HemaSphere最新文献

{"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}

{"title":"IL-11—An aging-related cytokine with opportunities for regulating hematopoiesis","authors":"David G. Kent","doi":"10.1002/hem3.70050","DOIUrl":"10.1002/hem3.70050","url":null,"abstract":"&lt;p&gt;Cytokines have long been known as chemical messengers that act upon cells in the blood system to induce proliferation and response to disease. Studying them at scale in a tissue context has been challenging due to functional redundancy and pleiotropic effects, but they remain an area of active investigation for a wide range of groups, especially now that new approaches are emerging to studying cytokine signaling dynamics at the single molecule level.&lt;span&gt;&lt;sup&gt;1-3&lt;/sup&gt;&lt;/span&gt; This summer, a huge study on the proinflammatory cytokine Interleukin 11 (IL-11) emerged in &lt;i&gt;Nature&lt;/i&gt; magazine from the group of Stuart Cook—the paper &lt;i&gt;Inhibition of IL-11 signaling extends mammalian healthspan and lifespan&lt;/i&gt;&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; dropped into the hyperactive aging research community and caused quite a stir.&lt;/p&gt;&lt;p&gt;The headline statement: “Genetic deletion of &lt;i&gt;Il11&lt;/i&gt; extended the lives of mice of both sexes, by 24.9% on average” caught the research world's attention. This was impressively followed by a series of studies that involved treating mice with an anti-IL-11 antibody from middle age (75 weeks) until death where the researchers observed another impressive increase in lifespan (&gt;20%), strongly suggesting that early life events do not irrevocably sentence an organism to an early death. Simple in design and elegant in execution, the study details the genetic and pharmacological modulation of aging in both sexes. This positions the paper as one of the few that demonstrates a clear extension of lifespan through the removal of a single gene—one of the earliest examples of which is the &lt;i&gt;daf-2&lt;/i&gt; c.elegans mutants&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; that have an extended lifespan. The authors go on to detail a wide range of metabolic and pathway profiling and imply that the metabolic, proinflammatory, and profibrotic roles of IL-11 are the mechanistic drivers of aging through the ERK-mTORC1 and JAK/STAT signaling pathways. This also suggests that JAK inhibitors, metformin, rapamycin, and so forth might have antiaging and antifibrotic roles as well, but the authors note that some of these current therapies struggle with on- and off-target toxicities that an anti-IL-11 therapy might not have. Indeed, an early-stage clinical trial is already underway using anti-IL-11 for the treatment of fibro-inflammatory diseases.&lt;/p&gt;&lt;p&gt;IL-11 is no stranger to stem cell and hematopoiesis research. It is one of a handful of critical molecules that interact with the glycoprotein 130 (gp130) family for signal transduction, in the good company of leukemia inhibitory factor (LIF) and interleukin 6 (IL-6) among others. These molecules have long been studied in stem cell systems (e.g., LIF in mouse embryonic stem cells and ciliary neurotrophic factor [CNTF] in neural stem cells) and have also been among the key regulators of hematopoietic stem cell (HSC) self-renewal in the form of IL-6 and IL-11. Early studies highlighted IL-11's partnership with the stem cell factor (S","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 11","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11574441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical evaluation of the CD38-targeting engineered toxin body MT-0169 against multiple myeloma","authors":"Wassilis S. C. Bruins,&nbsp;Rosa Rentenaar,&nbsp;John Newcomb,&nbsp;Wenrou Zheng,&nbsp;Ruud W. J. Ruiter,&nbsp;Thomas Baardemans,&nbsp;Eric Poma,&nbsp;Chris Moore,&nbsp;Garrett L. Robinson,&nbsp;Anya Lublinsky,&nbsp;Yuhong Zhang,&nbsp;Sakeena Syed,&nbsp;Michael Milhollen,&nbsp;Ajeeta B. Dash,&nbsp;Niels W. C. J. van de Donk,&nbsp;Richard W. J. Groen,&nbsp;Sonja Zweegman,&nbsp;Tuna Mutis","doi":"10.1002/hem3.70039","DOIUrl":"10.1002/hem3.70039","url":null,"abstract":"<p>Despite significant progress in the treatment of multiple myeloma (MM), relapsed/refractory patients urgently require more effective therapies. We here describe the discovery, mechanism of action, and preclinical anti-MM activity of engineered toxin body MT-0169, a next-generation immunotoxin comprising a CD38-specific antibody fragment linked to a de-immunized Shiga-like toxin A subunit (SLTA) payload. We show that specific binding of MT-0169 to CD38 on MM cell lines triggers rapid internalization of SLTA, causing cell death via irreversible ribosome inhibition, protein synthesis blockade, and caspase 3/7 activation. In co-culture experiments, bone marrow mesenchymal stromal cells did not induce drug resistance against MT-0169. In the preclinical setting, MT-0169 effectively lysed primary MM cells from newly diagnosed and heavily pretreated MM patients, including those refractory to daratumumab, with minimal toxicity against nonmalignant hematopoietic cells. MM cell lysis showed a significant correlation with their CD38 expression levels but not with cytogenetic risk, tumor load, or number of prior lines of therapy. Finally, MT-0169 showed efficient in vivo anti-MM activity in various mouse xenograft models, including one in which MM cells are grown in a humanized bone marrow-like niche. These findings support clinical investigation of MT-0169 in relapsed/refractory MM patients, including those refractory to CD38-targeting immunotherapies.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 11","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561653/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Results of the prospective EORTC Children Leukemia Group study 58081 in precursor B- and T-cell acute lymphoblastic leukemia","authors":"Carine Domenech,&nbsp;Michal Kicinski,&nbsp;Barbara De Moerloose,&nbsp;Caroline Piette,&nbsp;Wadih A. Chahla,&nbsp;Laure Kornreich,&nbsp;Marlène Pasquet,&nbsp;Anne Uyttebroeck,&nbsp;Alexandre Theron,&nbsp;Marilyne Poirée,&nbsp;Chloé Arfeuille,&nbsp;Marleen Bakkus,&nbsp;Nathalie Grardel,&nbsp;Catherine Paillard,&nbsp;Claire Freycon,&nbsp;Frédéric Millot,&nbsp;Pauline Simon,&nbsp;Pierre Philippet,&nbsp;Claire Pluchart,&nbsp;Stefan Suciu,&nbsp;Pierre Rohrlich,&nbsp;Alina Ferster,&nbsp;Yves Bertrand,&nbsp;Hélène Cavé,&nbsp;for the Children's Leukemia Group (CLG) of the European Organization for Research and Treatment of Cancer (EORTC)","doi":"10.1002/hem3.70025","DOIUrl":"10.1002/hem3.70025","url":null,"abstract":"<p>Here, we report the results of the prospective cohort study EORTC-CLG 58081 and compare them to the control arm of the randomized phase 3 trial EORTC-CLG 58951, on which treatment recommendations were built. In both studies, patients aged 1–18 years with <i>BCR::ABL1</i> negative acute lymphoblastic leukemia of the B-lineage (B-ALL) or T-lineage (T-ALL) were treated using a BFM backbone without cranial irradiation. Similarly to the control arm of 58951, prednisolone (PRED) 60 mg/m²/day was used for induction therapy, but a few modifications were made. Dexamethasone (DXM) was used in average-risk 2 (AR2) T-ALL and B-ALL during induction, 10 and 6 mg/m²/day, respectively. Leucovorin rescue was delayed to 42 h instead of 36 h after initiation of high-dose methotrexate, and a postconsolidation MRD time point was added to stratify patients. Between 2011 and 2017, 835 patients were prospectively enrolled in the 58081 study. Overall, the 5-year event-free survival (EFS) was 84.8% versus 83.6% (hazard ratio [HR], 0.96 [95% confidence interval [CI]: 0.76–1.21]) for 58081 versus 58951 considered as a control group, respectively, 84.3% versus 84.9% (HR, 1.06 [99% CI: 0.75–1.49]) in B-ALL but 87.3% versus 76.6% (HR, 0.59 [99% CI: 0.28–1.24]) in T-ALL. The comparison between the two studies regarding EFS differed by risk group (<i>p</i> = 0.012). The HR was 2.15 (99% CI: 0.67–6.85) for very low-risk but 0.34 (99% CI: 0.13–0.89) for AR2. The particularly favorable results observed in the T-ALLs and AR2 subgroups suggest the benefit of using DXM in specific patient groups and highlight the importance of risk stratification.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 11","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11558101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619099","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":"Prognostic risk and survival of asymptomatic IgM monoclonal gammopathy: Results from a Spanish Multicenter Registry","authors":"David F. Moreno,&nbsp;Cristina Jiménez,&nbsp;Fernando Escalante,&nbsp;Elham Askari,&nbsp;Marta Castellanos-Alonso,&nbsp;Mario Arnao,&nbsp;Ángela Heredia,&nbsp;Miguel Á. Canales,&nbsp;Magdalena Alcalá,&nbsp;Arancha Bermúdez,&nbsp;Ana Saus Carreres,&nbsp;María Casanova,&nbsp;Luis Palomera,&nbsp;Cristina Motlló,&nbsp;Ricarda García-Sánchez,&nbsp;Pablo Ríos Rull,&nbsp;Ramón García-Sanz,&nbsp;Carlos Fernández de Larrea","doi":"10.1002/hem3.70029","DOIUrl":"10.1002/hem3.70029","url":null,"abstract":"<p>Asymptomatic IgM gammopathy encompasses IgM monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic Waldenström macroglobulinemia (AWM), both having a risk of progression to symptomatic disease. Here, we assessed the risk of progression and the mortality of 956 patients with asymptomatic IgM gammopathy across 25 Spanish centers. After a median follow-up of 5.7 years, 156 patients progressed, most of them to symptomatic WM (SWM). The cumulative incidence of progression was 13% and 20% at 5 and 10 years, respectively. The serum IgM ≥10 g/L, bone marrow (BM) infiltration ≥20%, β2-microglobulin ≥3 mg/L, and albumin &lt;4 g/dL were the most potent predictors of disease progression in a multivariate Cox regression model, allowing the identification of three risk categories. The probability of progression to symptomatic disease at 5 years was 4.5%, 15.7%, and 42.8% for low-, intermediate-, and high-risk groups, respectively. In patients without a BM evaluation, the presence of none or 1 risk factor and 2 or 3 risk factors conferred a progression risk of 6% and 27% at 5 years, respectively. The model was independent of the presence of <i>MYD88</i> L265P, which conferred a negative impact only in AWM patients. The relative survival (RS) ratio at 5 years of asymptomatic patients was similar to the Spanish population, which contrasted with the 0.76 5-year RS of SWM patients. Overall, the Spanish Multicenter Model comprehensively describes the risk of progression of asymptomatic patients and shows that the excess mortality is increased only in the symptomatic stage of the disease.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 11","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619096","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":"Causes of death among patients diagnosed with chronic lymphocytic leukemia: A population-based study in the Netherlands, 1996–2020","authors":"Lina van der Straten,&nbsp;Mark-David Levin,&nbsp;Manette A. W. Dinnessen,&nbsp;Otto Visser,&nbsp;Eduardus F. M. Posthuma,&nbsp;Jeanette K. Doorduijn,&nbsp;Anton W. Langerak,&nbsp;Arnon P. Kater,&nbsp;Avinash G. Dinmohamed","doi":"10.1002/hem3.70015","DOIUrl":"10.1002/hem3.70015","url":null,"abstract":"<p>Chronic lymphocytic leukemia (CLL) manifests heterogeneously with varying outcomes. This population-based study examined causes of death (CODs), as registered by the physician who established the death, among 20,588 CLL patients diagnosed in the Netherlands between 1996 and 2020. Utilizing cause-specific flexible parametric survival models, we estimated cause-specific hazard ratios (HRs) and cumulative incidences of death due to CLL, solid malignancies, other hematological malignancies, infections, and other causes. Our findings reveal CLL as the predominant COD, contributing to around 40% of relative mortality, with a declining 5-year death probability from 16.8% in 1996–2002 to 7.6% in 2010–2020. Also, deaths attributed to solid malignancies, other hematological malignancies, and other COD diminished over time, as evidenced by respective HRs (95% confidence interval) of 0.68 (0.60%–0.77%), 0.45 (0.38%–0.53%), and 0.77 (0.66%–0.90%). In summary, our comprehensive, population-based analysis underscores a noticeable reduction in CLL-attributed deaths and other competing causes over the studied period. Nonetheless, CLL is registered as the most prevalent cause of mortality among contemporary diagnosed patients with CLL, emphasizing the continued relevance of CLL-centric clinical strategies and research.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 11","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619077","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":"Antibiotic-associated neutropenia is marked by the depletion of intestinal Lachnospiraceae and associated metabolites in pediatric patients","authors":"Josaura Fernandez-Sanchez,&nbsp;Rachel Rodgers,&nbsp;Arushana A. Maknojia,&nbsp;Nusrat Shaikh,&nbsp;Hannah Yan,&nbsp;Marlyd E. Mejia,&nbsp;Hope Hendricks,&nbsp;Robert R. Jenq,&nbsp;Pavan Reddy,&nbsp;Ritu Banerjee,&nbsp;Jeremy M. Schraw,&nbsp;Megan T. Baldridge,&nbsp;Katherine Y. King","doi":"10.1002/hem3.70038","DOIUrl":"10.1002/hem3.70038","url":null,"abstract":"<p>Prolonged antibiotic exposure causes dangerous hematologic side effects, including neutropenia, in up to 34% of patients. Murine studies established a link between the intestinal microbiota and hematopoiesis. To identify factors that predispose to neutropenia in pediatric patients, we evaluated changes in microbiota-derived metabolites and intestinal microbiota composition after prolonged courses of antibiotics. In this multi-center study, patients with infections requiring anticipated antibiotic treatment of two or more weeks were enrolled. Stool samples were obtained at the start and completion of antibiotics or at neutropenia onset (prospective arm). Some patients were enrolled in a retrospective arm in which a stool sample was collected at the time of neutropenia during antibiotic therapy and 2–4 weeks after completion of antibiotics with recovery of blood counts. We identified 10 patients who developed neutropenia on antibiotics and 29 controls matched for age, sex, race, and ethnicity. Clinical data demonstrated no association between neutropenia and the type of infection or antibiotic used; however, patients with neutropenia were admitted to the intensive care unit more often and received longer courses of antibiotics. Reduced intestinal microbiome richness and, specifically, decreased abundance of <i>Lachnospiraceae</i> family members correlated with neutropenia. Untargeted stool metabolomic profiling revealed several metabolites that were depleted exclusively in patients with neutropenia, including members of the urea cycle pathway, pyrimidine metabolism, and fatty acid metabolism that are known to be produced by <i>Lachnospiraceae</i>. Our study shows a relationship between intestinal microbiota disruption and abnormal hematopoiesis and identifies taxa and metabolites likely to contribute to microbiota-sustained hematopoiesis.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 11","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11543857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619073","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":"30-Minute infusion of isatuximab in patients with newly diagnosed multiple myeloma: Results of a Phase 1b study analysis","authors":"Enrique M. Ocio,&nbsp;Aurore Perrot,&nbsp;Philippe Moreau,&nbsp;Maria-Victoria Mateos,&nbsp;Sara Bringhen,&nbsp;Joaquín Martínez-López,&nbsp;Lionel Karlin,&nbsp;Song-Yau Wang,&nbsp;Corina Oprea,&nbsp;Yi Li,&nbsp;Ercem Kodas,&nbsp;Jesus San-Miguel","doi":"10.1002/hem3.70041","DOIUrl":"10.1002/hem3.70041","url":null,"abstract":"&lt;p&gt;The addition of an anti-CD38 antibody to standard treatment regimens, in combination with an immunomodulatory drug or a proteasome inhibitor and dexamethasone, provides benefit to multiple myeloma (MM) patients in the relapsed/refractory setting (RRMM), as well as at an earlier disease stage in quadruplet combinations for transplant-eligible or non-eligible patients with newly diagnosed MM (NDMM).&lt;span&gt;&lt;sup&gt;1-3&lt;/sup&gt;&lt;/span&gt; Isatuximab (Isa) is approved in various countries in combination with pomalidomide-dexamethasone or carfilzomib-dexamethasone for the treatment of RRMM patients.&lt;span&gt;&lt;sup&gt;4-6&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Study findings in transplant-eligible NDMM patients demonstrated significant efficacy of Isa in quadruplet combinations with bortezomib-lenalidomide-dexamethasone (VRd) for induction therapy in the Phase 3 GMMG-HD7 trial (minimal residual disease [MRD] negativity: 50% with Isa-VRd vs 36% with VRd; &lt;i&gt;p&lt;/i&gt; = 0.00017), and with carfilzomib-lenalidomide-dexamethasone (KRd) for induction/consolidation treatment in the Phase 3 IsKia/EMN24 trial (MRD negativity after consolidation: 77% with Isa-KRd vs 67% with KRd; &lt;i&gt;p&lt;/i&gt; = 0.049), without new safety signals.&lt;span&gt;&lt;sup&gt;7, 8&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;In transplant-ineligible NDMM patients, significant PFS benefit (hazard ratio [HR], 0.60; 98.5% confidence interval [CI], 0.41–0.88; &lt;i&gt;p&lt;/i&gt; &lt; 0.001) and deep, sustained responses were reported with Isa in combination with VRd followed by Isa-Rd versus VRd followed by Rd, in a prespecified interim analysis of the Phase 3 IMROZ trial, with a manageable safety profile.&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt; In the Phase 3 BENEFIT trial, the addition of weekly bortezomib to Isa-Rd (reduced-dose VRd) induced a significant improvement in MRD negativity at 18 months versus Isa-Rd (53% vs. 26%, &lt;i&gt;p&lt;/i&gt; &lt; 0.0001).&lt;span&gt;&lt;sup&gt;10&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;The evaluation of Isa with either bortezomib-cyclophosphamide-dexamethasone (VCd) or VRd has shown safety and efficacy of these quadruplet regimens in the Phase 1b trial TCD13983 (NCT02513186) in transplant-ineligible NDMM patients (all cohorts) or patients with no immediate intent for autologous stem cell transplantation included in Isa-VRd/Part-B, as previously reported.&lt;span&gt;&lt;sup&gt;11, 12&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;To enhance the convenience of long-term treatment with IV Isa for patients and healthcare providers, by improving the current duration of Isa infusion (75 min), we prospectively evaluated the feasibility, safety, and tolerability of a novel, fast, 30-min infusion method for Isa in patients who were on maintenance therapy in the TCD13983 study.&lt;/p&gt;&lt;p&gt;All patients on maintenance treatment, regardless of treatment cohort, were switched to 30-min infusion with Isa at 10 mg/kg (250-mL fixed-volume infusion). Details on study treatments before switching, premedications, and patient characteristics are provided in Supporting Information and Supporting Information S1: Figure S1. To accelerate the infusions to a target durat","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 11","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11538320/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590294","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}