HemaSphere最新文献_第8页

High levels of global hydroxymethylation predict worse overall survival in MDS patients treated with azacitidine 在阿扎胞苷治疗的MDS患者中，高水平的整体羟甲基化预示着更差的总生存率。

IF 7.6 2区医学

HemaSphere Pub Date : 2025-01-03 DOI: 10.1002/hem3.70034

Francesca Tiso, Florentien E. M. in 't Hout, Ruth Knops, Leonie I. Kroeze, Arno van Rooij, Arjan A. van de Loosdrecht, Theresia M. Westers, Saskia M. C. Langemeijer, Claude Preudhomme, Nicolas Duployez, Pierre Fenaux, Olivier Kosmider, Didier Bouscary, Aniek O. de Graaf, Joost H. A. Martens, Bert A. van der Reijden, Lionel Adès, Michaela Fontenay, Joop H. Jansen

{"title":"High levels of global hydroxymethylation predict worse overall survival in MDS patients treated with azacitidine","authors":"Francesca Tiso, Florentien E. M. in 't Hout, Ruth Knops, Leonie I. Kroeze, Arno van Rooij, Arjan A. van de Loosdrecht, Theresia M. Westers, Saskia M. C. Langemeijer, Claude Preudhomme, Nicolas Duployez, Pierre Fenaux, Olivier Kosmider, Didier Bouscary, Aniek O. de Graaf, Joost H. A. Martens, Bert A. van der Reijden, Lionel Adès, Michaela Fontenay, Joop H. Jansen","doi":"10.1002/hem3.70034","DOIUrl":"10.1002/hem3.70034","url":null,"abstract":"Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological malignancies characterized by cytopenia, dysplasia, and a risk of progressing to acute myeloid leukemia (AML).1 Using the international prognostic scoring systems (IPSS, IPSS-R, and recently IPSS-M), patients can be categorized into different risk groups for overall and leukemia-free survival.2-4 In combination with fitness and individual preferences, the therapeutic strategy for each patient is determined.5 Currently, the strategies most commonly used are best supportive care (BSC) with or without EPO/G-CSF in lower-risk MDS, lenalidomide (LEN) in patients with a del(5q), or luspatercept in patients with ring sideroblasts/SF3B1 mutations. In higher-risk MDS, hypomethylating agents (HMAs), chemotherapy, and/or stem cell transplantation can be considered. MDS patients carry mutations in genes involved in DNA methylation including TET2 (20%–30%), DNMT3A (10%), and IDH1/2 (5%–10%).6 DNMT3A is a DNA methyltransferase that converts cytosine (C) into 5-methylcytosine (5mC). Methylated DNA can in turn be actively demethylated by TET enzymes (including TET2), converting 5mC into 5-hydroxymethylcytosine (5hmC) which is further converted into cytosine by subsequent actions of TET proteins, thymidine DNA glycosylase (TDG), and the base excision repair (BER) pathway. Mutations in TET2 result in defective enzymatic activity and significantly decreased levels of 5hmC. TET proteins need vitamin C, Fe2+, and alpha-ketoglutarate (α-KG) as cofactors for proper enzymatic activity. The latter is produced by IDH1/2 enzymes. Mutations in IDH1 and IDH2 result in the aberrant production of 2-hydroxyglutarate instead of α-KG, which inhibits TET activity. Therefore, also in IDH1/2 mutated cells, decreased 5hmC levels can be observed.7Cancer cells often show hypermethylation, which may result in silencing of tumor suppressor genes.8 The methylation process is reversible and can be influenced by the administration of HMAs like azacitidine (AZA) and decitabine. Both compounds have shown important activity in MDS and AML.9 HMAs are analogs of the nucleoside cytidine and they are incorporated into the DNA during DNA replication, inhibiting the DNA methylation process and causing hypomethylation. In addition, 80%–90% of azacitidine is incorporated into the RNA. As not all patients respond to HMAs and the response may take several courses of therapy before an effect becomes apparent,10 the identification of markers that predict response is warranted. Recently, a set of 39 methylation sites was found significantly different in MDS patients responding to AZA, compared to nonresponders.11 We previously demonstrated that ","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142931623","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}

引用次数: 0

Annual Sickle Cell & Thalassaemia Conference (ASCAT) - October 2024

IF 7.6 2区医学

HemaSphere Pub Date : 2024-12-23 DOI: 10.1002/hem3.70009

{"title":"Annual Sickle Cell & Thalassaemia Conference (ASCAT) - October 2024","authors":"","doi":"10.1002/hem3.70009","DOIUrl":"https://doi.org/10.1002/hem3.70009","url":null,"abstract":"Topic: 001–Basic and translationalA. Ejaz1, S. Liu1, S. Holliman1, C. Scott1, D. Songdej2, V. Viprakasit3, J. Davies1, C. Babbs1, D.R. Higgs1University of Oxford1, Ramathibodi Hospital2, Siriraj Hospital3Zeta globin, an embryonic alpha-like globin, is repressed from 8 weeks gestation in humans.1 Its de-repression is of clinical interest as transgenic mouse models have shown that it can substitute for alpha globin2—making it an attractive target for de-repressive gene editing strategies as a therapy for alpha thalassemia. Work from our lab examining cis regulatory factors has found that a discrete region of chromatin overlying zeta globin is deacetylated in mouse definitive erythropoiesis; while it is acetylated in primitive erythropoiesis when the gene is active.3 Previous work has also identified two trans regulatory factors—BCL11A and LRF. Knockout models of these factors show de-repression of zeta-globin to 15% of all alpha-like globin expression, less than that seen in primitive erythropoiesis when zeta globin is expressed maximally at 40% of all alpha-like globin.3 There are likely to be additional, as yet unidentified, factors involved in zeta globin regulation.Human models of persistence of zeta globin expression are key to uncovering these factors. Studies in patients with compound heterozygous KLF1 mutations have found increased embryonic globin levels, likely due to KLF1's role in activating BCL11A and LRF (4). Some survivors of alpha thalassemia major (Barts hydrops fetalis syndrome) express high quantities of zeta globin, more than would be expected purely from deletions of the alpha globin genes. We have undertaken transcriptomic and chromatin analyses in these patients to characterize novel factors that may be involved in zeta globin regulation. We have identified several candidate genes, which have been intersected with results from CRISPR/Cas9 knockout screens of epigenetic modulators and transcription factors, to further refine our results. We are now undertaking exploratory studies of these factors to uncover the mechanisms by which they interact with the zeta globin locus, and plan ultimately to develop strategies for de-repressing zeta globin.1. FB Piel, DJ Weatherall. The New England Journal of Medicine, 2014; 371(20), 1908–1916.2. JE Russell, SA Liebhaber. Blood, 1998; 92(9), 3057–3063.3. AJ King et al. Nature Communications, 2021; 12(1), 4439.4. V Viprakasit et al. Blood. 2014; 123(10), 1586–1595.Topic: 001–Basic and translationalM.J.M. Traets1, J.F. Bos1, S. Van der Veen2, A. Kidane Gebremeskel3, B.A. van Oirschot1, S.E.M. Schols4, M.N. Lauw5</sup","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 S4","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187085","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}

引用次数: 0

Annual Sickle Cell & Thalassaemia Conference (ASCAT) - October 2023

IF 7.6 2区医学

HemaSphere Pub Date : 2024-12-23 DOI: 10.1002/hem3.70021

{"title":"Annual Sickle Cell & Thalassaemia Conference (ASCAT) - October 2023","authors":"","doi":"10.1002/hem3.70021","DOIUrl":"https://doi.org/10.1002/hem3.70021","url":null,"abstract":"Topics 002–Novel therapies, gene therapies and bone marrow transplantF. Locatelli1, P. Lang2, S. Corbacioglu3, A. Li4, J. de la Fuente5, D. Wall6, R. Meisel7, A. Shah8, R. Liem9, M. Mapara10, B. Carpenter11, J. Kwiatkowski12, M.D. Cappellini13, A. Kattamis14, S. Sheth15, S. Grupp16, P. Kohli17, D. Shi17, L. Ross17, Y. Bobruff17, C. Simard17, L. Zhang17, P.K. Morrow18, B. Hobbs17, H. Frangoul19IRCCS, Ospedale Pediatrico Bambino Gesù Rome, Catholic University of the Sacred Heart1, University of Tübingen2, University of Regensburg3, BC Children's Hospital, University of British Columbia4, Imperial College Healthcare NHS Trust, St Mary's Hosp ital5, The Hospital for Sick Children/University of Toronto6, Heinrich-Heine-University7, Stanford University8, Ann & Robert H. Lurie Children's Hospital of Chicago9, Herbert Irving Comprehensive Cancer Center, Columbia University10, University College Hospital NHS Trust11, Children's Hospital of Philadelphia12, University of Milan13, University of Athens14, Joan and Sanford I Weill Medical College of Cornell University15, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania16, Vertex Pharmaceuticals17, CRISPR Therapeutics18, Sarah Cannon Center for Blood Cancer at The Children's Hospital at TriStar Centennial19Background: Exagamglogene autotemcel (exa-cel) is a one-time non-viral cell therapy designed to reactivate fetal hemoglobin (HbF) via ex vivo CRISPR/Cas9 gene-editing at the erythroid enhancer region of BCL11A in autologous CD34+ hematopoietic stem and progenitor cells.Aims: Evaluate efficacy and safety of exa-cel in patients (pts) with transfusion-dependent β-thalassemia (TDT) in a pre-specified interim analysis of the CLIMB THAL-111 trial.Methods: CLIMB THAL-111 is an ongoing phase 3 trial of exa-cel in pts age 12–35 y with TDT and a history of ≥100 mL/kg/y or ≥10 U/y of packed red blood cell (RBC) transfusions 2 y before screening. Primary and key secondary efficacy endpoints are proportion of pts who maintain a weighted average hemoglobin (Hb) ≥9g/dL without RBC transfusion for ≥12 mos (TI12; primary) and ≥6 mos (TI6; key secondary). Evaluable pts were followed for ≥16 mos after exa‑cel infusion. Evaluation of TI12 and TI6 started 60 days after last RBC transfusion for post-transplant support or TDT management. Pts completing trial enrolled in long-term follow-up Study 131.Results: As of 6 Se","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 S3","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70021","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143253115","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}

引用次数: 0

Proliferating CLL cells express high levels of CXCR4 and CD5 增殖的CLL细胞表达高水平的CXCR4和CD5。

IF 7.6 2区医学

HemaSphere Pub Date : 2024-12-17 DOI: 10.1002/hem3.70064

Daniel Friedman, Drshika P. Mehtani, Jennifer B. Vidler, Piers E. M. Patten, Robbert Hoogeboom

{"title":"Proliferating CLL cells express high levels of CXCR4 and CD5","authors":"Daniel Friedman, Drshika P. Mehtani, Jennifer B. Vidler, Piers E. M. Patten, Robbert Hoogeboom","doi":"10.1002/hem3.70064","DOIUrl":"10.1002/hem3.70064","url":null,"abstract":"Chronic lymphocytic leukemia (CLL) is an incurable progressive malignancy of CD5+ B cells with a birth rate between 0.1% and 1% of the entire clone per day. However, the phenotype and functional characteristics of proliferating CLL cells remain incompletely understood. Here, we stained peripheral blood CLL cells for ki67 and DNA content and found that CLL cells in G1-phase have a CXCR4loCD5hi phenotype, while CLL cells in S/G2/M-phase express high levels of both CXCR4 and CD5. Induction of proliferation in vitro using CD40L stimulation results in high ki67 levels in CXCR4loCD5hi cells with CXCR4 expression increasing as CLL cells progress through S and G2/M-phases, while CXCR4hiCD5lo CLL cells remained quiescent. Dye dilution experiments revealed an accumulation of Ki67hi-divided cells in the CXCR4hiCD5hi fraction. In Eµ-TCL1 transgenic mice, the CXCR4hiCD5hi fraction expressed high levels of ki67 and was expanded in enlarged spleens of diseased animals. Human peripheral blood CXCR4hiCD5hi CLL cells express increased levels of IgM and the chemokine receptors CCR7 and CXCR5 and migrate efficiently toward CCL21. We found higher levels of CXCR4 in patients with progressive disease and the CXCR4hiCD5hi fraction was expanded upon clinical relapse. Thus, this study defines the phenotype and functional characteristics of dividing CLL cells identifying a novel subclonal population that underlies CLL pathogenesis and may drive clinical outcomes.","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11651208/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846552","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}

引用次数: 0

Definitions matter: Multicenter investigation of incidence and outcome of poor graft function after hematopoietic cell transplantation 定义重要：对造血细胞移植后移植物功能不良发生率和结果的多中心调查。

IF 7.6 2区医学

HemaSphere Pub Date : 2024-12-17 DOI: 10.1002/hem3.70059

Konradin F. Müskens, Winny N. R. Collot-d'Escury, Rana Dandis, Saskia Haitjema, Jürgen Kuball, Moniek A. de Witte, Marc Bierings, Caroline A. Lindemans, Stefan Nierkens, Mirjam E. Belderbos

{"title":"Definitions matter: Multicenter investigation of incidence and outcome of poor graft function after hematopoietic cell transplantation","authors":"Konradin F. Müskens, Winny N. R. Collot-d'Escury, Rana Dandis, Saskia Haitjema, Jürgen Kuball, Moniek A. de Witte, Marc Bierings, Caroline A. Lindemans, Stefan Nierkens, Mirjam E. Belderbos","doi":"10.1002/hem3.70059","DOIUrl":"10.1002/hem3.70059","url":null,"abstract":"Despite advances in allogeneic hematopoietic cell transplantation (HCT), poor graft function (PGF) remains an important complication with substantial morbidity and mortality. The investigation of preventive and therapeutic PGF treatments is hindered by inconsistencies in reported incidence and outcomes across studies, which may be explained by heterogeneity in PGF definition. To assess the impact of definition heterogeneity, we conducted a multicenter study, analyzing over 35.000 longitudinal blood counts from 427 pediatric and 405 adult HCT recipients. We compared the incidence, risk factors, and outcome of PGF, based on the three most common definitions. We identified 97 pediatric and 75 adult HCT recipients fulfilling at least one PGF definition. The 2-year cumulative incidence of PGF varied significantly depending on the definition used, ranging from 6.8% to 20% in children and 4.9% to 18% in adults. Two-year mortality for PGF patients ranged from 33% to 40% in children and 46% to 65% in adults. Notably, PGF patients identified solely by lenient definitions had similar mortality to HCT recipients with good graft function. Risk factors for PGF also varied by definition in both cohorts, and included older recipient age and cord blood transplantation. In conclusion, our study demonstrates that differences in PGF definition significantly impact the reported incidence, risk factors, and outcome. This underscores the need to harmonize PGF definitions across scientific studies, clinical practice, and transplant registries. Future studies, using standardized, quantitative thresholds for PGF, are required to determine optimal treatment strategies for both mild and severe forms of PGF.","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11650888/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846537","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}

引用次数: 0

Expression profile of Bcl-2 family proteins in newly diagnosed multiple myeloma patients 新诊断的多发性骨髓瘤患者中 Bcl-2 家族蛋白的表达谱。

IF 7.6 2区医学

HemaSphere Pub Date : 2024-12-13 DOI: 10.1002/hem3.70036

Cristina De Ramón, Elizabeta A. Rojas, Irena Misiewicz-Krzeminska, Ignacio J. Cardona-Benavides, Myriam Cuadrado, Isabel Isidro, María-José Calasanz, Manuela Fernandez, Ramón García-Sanz, Noemi Puig, M. Teresa Cedena, Bruno Paiva, Laura Rosiñol, Joaquín Martínez-López, Joan Bladé, Juan J. Lahuerta, Jesús F. San Miguel, María V. Mateos, Luis A. Corchete, Norma C. Gutiérrez, GEM/PETHEMA cooperative study group

{"title":"Expression profile of Bcl-2 family proteins in newly diagnosed multiple myeloma patients","authors":"Cristina De Ramón, Elizabeta A. Rojas, Irena Misiewicz-Krzeminska, Ignacio J. Cardona-Benavides, Myriam Cuadrado, Isabel Isidro, María-José Calasanz, Manuela Fernandez, Ramón García-Sanz, Noemi Puig, M. Teresa Cedena, Bruno Paiva, Laura Rosiñol, Joaquín Martínez-López, Joan Bladé, Juan J. Lahuerta, Jesús F. San Miguel, María V. Mateos, Luis A. Corchete, Norma C. Gutiérrez, GEM/PETHEMA cooperative study group","doi":"10.1002/hem3.70036","DOIUrl":"10.1002/hem3.70036","url":null,"abstract":"Antiapoptotic Bcl-2 family proteins are involved in myeloma cell survival. To date, their expression in multiple myeloma (MM) patients has mostly been analyzed at the RNA level. In the present study, we quantified for the first time the protein expression of the Bcl2-family members using a capillary electrophoresis immunoassay in 120 newly diagnosed MM patients, aged ≤65 years, treated in the context of the PETHEMA/GEM2012 study. We found that the pattern of expression of Bcl-2 family proteins was highly heterogeneous among patients. Although cases with t(11;14) had significantly higher levels of Bcl-2/Bcl-xL and Bcl-2+Bim+Bax/Bcl-xL ratios than those without t(11;14), the presence of this translocation was not synonymous with such high levels of expression. Conversely, some patients with other genetic alterations also showed higher levels of those ratios. Survival analysis revealed that the high expression of Bad and Puma proteins was associated with significantly longer overall survival (p = 0.001 and p < 0.001, respectively). Bcl-2 protein ratios predicting sensitivity to venetoclax in vitro were also able to distinguish patients with shorter time to progression after triplet-based induction therapy and ASCT. This is the first study to assess the expression of the most important Bcl-2 family proteins by a quantitative method in a large set of MM patients according to their cytogenetic abnormalities. We shed light on the impact of these proteins on MM prognosis, which could help to consider the levels of proteins involved in apoptosis in the development of new therapeutic strategies.","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11645297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828239","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}

引用次数: 0

Novel approaches in myelofibrosis 骨髓纤维化的新方法。

IF 7.6 2区医学

HemaSphere Pub Date : 2024-12-12 DOI: 10.1002/hem3.70056

Steffen Koschmieder

{"title":"Novel approaches in myelofibrosis","authors":"Steffen Koschmieder","doi":"10.1002/hem3.70056","DOIUrl":"10.1002/hem3.70056","url":null,"abstract":"Myelofibrosis (MF) is a clonal myeloid neoplasm characterized by bone marrow fibrosis, splenomegaly, and disease-associated symptoms, as well as increased mortality, due to thrombosis, severe bleeding, infections, or progression to acute leukemia. Currently, the management of MF patients is tailored according to risk scores, with higher-risk (intermediate-2 and high-risk) patients being assessed for allogeneic stem cell transplantation, which remains the only potentially curative treatment option. On the other hand, lower risk (low- and intermediate-1 risk) patients who are symptomatic may be treated with JAK inhibitors or other drugs. However, none of these drug treatments have induced relevant rates of durable complete remissions, and, therefore, novel treatments are needed to improve the long-term outcomes of MF patients. This review summarizes current preclinical and clinical approaches to MF therapy, including novel drug combinations involving JAK inhibitors and innovative monotherapies. These drugs target transcription, nuclear export, survival pathways, or various intracellular pathways, ranging from JAK-STAT signaling to PI3-Kinase, TP53, PIM1, or S100A8/A9/toll-like receptor pathways. Also, extracellular targeting using interferon, calreticulin mutant-specific antibodies, and other immunotherapeutic approaches are discussed, as well as various antifibrotic strategies. In addition, preclinical approaches that target individual mutated clones, for example, by mutation-specific JAK2V617F inhibitors or DNA repair pathway inhibitors, are presented. Finally, current efforts of generating novel endpoints for clinical trials aim more at disease modification and overall survival than at improvements of splenomegaly or symptoms. Together, the new generations of clinical trials promise to offer substantial improvements in the management of MF patients and long-term disease control.","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11636632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817913","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}

引用次数: 0

Analysis of smoldering multiple myeloma according to the target of the monoclonal immunoglobulin of patients 根据患者单克隆免疫球蛋白的靶点分析多发性骨髓瘤的 "烟雾"。

IF 7.6 2区医学

HemaSphere Pub Date : 2024-12-11 DOI: 10.1002/hem3.70053

Sylvie Hermouet, Nicolas Mennesson, Sophie Allain-Maillet, Edith Bigot-Corbel, Andri Olafsson, Brynjar Viðarsson, Páll T. Önundarson, Bjarni A. Agnarsson, Margrét Sigurðardóttir, Ingunn Þorsteinsdóttir, Ísleifur Ólafsson, Elías Eyþórsson, Ásbjörn Jónsson, Thorvardur J. Love, Saemundur Rognvaldsson, Einar S. Björnsson, Sigrún Thorsteinsdóttir, Sigurdur Y. Kristinsson

{"title":"Analysis of smoldering multiple myeloma according to the target of the monoclonal immunoglobulin of patients","authors":"Sylvie Hermouet, Nicolas Mennesson, Sophie Allain-Maillet, Edith Bigot-Corbel, Andri Olafsson, Brynjar Viðarsson, Páll T. Önundarson, Bjarni A. Agnarsson, Margrét Sigurðardóttir, Ingunn Þorsteinsdóttir, Ísleifur Ólafsson, Elías Eyþórsson, Ásbjörn Jónsson, Thorvardur J. Love, Saemundur Rognvaldsson, Einar S. Björnsson, Sigrún Thorsteinsdóttir, Sigurdur Y. Kristinsson","doi":"10.1002/hem3.70053","DOIUrl":"10.1002/hem3.70053","url":null,"abstract":"Antigenic stimulation initiates subsets of plasma cell dyscrasias, including monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM).1 MGUS and MM are characterized by genetically altered clonal plasma cells that produce large quantities of a single immunoglobulin (Ig), termed “monoclonal Ig (mcIg),” or M-protein. Smoldering multiple myeloma (SMM) is the intermediate stage between asymptomatic MGUS and MM.2-4 In clonal gammopathies, the initial antigenic stimulation can be identified by studying the specificity of recognition of the patient's mcIg. In MGUS and MM, targets of mcIgs (potential initiating events) include infectious pathogens (Epstein-Barr virus [EBV], cytomegalovirus [CMV], Enteroviruses, Helicobacter pylori [H. pylori], hepatitis C virus [HCV], hepatitis B virus [HBV]), and self-antigens (glucosylsphingosine [GlcSph]).1, 5-9 Importantly, MGUS or MM linked to CMV infection or anti-GlcSph autoimmunity seem to be benign cases,1, 5-7 and suppression of the antigen target can be envisioned as a potential therapy. Studies of MGUS during Gaucher disease (GD) showed that GlcSph, the immunogenic lipid accumulated in GD, is a frequent target of GD mcIgs.5, 6 Confirming the link between GlcSph and MGUS in GD patients, GlcSph-reducing eliglustat therapy successfully suppressed the plasma clone and mcIg production.10 Viral target antigen reduction also improved response to chemotherapy, as observed with antiviral treatments for MM patients who presented with an HCV- or HBV-specific mcIg, thus likely had HCV- or HBV-initiated disease.11, 12Previous studies have shown that ~15% of sporadic MGUS and MM have a mcIg specific for GlcSph, consistent with chronic autoimmunity, and ~60% MGUS and ~30% MM patients have a mcIg specific for a pathogen, implying that infection initiated the gammopathy.1, 7-9, 13 However, antigen targets of mcIg in SMM remain unknown. Here we analyzed the targets of mcIg of an SMM cohort from the Iceland Screens, Treats or Prevents Multiple Myeloma (iStopMM) consortium14, 15; patient characteristics according to the target of the mcIg; and the effect of target reduction therapy for SMM patients with H. pylori-specific mcIg.We examined 182 individuals (109 males, 73 females) diagnosed with SMM in the iStopMM study during the 2016–2022 period. Serum samples were collected at diagnosis or follow-up visits (every 4–6 months), aliquoted, and frozen (−80°C). McIgs were IgG (n = 105), IgA (n = 45), IgM (n = 1), and light chains (LC) (n = 26). Five patients (P41, P107, P153, P166, P168) were bi-clonal (had two mcIgs). The male ratio was 60%, and at diagnosis, the median age of patients was 67.5 years, and the median M-protein amo","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11635023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817962","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}

引用次数: 0

Time-restricted versus standard-duration immunosuppression after allogeneic hematopoietic stem cell transplantation: Results of the prospective randomized HOVON-96 trial 同种异体造血干细胞移植后限制性免疫抑制与标准持续时间免疫抑制：前瞻性随机HOVON-96试验的结果

IF 7.6 2区医学

HemaSphere Pub Date : 2024-12-11 DOI: 10.1002/hem3.70040

Annoek E. C. Broers, Ellen Meijer, Bronno van der Holt, Cornelis N. de Jong, Erfan Nur, Geerte L. van Sluis, Goda Choi, Michel van Gelder, Johan A. Maertens, Jürgen Kuball, Dries Deeren, Heleen A. Visser-Wisselaar, Lamberdina A. H. M. Meulendijks, Jan J. Cornelissen, the HOVON Stem Cell Transplantation Working Group

{"title":"Time-restricted versus standard-duration immunosuppression after allogeneic hematopoietic stem cell transplantation: Results of the prospective randomized HOVON-96 trial","authors":"Annoek E. C. Broers, Ellen Meijer, Bronno van der Holt, Cornelis N. de Jong, Erfan Nur, Geerte L. van Sluis, Goda Choi, Michel van Gelder, Johan A. Maertens, Jürgen Kuball, Dries Deeren, Heleen A. Visser-Wisselaar, Lamberdina A. H. M. Meulendijks, Jan J. Cornelissen, the HOVON Stem Cell Transplantation Working Group","doi":"10.1002/hem3.70040","DOIUrl":"10.1002/hem3.70040","url":null,"abstract":"Cyclosporine A combined with mycophenolate mofetil (CsA/MMF) has become an established regimen for the prevention of graft-versus-host disease (GVHD) following non-myeloablative (NMA) allogeneic hematopoietic stem cell transplantation (alloHSCT). However, the optimal duration of immunosuppression (IS) has not yet been defined and overtreatment is of concern. We hypothesized that time-restricted IS with CsA/MMF would increase the proportion of patients with non-severe GVHD compared to standard-duration IS, thereby resulting in reduction of the relapse rate and improvement of progression-free survival (PFS) and overall survival (OS). In a prospective randomized, multicenter, phase III trial, patients were allocated (1:1) to standard or time-restricted IS. A total of 389 patients were randomized, of whom 369 were transplanted (184 vs. 185 patients). The primary endpoint, the proportion of patients with non-severe GVHD defined as acute GVHD grades I–II without gut involvement or chronic GVHD not requiring systemic treatment within 180 days posttransplant, was 23% after standard-duration IS versus 24% after time-restricted IS (odds ratio: 1.02; 95% confidence interval (CI) 0.63–1.66, p = 0.92). The cumulative incidence of grade III–IV acute GVHD at 6 months posttransplant was not significantly different (14% vs. 18%; p = 0.20). The two-year cumulative incidence of chronic extensive GVHD was 50% versus 46% (p = 0.62). There were no significant differences in the rates of relapse/progression, non-relapse mortality, PFS, OS, and GVHD-free, relapse-free survival. Time-restricted IS with CsA/MMF did not increase the proportion of patients with non-severe GVHD, and secondary outcomes were not different compared to standard-duration IS following NMA-matched alloHSCT.","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11632395/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813040","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}

引用次数: 0

Early progression beyond first-line chemoimmunotherapy in follicular lymphoma: Insights from a Fondazione Italiana Linfoma (FIL) study 滤泡性淋巴瘤在一线化疗免疫治疗后的早期进展：来自意大利淋巴瘤基金会（FIL）研究的见解

IF 7.6 2区医学

HemaSphere Pub Date : 2024-12-10 DOI: 10.1002/hem3.70049

Alberto Bavieri, Maria E. Nizzoli, Alessandra Tucci, Vittorio R. Zilioli, Jacopo Olivieri, Benedetta Bianchi, Mansueto G. Rosaria, Ombretta Annibali, Alessia Bari, Gloria M. Casaluci, Michele Cimminiello, Nicola Di Renzo, Federica Cavallo, Vicenzo Pavone, Clara Mannarella, Annalisa Arcari, Maggi Alessandro, Antonella Anastasia, Vittoria Tarantino, Antonino Neri, Massimo Gentile, Fortunato Morabito, Stefano Luminari

{"title":"Early progression beyond first-line chemoimmunotherapy in follicular lymphoma: Insights from a Fondazione Italiana Linfoma (FIL) study","authors":"Alberto Bavieri, Maria E. Nizzoli, Alessandra Tucci, Vittorio R. Zilioli, Jacopo Olivieri, Benedetta Bianchi, Mansueto G. Rosaria, Ombretta Annibali, Alessia Bari, Gloria M. Casaluci, Michele Cimminiello, Nicola Di Renzo, Federica Cavallo, Vicenzo Pavone, Clara Mannarella, Annalisa Arcari, Maggi Alessandro, Antonella Anastasia, Vittoria Tarantino, Antonino Neri, Massimo Gentile, Fortunato Morabito, Stefano Luminari","doi":"10.1002/hem3.70049","DOIUrl":"10.1002/hem3.70049","url":null,"abstract":"Follicular lymphoma (FL) is the most common indolent B-cell lymphoma.1, 2 While most patients with FL have a truly indolent clinical course with standard therapy (ICT),3 one out five patients experience early relapse or progression (R/P), leading to notably poor outcomes with a 5-year overall survival (OS) of only 60%.4, 5 These so-called POD24 patients usually show aggressive behavior mainly due to histological transformation (HT) and emergent chemo-resistant disease.6-13 However, not all POD24 patients face unfavorable outcomes, underscoring the need for extensive real-life data to elucidate FL behavior after the first relapse.14 We conducted a retrospective multicenter study to assess the outcomes of a real-world cohort of FL patients at their first relapse. Patients with grade 1 to 3a FL who experienced their first R/P after first-line standard ICT between 2002 and 2017 were eligible. Of note, patients with HT at first relapse were excluded in order to describe a homogeneous FL population. Clinical and laboratory features were documented at diagnosis and the first and second R/P, with optional histological confirmation details of first R/P. The study received approval from ethic committees at each participating institution, and all patients provided informed consent. The primary endpoint was progression-free survival from first relapse (index date; PFS2). The secondary endpoint was survival after the first relapse (SAR). POD24r was defined as disease R/P within 24 months after the start of the first salvage therapy. The endpoint definition is reported in the supplementary material.The initial cohort included 175 patients, enrolled by 16 centers of Fondazione Italiana Linfomi (FIL), and 155 were confirmed eligible (Supporting Information S1: Figure 1). The key characteristics of patients both at diagnosis and at index date are shown in Table 1. Even if a biopsy was not mandatory, a pathology report consistent with FL at index date was available for 117 cases. Regarding initial therapy, most of the patients were treated with the R-CHOP regimen (98, 63%), and rituximab maintenance was administered in 59 cases. POD24 was documented in 59 patients (38%); 141 patients received a second-line therapy consisting mainly of R-Bendamustine and platinum-based therapy (41; 29%, and 37; 26%, respectively) (Table 1).After a median follow-up of 48 months from the index date (interquartile range [IQR]: 25–68 months), 64 patients experienced a subsequent relapse or progression with a median PFS2 of 55 months (95% confidence interval [CI], 44–83 months). 4-year PFS2 rates was 55% (95% CI: 46%–63%). In univariate analysis, only male sex, increased beta-2-microglobulin (β2-M) levels at index date, and POD24 predicted lower PFS rates (Supporting Information S1: Table 1 and Supporting Information S1: Figure 2). In multivariate anal","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 12","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11655126/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854068","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}

引用次数: 0