templin, Marc Sturm, Olaf Rieß, Cornelia Zeidler, Karl Welte, Anna Shcherbina, Maksim Klimiankou, Julia Skokowa","doi":"10.1182/blood.2023022576","DOIUrl":"10.1182/blood.2023022576","url":null,"abstract":"<p><strong>Abstract: </strong>We have identified a new inherited bone marrow failure syndrome with severe congenital neutropenia (CN) caused by autosomal recessive mutations in the coatomer protein complex I (COPI) subunit zeta 1 (COPZ1) gene. A stop-codon COPZ1 mutation and a missense (MS) mutation were found in 3 patients from 2 unrelated families. Although 2 affected siblings with a stop-codon COPZ1 mutation suffered from CN that involves other hematologic lineages and nonhematologic tissues, the patient with a MS COPZ1 mutation had isolated neutropenia. Both COPZ1 mutations were localized to a highly evolutionarily conserved region. The resulting truncated (TR) COPZ1 protein was predicted to display diminished interaction with its COPI complex partner, COPG1. These findings were consistent with the observed block in retrograde protein transport from the Golgi apparatus to the endoplasmic reticulum (ER) in human fibroblasts carrying TR COPZ1. Human CD34+ cells with TR or MS COPZ1 had significantly impaired granulocytic differentiation, and in zebrafish embryos, TR Copz1 also resulted in defective myelopoiesis. Intracellularly, TR COPZ1 downregulated JAK/STAT/CEBPE/G-CSFR signaling and hypoxia-responsive pathways, while inducing STING, interferon-stimulated genes, stimulating oxidative phosphorylation activity, and increasing reactive oxygen species levels in hematopoietic cells. MS COPZ1 deregulated interferon and JAK/STAT signaling but less than the TR protein. Finally, treatment with the small molecule HIF1α stabilizer IOX2 or transduction of cells with COPZ2 restored defective granulopoiesis in COPZ1-mutated human CD34+ cells, offering potential therapeutic options.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2317-2335"},"PeriodicalIF":21.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142789610","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":"N-homocysteinylation of β-arrestins biases GPCR signaling and promotes platelet activation.","authors":"Lin-Qi Zhang, Chang-Xiao Che, Ya-Qin Du, Lu-Lu Han, Jia-Le Wang, Chen-Yu Zhang, Shen-Ming Huang, Zhong-Yuan Zheng, Qing-Tao He, Zhao Yang, Long Zhang, Nan Chen, Fan Yang, Ying-Li Jia, Shi-Min Zhao, De-Min Zhou, Chu Wang, Xian Wang, Jin-Peng Sun, Lu Tie","doi":"10.1182/blood.2024025593","DOIUrl":"10.1182/blood.2024025593","url":null,"abstract":"<p><strong>Abstract: </strong>Hyperhomocysteinemia (HHcy) is strongly associated with cardiovascular diseases (CVDs), and it has been identified as a risk factor for thrombotic diseases. Most patients with HHcy die from various complications closely related to thrombotic diseases. However, the underlying mechanisms have not been fully elucidated. G protein-coupled receptors (GPCRs), the central regulators of the cardiovascular system, primarily control platelet activation. By examining the effects of HHcy on a panel of GPCRs involved in platelet aggregation, we found that HHcy systematically modulated biased GPCR signaling through the inhibition of desensitization by β-arrestins and the amplification of G protein signals. We further revealed that the N-homocysteinylation of β-arrestin1/2 at lysine (K) residues (K294/K296) disrupted the interaction between β-arrestins and GPCRs. The aforementioned phenomenon may be universal because HHcy was found to modulate the signaling bias of 9 other randomly selected GPCRs. Moreover, we found that the proinflammatory effects of homocysteine and homocysteine thiolactone were weakened in Arrb2-/- mice and that the reintroduction of wild-type but not K296R β-arrestin2 mutants (in mice) into primary peritoneal macrophages reversed these effects. Notably, in Arrb2K296R mice, HHcy-induced thrombus formation and platelet aggregation were reversed. Our results suggest that a G-biased agonist could be a better choice for disease therapy under HHcy conditions. Collectively, our findings demonstrate that the N-homocysteinylation of β-arrestin1/β-arrestin2 actively modulates the biased property of GPCR signaling, which contributes to the pathophysiology of HHcy-related CVDs and provides insight into the selection of agonists for the treatment of diseases under HHcy conditions.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2374-2389"},"PeriodicalIF":21.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389997","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":"Sustained MRD negativity drives maintenance stop.","authors":"","doi":"10.1182/blood.2025029434","DOIUrl":"https://doi.org/10.1182/blood.2025029434","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"8 1","pages":"2397"},"PeriodicalIF":20.3,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991974","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}