Blood advances最新文献

{"title":"Real-world treatment patterns and outcomes in relapsed/refractory multiple myeloma (1-3 prior lines): Flatiron database.","authors":"Binod Dhakal, Hermann Einsele, Jordan M Schecter, William Deraedt, Nikoletta Lendvai, Ana Slaughter, Carolina Lonardi, Sandhya Nair, Jianming He, Akshay Kharat, Patricia Cost, Satish Valluri, Kwee Yong","doi":"10.1182/bloodadvances.2024012640","DOIUrl":"10.1182/bloodadvances.2024012640","url":null,"abstract":"<p><strong>Abstract: </strong>In the context of multiple myeloma (MM), early use of the immunomodulatory drug lenalidomide has led to an increased population of patients with lenalidomide-refractory MM in early-line settings, but their outcomes are not well characterized. Herein, we report treatment patterns, survival outcomes, prognostic variables, and attrition rates for patients with proteasome inhibitor-exposed, lenalidomide-refractory MM, treated with 1 to 3 prior lines of therapy (LOT). From 12 767 patients with MM in the Flatiron Health database between January 2016 and April 2022, 1455 met the inclusion criteria. The most common subsequent treatments were triplet combinations (41.6% of patients); daratumumab/pomalidomide/dexamethasone was the most common treatment regimen (13.2%). Median real-world progression-free survival (RW-PFS) and overall survival (OS) were 6.5 months and 44.4 months, respectively. RW-PFS was similar in patients with 1, 2, or 3 prior LOT. International Staging System stage III, Eastern Cooperative Oncology Group performance status of 1, hemoglobin <12 g/dL, high-risk cytogenetics, and refractoriness to anti-CD38 antibody at baseline were associated with worse RW-PFS and OS. Outcomes remained similar for patients who received National Comprehensive Cancer Network-preferred treatments and those who received treatments after 2020. In 561 patients with 1 prior LOT at inclusion, the cumulative attrition rate from LOT 2 to 5 was 85%, which included 25% patients who died and 60% with no further treatment. Patients with lenalidomide-refractory MM who have received 1 to 3 prior LOT have poor outcomes and progress rapidly through available therapies, highlighting the need for more effective treatments early in the disease course, before patients are lost to attrition.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11459902/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141900971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Factor XI inhibitors: a new class of anticoagulants.","authors":"Jean M Connors","doi":"10.1182/bloodadvances.2024013852","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024013852","url":null,"abstract":"","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388146","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":"Complete absence of GLUT1 does not impair human terminal erythroid differentiation.","authors":"Catarina Martins Freire, Nadine R King, Monika Dzieciatkowska, Daniel Stephenson, Pedro L Moura, Johannes G G Dobbe, Geert J Streekstra, Angelo D'Alessandro, Ashley M Toye, Timothy J Satchwell","doi":"10.1182/bloodadvances.2024012743","DOIUrl":"10.1182/bloodadvances.2024012743","url":null,"abstract":"<p><strong>Abstract: </strong>The glucose transporter 1 (GLUT1) is 1 of the most abundant proteins within the erythrocyte membrane and is required for glucose and dehydroascorbic acid (vitamin C precursor) transport. It is widely recognized as a key protein for red cell structure, function, and metabolism. Previous reports highlighted the importance of GLUT1 activity within these uniquely glycolysis-dependent cells, in particular for increasing antioxidant capacity needed to avoid irreversible damage from oxidative stress in humans. However, studies of glucose transporter roles in erythroid cells are complicated by species-specific differences between humans and mice. Here, using CRISPR-mediated gene editing of immortalized erythroblasts and adult CD34+ hematopoietic progenitor cells, we generate committed human erythroid cells completely deficient in expression of GLUT1. We show that absence of GLUT1 does not impede human erythroblast proliferation, differentiation, or enucleation. This work demonstrates, to our knowledge, for the first time, generation of enucleated human reticulocytes lacking GLUT1. The GLUT1-deficient reticulocytes possess no tangible alterations to membrane composition or deformability in reticulocytes. Metabolomic analyses of GLUT1-deficient reticulocytes reveal hallmarks of reduced glucose import, downregulated metabolic processes and upregulated AMP-activated protein kinase signaling, alongside alterations in antioxidant metabolism, resulting in increased osmotic fragility and metabolic shifts indicative of higher oxidant stress. Despite detectable metabolic changes in GLUT1-deficient reticulocytes, the absence of developmental phenotype, detectable proteomic compensation, or impaired deformability comprehensively alters our understanding of the role of GLUT1 in red blood cell structure, function, and metabolism. It also provides cell biological evidence supporting clinical consensus that reduced GLUT1 expression does not cause anemia in GLUT1-deficiency syndrome.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11470287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141449737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unexpected diagnosis of WHIM syndrome in refractory autoimmune cytopenia.","authors":"Yolanda Garcia-Carmona, Jose Chavez, Yael Gernez, Julia T Geyer, James B Bussel, Charlotte Cunningham-Rundles","doi":"10.1182/bloodadvances.2024013301","DOIUrl":"10.1182/bloodadvances.2024013301","url":null,"abstract":"<p><strong>Abstract: </strong>WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is a rare primary immunodeficiency predominantly caused by heterozygous gain-of-function mutations in the C-terminus of the gene CXCR4. These CXCR4 variants display impaired receptor trafficking with persistence of the CXCR4 receptor on the surface, resulting in hyperactive downstream signaling after CXCL12 stimulation. In turn, this results in defective lymphoid differentiation, and reduced blood neutrophil and lymphocyte numbers. Here, we report a CXCR4 mutation that in 2 members of a kindred, led to life-long autoimmunity and lymphoid hypertrophy as the primary clinical manifestations of WHIM syndrome. We examine the functional effects of this mutation, and how these have affected phosphorylation, activation, and receptor internalization.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11460441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141726939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential inflammatory conditioning of the bone marrow by acute myeloid leukemia and its impact on progression.","authors":"Valentina R Minciacchi, Christina Karantanou, Jimena Bravo, Raquel S Pereira, Costanza Zanetti, Theresa Krack, Rahul Kumar, Katrin Bankov, Sylvia Hartmann, Brian J P Huntly, Eshwar Meduri, Wolfram Ruf, Daniela S Krause","doi":"10.1182/bloodadvances.2024012867","DOIUrl":"10.1182/bloodadvances.2024012867","url":null,"abstract":"<p><strong>Abstract: </strong>Inflammation promotes solid tumor progression, but how regulatory mechanisms of inflammation may affect leukemia is less well studied. Using annexin A5 (ANXA5), a calcium-binding protein known for apoptosis, which we discovered to be differentially expressed in the bone marrow microenvironment (BMM) of mice with acute myeloid (AML) vs chronic myeloid leukemia, as a model system, we unravel here a circuit in which AML-derived tumor necrosis factor α (TNF-α) dose-dependently reduces ANXA5 in the BMM. This creates an inflammatory BMM via elevated levels of prostaglandin E2 (PGE2). Via binding to its EP4 receptor, PGE2 increases β-catenin and hypoxia-inducible factor 1α signaling in AML cells, thereby accelerating PGE2-sensitive AML. Human trephine biopsies may show lower ANXA5 expression and higher PGE2 expression in AML than other hematologic malignancies. Furthermore, syngeneic and xenogeneic transplantation models suggest a survival benefit after treatment with the inhibitor of prostaglandin-endoperoxide synthase 2 (cyclooxygenase 2 [COX2]), celecoxib, plus cytarabine in those AML types highly sensitive to PGE2 compared with cytarabine alone. Taken together, TNF-α/ANXA5/NF-κB/COX2/PGE2-mediated inflammation influences AML course in a highly differential and circular manner, and patients with AML with \"inflammatory AML\" may benefit from antiphlogistic agents as adjunct therapy.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11465066/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141598440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Class II ferroptosis inducers are a novel therapeutic approach for t(4;14)-positive multiple myeloma.","authors":"Jiasi Zhang, Yuxi Liu, Liping Zuo, Fengjuan Fan, Han Yan, Fei Zhao, Junying Li, Chi Ma, Qun Li, Aoshuang Xu, Jian Xu, Bo Zhang, Yu Hu, Chunyan Sun","doi":"10.1182/bloodadvances.2023010335","DOIUrl":"10.1182/bloodadvances.2023010335","url":null,"abstract":"<p><strong>Abstract: </strong>Multiple myeloma (MM) is a clonal plasma cell malignancy that is characterized by genetic heterogeneity. The cytogenetic abnormality t(4;14) strongly predicts poor outcome in patients with MM, even in the era of novel drugs. Ferroptosis is a new approach to antitumor therapy, but the relationship between ferroptosis and MM cytogenetic abnormalities remains largely unclear. In this study, we show that t(4;14)-positive but not t(4;14)-negative MM cells are susceptible to class II ferroptosis inducers (FINs) in a preclinical setting, which is dependent on the significant upregulation of the MM SET domain-containing protein (MMSET). Mechanistically, MMSET upregulates acyl-coenzyme A synthetase long-chain family member 4 transcription by binding to its promoter region, leading to increased polyunsaturated fatty acid (PUFA) levels and enhanced sensitivity of t(4;14)-positive MM cells to ferroptosis. Supplementation with PUFAs efficiently restores the susceptibility of t(4;14)-negative MM cells to ferroptosis. In addition, combining class II FIN treatment with bortezomib in t(4;14)-positive MM cells attenuates cellular glutathione and induces both apoptosis and ferroptosis levels by inhibiting the increase in solute carrier family 7 member 11, demonstrating synergistic antitumor activity in vitro and in a xenograft model. Taken together, our findings suggest that targeting ferroptosis with class II FINs is a novel and promising therapeutic approach to improve the outcome of t(4;14)-positive patients with MM.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11465055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141751116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bridging radiotherapy before CAR-T therapy in CNS lymphoma.","authors":"Ulrike Bacher, Thomas Pabst","doi":"10.1182/bloodadvances.2024013924","DOIUrl":"10.1182/bloodadvances.2024013924","url":null,"abstract":"","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11530399/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sustained Remission at long-term Follow-up in Adolescents and Young Adults with Chronic Primary Immune Thrombocytopenia.","authors":"Alexandra Schifferli, Gautier Le Gavrian, Nathalie Aladjidi, Guillaume Moulis, Bertrand Godeau, Thierry M Leblanc, Sebastien Heritier, Helder Fernandes, Thomas Kühne","doi":"10.1182/bloodadvances.2024014381","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024014381","url":null,"abstract":"<p><p>Adolescents and young adults (AYAs) with immune thrombocytopenia (ITP) exhibit distinct clinical features and needs, defying categorization as either adults or children. Previous findings revealed a 50% risk of chronic disease at 12 months, yet the long-term course remains unclear. This study aimed to delineate the clinical and laboratory characteristics of AYAs with chronic primary ITP. Data from patients aged 12-25 years with chronic disease at 1 year were extracted from three registries (PARC-ITP, CEREVANCE, CARMEN), covering the period from 2004 to 2021. Sustained complete remission off treatment (SCROT) occurring beyond 12 months was defined as platelet count >100 × 109/L without treatment for at least 12 months, independently of the previous treatment strategy. A total of 427 AYAs (64% female) with chronic primary ITP were included. Clinical information was available for ~100% of patients at initial diagnosis, 6- and 12-month follow-ups, and for 88%, 77%, and 59% at 24, 36, and 48 months, respectively. Over time, clinical features improved gradually, with fewer patients requiring treatment. Throughout the follow-up period, second-line drug use increased steadily among treated patients, without impacting the need for corticosteroids and intravenous immunoglobulins. The proportion of new patients achieving SCROT at 24-, 36-, and 48-months FU was 10% (38/375), 9.5% (31/327), and 12% (30/250), respectively, including 23 who underwent splenectomy. AYAs achieving SCROT between 12-36 months displayed higher platelet counts in the first year (excluding the initial period) and received fewer intravenous immunoglobulin treatments beyond 12 months compared to those with ongoing disease.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388162","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 as Predictor of Post-Day +100 Relapses Following Allografting in Adult AML.","authors":"Naveed Ali, Megan Othus, Eduardo Rodríguez-Arbolí, Corentin Orvain, Filippo Milano, Brenda M Sandmaier, Chris Davis, Ryan Basom, Fred R Appelbaum, Roland B Walter","doi":"10.1182/bloodadvances.2024013214","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024013214","url":null,"abstract":"<p><p>Measurable residual disease (MRD) by multiparametric flow cytometry (MFC) before allogeneic hematopoietic cell transplantation (HCT) identifies patients at high risk of acute myeloid leukemia (AML) relapse, often occurring early after allografting. To examine the role of MFC MRD testing for the prediction of later relapses, we examined 935 adults with AML or myelodysplastic neoplasm (MDS)/AML transplanted in first or second morphologic remission who underwent bone marrow restaging studies between day 70 and 100 post-HCT and were alive and without relapse by day +100. Of these 136 (15%) had MRD before HCT, whereas only 11 (1%) had MRD at day +70-100. In day +100 landmark analyses, pre-HCT and day +70-100 MFC MRD were both associated with relapse (both P<0.001), relapse-free survival (RFS; both P<0.001) overall survival (OS; both P<0.001), and, for post-HCT MRD, non-relapse mortality (P=0.001) after multivariable adjustment. Importantly, while 126 of the 136 patients (92%) with MRD before HCT tested negative for MRD at day +70-100, their outcomes were inferior to those without MRD before HCT and at day +70-100, with 3-year relapse risk of 40% vs. 15% (P<0.001), 3-year RFS of 50% vs. 72% (P<0.001), and 3-year OS of 56% vs. 76% (P<0.001), whereas 3-year NRM estimates were similar (P=0.53). Thus, despite high MRD conversion rates, outcomes for MRDpos/MRDneg patients are inferior to MRDneg/MRDneg patients, suggesting all patients with pre-HCT MRD should be considered for pre-emptive therapeutic strategies after allografting.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388151","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":"PI3Kδ activation, IL6 overexpression, and CD37 loss cause resistance to naratuximab emtansine in lymphomas.","authors":"Alberto J Arribas, Sara Napoli, Eugenio Gaudio, Charles Herbaux, Eleonora Cannas, Chiara Tarantelli, Roberta Bordone Pittau, Luciano Cascione, Nicolas Munz, Luca Aresu, Jacopo Sgrignani, Andrea Rinaldi, Ivo Kwee, Davide Rossi, Andrea Cavalli, Emanuele Zucca, Georg Stussi, Anastasios Stathis, Callum Sloss, Matthew S Davids, Francesco Bertoni","doi":"10.1182/bloodadvances.2023012291","DOIUrl":"https://doi.org/10.1182/bloodadvances.2023012291","url":null,"abstract":"<p><p>CD37-directed antibody and cellular-based approaches have shown preclinical and promising early clinical activity. Naratuximab emtansine (Debio 1562, IMGN529) is an antibody-drug conjugate (ADC) incorporating an anti-CD37 monoclonal antibody conjugated to the maytansinoid DM1 as payload, with activity as a single agent and in combination with rituximab in lymphoma patients. We studied naratuximab emtansine and its free payload in 54 lymphoma models, correlated its activity with CD37 expression, characterized two resistance mechanisms, and identified combination partners providing synergy. The activity, primarily cytotoxic, was more potent in B- than T-cell lymphoma cell lines. After prolonged exposure to the ADC, one diffuse large B-cell lymphoma (DLBCL) cell line developed resistance to the ADC due to the CD37 gene biallelic loss. After CD37 loss, we also observed upregulation of IL6 and related transcripts. Recombinant IL6 led to resistance. Anti-IL6 antibody tocilizumab improved the ADC's cytotoxic activity in CD37+ cells. In a second model, resistance was sustained by PIK3CD activating mutation, with increased sensitivity to PI3Kδ inhibition and a functional dependence switch from MCL1 to BCL2. Adding idelalisib or venetoclax overcame resistance in the resistant derivative and improved the cytotoxic activity in the parental cells. In conclusion, targeting B-cell lymphoma with the naratuximab emtansine showed vigorous anti-tumor activity as a single agent, which was also observed in models bearing genetic lesions associated with inferior outcomes, such as MYC translocations and TP53 inactivation or R-CHOP resistance. Resistant DLBCL models identified active combinations of naratuximab emtansine with drugs targeting IL6, PI3Kδ, and BCL2.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388161","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}