HemaSphere最新文献_第7页

Mitochondrial retention in mature red blood cells from patients with sickle cell disease is associated with stress erythropoiesis but not with proinflammatory state 镰状细胞病患者成熟红细胞中的线粒体滞留与红细胞生成压力有关，但与促炎状态无关

IF 7.6 2区医学

HemaSphere Pub Date : 2024-10-28 DOI: 10.1002/hem3.70030

Marc Romana, Sandrine Laurance, Marie-Dominique Hardy-Dessources, Laetitia Claer, Sylvie Ravion, Karim Dorgham, Yohann Garnier, Lea Kuznicki, Vanessa Tarer, Benoit Tressières, Sophie D. Lefevre, Veronique Baccini, Mariano A. Ostuni, Caroline Le Van Kim, Maryse Etienne-Julan

{"title":"Mitochondrial retention in mature red blood cells from patients with sickle cell disease is associated with stress erythropoiesis but not with proinflammatory state","authors":"Marc Romana, Sandrine Laurance, Marie-Dominique Hardy-Dessources, Laetitia Claer, Sylvie Ravion, Karim Dorgham, Yohann Garnier, Lea Kuznicki, Vanessa Tarer, Benoit Tressières, Sophie D. Lefevre, Veronique Baccini, Mariano A. Ostuni, Caroline Le Van Kim, Maryse Etienne-Julan","doi":"10.1002/hem3.70030","DOIUrl":"https://doi.org/10.1002/hem3.70030","url":null,"abstract":"Sickle cell disease (SCD) is a hemoglobinopathy characterized by the occurrence of vaso-occlusive events, severe chronic hemolytic anemia, and ultimately chronic complications and end-organ damages.1-3 SCD pathophysiology has been shown to be extremely complex, resulting from microcirculatory dysfunctions associated with altered vaso-regulation and activation of inflammation cascades responsible of sterile inflammatory state, endothelial and neutrophil activation, and release of neutrophil extracellular trap (NET).1, 4-6 More recently, a dysfunctional erythropoiesis has been described in SS patients characterized by high level of reticulocytes, increased apoptosis at the later stage of erythropoiesis, and abnormal retention of mitochondria in red blood cells (RBCs).7-13 It is noteworthy that the functionality of these mitochondria in mature sickle RBCs remains controversial11, 12 and mechanisms responsible for the mitochondrial retention during erythropoiesis have not been identified. Besides these unanswered points, several groups reported in vitro evidence that plasma mitochondrial DNA released by hemolysis of these abnormal RBCs could trigger type I interferon production12 and NET release in SCD patients.13 Altogether, these studies suggested that mitochondrial DNA from sickle mature RBCs could play a key role in the proinflammatory state associated with the disease.In the present study, we characterized mature RBCs retaining mitochondria in a large cohort of the two main SCD genotypes, that is, SS and SC adult patients (71 and 40 patients, respectively) compared to 21 AA control individuals. We analyzed associations between mitochondria retention and hemolysis as well as inflammation markers (see patients and methods in Supporting Information and Supporting Information S1: Table 1 for the biological and demographic parameters).Mitochondria presence in mature RBCs, total, and stress reticulocytes was assessed using flow cytometry (CD71/TO and/or MitoTracker Deep Red (MTKDR) staining) (Figure 1A). SS patients exhibited significant higher percentage of total circulating reticulocytes (5.0% ± 2.2%) compared to AA healthy donors (1.1% ± 0.4%), with a significant intermediate phenotype for SC patients (3.6% ± 1.7%) (Figure 1Bi). SS patients presented significant high levels of stress reticulocytes (2.6% ± 1.2%) compared to very low level observed in AA healthy donors (0.14 ± 0.09) while SC patients exhibited significant intermediate level (1.8% ± 1.0%) (Figure 1Bii). We did not observe significant difference of total and stress reticulocyte percentages between hydroxyurea (HU)-treated and nontreated SS patients (Figure 1Biii,iv). Percentage of mitochondria+-total reticulocytes was significantly higher in SS patients (25.0% ± 13.2%) compared to AA healthy donors (11.9% ± 8.","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 11","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70030","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142525355","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

Abstract Book 摘要手册

IF 7.6 2区医学

HemaSphere Pub Date : 2024-10-24 DOI: 10.1002/hem3.70012

{"title":"Abstract Book","authors":"","doi":"10.1002/hem3.70012","DOIUrl":"https://doi.org/10.1002/hem3.70012","url":null,"abstract":"Alex F. Herrera1, Michael Leblanc2, Sharon M. Castellino3, Hongli Li2, Sarah Rutherford4, Andrew Evens5, Kelly Davison6, Angela Punnett7, Susan K. Parsons8, Sairah Ahmed9, Carla Casulo10, Nancy L. Bartlett11, Joseph Tuscano12, Matthew Mei1, Brian Hess13, Ryan Jacobs14, Hayder Saeed15, Pallawi Torka16, Boyu Hu17, Craig H. Moskowitz18, Supreet Kaur19, Gaurav Goyal20, Christopher Forlenza16, Andrew Doan21, Adam Lamble22, Pankaj Kumar23, Saeeda Chowdury24, Brett Brinker25, Namita Sharma26, Avina Singh27, Kristie Blum28, Anamarija Perry29, Alexandra Kovach21, David Hodgson30, Louis Constine10, Lale Kostakoglu31, Anca Prica30, Hildy Dillon32, Richard F. Little33, Margaret A. Shipp34, Michael Crump30, Brad S. Kahl11, John Leonard4, Sonali Smith35, Kara M. Kelly36, Jonathan W. Friedberg101City of Hope, 2SWOG Statistics and Data Management Center, 3Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, 4Weill Cornell Medicine, 5Rutgers Cancer Institute of New Jersey, 6McGill University Health Center, 7SickKids Hospital, 8Tufts Medical Center, 9MD Anderson Cancer Center, 10University of Rochester, 11Washington University in St. Louis, 12UC Davis, 13Medical University of South Carolina, 14Levine Cancer Institute, 15Moffitt Cancer Center, 16Memorial Sloan Kettering Cancer Center, 17Huntsman Cancer Institute, University of Utah, 18University of Miami, 19University of Texas at San Antonio, 20University of Alabama at Birmingham, 21Children's Hospital of Los Angeles, 22Seattle Children's Hospital, 23Illinois Cancer Care, 24Prisma Health Cancer Institute, 25Cancer & Hematology Center, 26Geisinger Community Medical Center, 27Fairview Ridges Hospital, 28Emory University, Winship Cancer Institute, 29University of Michigan, 30Princess Margaret Cancer Centre, 31University of Virginia, 32SWOG Cancer Research Network, 33National Cancer Institute, 34Dana-Farber Cancer Institute, 35University of Chicago, 36Roswell Park Comprehensive Cancer CenterFigure 1: Progression-Free Survival in in Modified Intent-to-treat Analysis Set.<b","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 S2","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142524543","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

Long-term outcome of 2-year survivors after allogeneic hematopoietic cell transplantation for acute leukemia 急性白血病异基因造血细胞移植后两年幸存者的长期预后。

IF 7.6 2区医学

HemaSphere Pub Date : 2024-10-22 DOI: 10.1002/hem3.70026

Marion Larue, Myriam Labopin, Thomas Schroeder, Xiao-jun Huang, Igor W. Blau, Johannes Schetelig, Arnold Ganser, Rose-Marie Hamladji, Wolfgang Bethge, Nicolaus Kröger, Gerard Socié, Urpu Salmenniemi, Henrik Sengeloev, Bhagirathbhai Dholaria, Bipin N. Savani, Arnon Nagler, Fabio Ciceri, Mohamad Mohty

{"title":"Long-term outcome of 2-year survivors after allogeneic hematopoietic cell transplantation for acute leukemia","authors":"Marion Larue, Myriam Labopin, Thomas Schroeder, Xiao-jun Huang, Igor W. Blau, Johannes Schetelig, Arnold Ganser, Rose-Marie Hamladji, Wolfgang Bethge, Nicolaus Kröger, Gerard Socié, Urpu Salmenniemi, Henrik Sengeloev, Bhagirathbhai Dholaria, Bipin N. Savani, Arnon Nagler, Fabio Ciceri, Mohamad Mohty","doi":"10.1002/hem3.70026","DOIUrl":"10.1002/hem3.70026","url":null,"abstract":"Information on late complications in patients with acute leukemia who have undergone allogeneic hematopoietic cell transplantation (HCT) is limited. We performed a left-truncated analysis of long-term survival in patients with acute leukemia who were alive and disease-free 2 years after HCT. We included 2701 patients with acute lymphoblastic leukemia (ALL) and 9027 patients with acute myeloid leukemia (AML) who underwent HCT between 2005 and 2012. The 10-year overall survival (OS) rate was 81.3% for ALL and 76.2% for AML, with the main causes of late mortality being relapse (ALL-33.9%, AML-44.9%) and chronic graft-versus-host disease (ALL-29%, AML-18%). At 10 years, HCT-related mortality was 16.8% and 20.4%, respectively. Older age and unrelated donor transplantation were associated with a worse prognosis for both types of leukemia. In addition, transplantation in the second or third complete remission and peripheral blood HSC for ALL are associated with worse outcomes. Similarly, adverse cytogenetics, female donor to male patient combination, and reduced intensity conditioning in AML contribute to poor prognosis. We conclude that 2-year survival in remission after HCT for acute leukemia is encouraging, with OS of nearly 80% at 10 years. However, the long-term mortality risk of HCT survivors remains significantly higher than that of the age-matched general population. These findings underscore the importance of tailoring transplantation strategies to improve long-term outcomes in patients with acute leukemia undergoing HCT.","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 10","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11494155/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142499347","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

Casting light on the national mission to eliminate sickle cell disease in India 揭示印度消除镰状细胞病的国家使命

IF 7.6 2区医学

HemaSphere Pub Date : 2024-10-19 DOI: 10.1002/hem3.70033

Frédéric B. Piel, Roshan Colah, Dipty L. Jain

{"title":"Casting light on the national mission to eliminate sickle cell disease in India","authors":"Frédéric B. Piel, Roshan Colah, Dipty L. Jain","doi":"10.1002/hem3.70033","DOIUrl":"https://doi.org/10.1002/hem3.70033","url":null,"abstract":"Sickle cell disease (SCD) is a neglected global public health burden.1 Although it primarily affects populations from sub-Saharan Africa,2 SCD is also prevalent across the Indian subcontinent, particularly among tribal (or scheduled) populations.3 India is the most populated country in the world. According to the latest population estimates of the United Nations World Population Prospects,4 its population includes 1.441 billion people, and it is expected to further increase to reach 1.697 billion in 2063. India ranks as the country with the third highest number of annual births affected by SCD, after Nigeria and the Democratic Republic of the Congo.2 Although SCD has long been considered to be mild across the Indian subcontinent, recent evidence has demonstrated that there was a much wider range of severity than previously thought.5 Finally, tribal populations tend to be largely over-represented in the low socio-economic groups across India, making them a vulnerable group for many communicable and non-communicable diseases.6Interventions to reduce SCD morbidity and mortality, such as newborn screening, vaccinations, penicillin prophylaxis, and hydroxyurea, have proven to be effective in large-scale studies in high- and upper-middle-income countries, including the United States,7 United Kingdom,8 Jamaica,9 and Brazil.10 Pilot studies of these interventions have been conducted in numerous low-income countries.11 Cost-benefit analyses conducted in sub-Saharan Africa12 and India13 suggested that these interventions would also be effective in these settings. Nevertheless, due to a lack of political and financial commitments, no national program has so far been launched in a low- or lower-middle-income country of high prevalence for SCD. Despite the curative promises of gene therapies,14 there is an urgent need to scale up interventions in the most affected countries to improve the quality of life of patients affected and reduce the global burden of SCD.11In July 2023, the Government of India launched the “National Sickle Cell Anaemia Elimination Mission.”15 Although this program was officially launched by Prime Minister Modi, it did not receive much attention internationally. The stated aims of the Mission are twofold: (i) to improve the care of all SCD patients for their better future and (ii) to lower the prevalence of the disease by 2047 through a multifaceted coordinated approach toward screening and awareness strategies. The ambitious plan at launch was to screen 70 million people across India over the first 3 years of the Missio","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 10","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70033","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451778","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

Promoting and supporting leadership in hematology departments 促进和支持血液科的领导能力

IF 7.6 2区医学

HemaSphere Pub Date : 2024-10-17 DOI: 10.1002/hem3.70028

Roch Houot, Emmanuel Gyan

{"title":"Promoting and supporting leadership in hematology departments","authors":"Roch Houot, Emmanuel Gyan","doi":"10.1002/hem3.70028","DOIUrl":"https://doi.org/10.1002/hem3.70028","url":null,"abstract":"In recent years, the hospital system has faced tremendous pressure from economic and societal crises, which were further aggravated by the COVID-19 pandemic. Today, the European healthcare system is in a continuous crisis, primarily due to underinvestment and workforce shortages.1 In such a situation, management skills at all levels of hospital departments become critical, especially for heads of departments—a position historically driven in many countries, including France, by academic rather than managerial competencies.Challenges with medical staff retention have also exacerbated the workload of healthcare professionals.2 The shortage of healthcare workers in Europe is projected to reach 4.1 million by 2030, including 0.6 million physicians.3 Workforce shortages contribute to burnout among physicians and other healthcare workers, which renders the tasks of heads of departments extremely challenging.4, 5In the past two decades, the practice of hematology has experienced accelerated advancements in diagnostics and therapeutics, with notable prolongation of patient survival, albeit at the cost of intensified medical care due to the novel time-consuming therapeutic approaches. As such, the diversity of hematologic diagnoses and specialized treatments have created an expanding curriculum with ever more limited human resources.2, 6 The number of hematologic specialists and the competence of their training have become a concern in European countries.6The European Hematology Association (EHA) has created solutions for training in hematology, including the European Hematology curriculum, developed through a “bottom-up” process, which has inspired national educational initiatives.6 The European Working Time Directive (EWTD), introduced in 2004, aims to reduce long working hours to enhance patient safety. In this context, the European Commission urged member states to adopt the EWTD for hospital physicians.2 However, these initiatives create challenges for department heads, who must manage increased workloads with limited staffing and heightened awareness of the adverse effects of inadequate organization on workers' health.In a recent survey conducted with 2390 university hospital faculty members in France between October and December 2021, 40% of participants had severe burnout, 14% had suicidal ideation, and 12% had job strain.4 The factors associated with the unfavorable experiences included heavy work overload, work-life imbalance, and perceived lack of support from the institution.4, 7 Although the impact of stressful events on the risk of burnout and suicide is undeniable, many personality traits, such as emotional stability, extraversion, and social integration, play a role.<","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 10","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70028","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449032","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

Overcoming a T-ALL order: A comprehensive study linking genomics to clinical outcomes 战胜 T-ALL 订单：将基因组学与临床结果联系起来的综合研究

IF 7.6 2区医学

HemaSphere Pub Date : 2024-10-13 DOI: 10.1002/hem3.70027

Yizhou Huang, Charles E. de Bock

{"title":"Overcoming a T-ALL order: A comprehensive study linking genomics to clinical outcomes","authors":"Yizhou Huang, Charles E. de Bock","doi":"10.1002/hem3.70027","DOIUrl":"https://doi.org/10.1002/hem3.70027","url":null,"abstract":"Acute lymphoblastic leukemia (ALL) remains a leading success story of how modern therapies have improved patient outcomes from less than 10% survival rate in the 1950s to exceeding 90% today. This has been in part from the decades of research in the optimal use of chemotherapeutics, and, for B-cell ALL (B-ALL), the implementation of risk stratification based on clinical factors (e.g., age and peripheral blood cell counts), minimal/measurable residual disease (MRD), and cytogenetics (favorable, neutral, or unfavorable). However, for T-cell ALL (T-ALL), risk stratification is currently only based on MRD levels at the end of induction and again at the end of consolidation therapy with genomics and cytogenetics not considered prognostic factors in treatment decision-making.1 In an effort to include genomics into the risk stratification for T-ALL, a new study led by Charles Mullighan and David Teachey2 has now been published as a landmark analysis of 1300 uniformly treated T-ALL cases that, for the first time, not only defines a total of 15 discrete genetic subtypes but also links them to clinical outcomes.This new study integrates whole genome sequencing (WGS), whole exome sequencing (WES), and whole transcriptome sequencing data to expand the classification of T-ALL into a total of 15 different subtypes (Figure 1). The most significant variation from the current classification is the definition of two new subtypes, including a new early T-cell precursor (ETP)-like ALL subtype and an LMO2 γδ-like subtype—both of which have a diverse set of genetic alterations. Of the many genetic alterations, an interesting discriminator is the KMT2A fusions present in the ETP-like subtype being mostly KMT2A::AFDN fusion, while the non-ETP subtypes exclusively have KMT2A::MLLT1 fusion. The authors also compared the gene expression signatures of all 15 subtypes with normal hematopoietic and T-cell development cell stages. They found that the different T-ALL subtypes mapped across the entire continuum of T-cell development, supporting the hypothesis that each subtype represented a “frozen” stage of cellular differentiation. In the case of the ETP-like subtype, despite the heterogenous genetic drivers, the most likely cell of origin was found to be hematopoietic stem and progenitor cells (HSPC).It will come as no surprise that this study confirms the high frequency of recurrent NOTCH1 mutations (69% of cases) in T-ALL, second only to CDKN2A alterations (71% of cases), with the majority being coding sequence mutations that lead to activation of NOTCH1 signaling. However, this study also found rare single-nucleotide variants (SNV) within intron 28 of the NOTCH1 gene which generated a new splice acceptor site and resulted in a 43 amino acid insertion between the heterodimerization (HD) domain and the transmembrane (TM) domain of NOTCH1. Functionally, this new mutation","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 10","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70027","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142435264","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

Outcomes and prognostic factors in 3306 patients with relapsed/refractory chronic lymphocytic leukemia treated with ibrutinib outside of clinical trials: A nationwide study 在临床试验之外接受伊布替尼治疗的 3306 例复发/难治性慢性淋巴细胞白血病患者的疗效和预后因素：一项全国性研究。

IF 7.6 2区医学

HemaSphere Pub Date : 2024-10-08 DOI: 10.1002/hem3.70017

Gian Matteo Rigolin, Pier Paolo Olimpieri, Valentina Summa, Simone Celant, Lydia Scarfò, Maria Pia Ballardini, Antonio Urso, Silvia Gambara, Francesco Cavazzini, Paolo Ghia, Antonio Cuneo, Pierluigi Russo

{"title":"Outcomes and prognostic factors in 3306 patients with relapsed/refractory chronic lymphocytic leukemia treated with ibrutinib outside of clinical trials: A nationwide study","authors":"Gian Matteo Rigolin, Pier Paolo Olimpieri, Valentina Summa, Simone Celant, Lydia Scarfò, Maria Pia Ballardini, Antonio Urso, Silvia Gambara, Francesco Cavazzini, Paolo Ghia, Antonio Cuneo, Pierluigi Russo","doi":"10.1002/hem3.70017","DOIUrl":"10.1002/hem3.70017","url":null,"abstract":"We performed a cohort study that included all patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL) who received ibrutinib in the Italian National Health Service. With a median follow-up of 42.2 months (IQR 30.8–54.6 months), the study involved 3306 patients with a median age of 72.1 years, of whom 42.6% had received ≥2 previous lines of treatment. The estimated 24-month probabilities of being on treatment and alive were 57.9% (95% confidence interval [CI]: 59.6–56.2) and 76.6% (95% CI: 75.2–78.1), respectively. The median time to treatment discontinuation (TTD) was 31.3 months (95% CI: 29.5–33.5). Out of 3306 patients, 2015 (60.9%) discontinued treatment, with 993 cases attributed to death or disease progression (30.0% of all cases). Among the 1022 patients who discontinued treatment for reasons other than progression or death, 564 (17.1%) patients did so due to toxicity or medical decision, while 458 patients (13.8%) were lost to follow-up. Multivariable analysis revealed that age, Eastern Cooperative Oncology Group Performance Status, the number of previous lines of therapy, refractoriness to the last treatment, and reduced renal function were associated with shorter TTD and overall survival (OS). The coexistence of 17p− and TP53 mutations had an independent unfavorable impact on TTD and OS. Nonstandard doses were associated with shorter TTD and advanced stage with shorter OS. The median OS postprogression and postdiscontinuation for other reasons were estimated at 12.9 (95% CI: 11.3–16.2) and 22.7 months (95% CI: 20.2–28.3), respectively. This large real-world study shows that ibrutinib is an effective treatment for R/R CLL. Baseline patient characteristics and double-hit TP53 aberrations were associated with inferior prognosis, and discontinuation due to CLL progression portended a poor outcome.","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 10","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11459203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390135","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

Combined inhibition of CTPS1 and ATR is a metabolic vulnerability in p53-deficient myeloma cells 对 CTPS1 和 ATR 的联合抑制是 p53 缺陷骨髓瘤细胞的代谢弱点。

IF 7.6 2区医学

HemaSphere Pub Date : 2024-10-08 DOI: 10.1002/hem3.70016

Romane Durand, Céline Bellanger, Géraldine Descamps, Christelle Dousset, Sophie Maïga, Jennifer Derrien, Laura Thirouard, Louise Bouard, Hélène Asnagli, Philip Beer, Andrew Parker, Patricia Gomez-Bougie, Marie-Claire Devilder, Philippe Moreau, Cyrille Touzeau, Agnès Moreau-Aubry, David Chiron, Catherine Pellat-Deceunynck

{"title":"Combined inhibition of CTPS1 and ATR is a metabolic vulnerability in p53-deficient myeloma cells","authors":"Romane Durand, Céline Bellanger, Géraldine Descamps, Christelle Dousset, Sophie Maïga, Jennifer Derrien, Laura Thirouard, Louise Bouard, Hélène Asnagli, Philip Beer, Andrew Parker, Patricia Gomez-Bougie, Marie-Claire Devilder, Philippe Moreau, Cyrille Touzeau, Agnès Moreau-Aubry, David Chiron, Catherine Pellat-Deceunynck","doi":"10.1002/hem3.70016","DOIUrl":"10.1002/hem3.70016","url":null,"abstract":"In multiple myeloma, as in B-cell malignancies, mono- and especially bi-allelic TP53 gene inactivation is a high-risk factor for treatment resistance, and there are currently no therapies specifically targeting p53 deficiency. In this study, we evaluated if the loss of cell cycle control in p53-deficient myeloma cells would confer a metabolically actionable vulnerability. We show that CTP synthase 1 (CTPS1), which encodes a CTP synthesis rate-limiting enzyme essential for DNA and RNA synthesis in lymphoid cells, is overexpressed in samples from myeloma patients displaying a high proliferation rate (high MKI67 expression) or a low p53 score (synonymous with TP53 deletion and/or mutation). This overexpression of CTPS1 was associated with reduced survival in two cohorts. Using scRNA-seq analysis in 24 patient samples, we further demonstrate that myeloma cells in the S or G2/M phase display high CTPS1 expression. Pharmacological inhibition of CTPS1 by STP-B induced cell cycle arrest in early S phase in isogenic NCI-H929 or XG7 TP53+/+, TP53−/−, and TP53R175H/R175H cells and in a TP53−/R123STOP patient sample. The functional annotation of transcriptional changes in 10 STP-B-treated myeloma cell lines revealed a decrease in protein translation and confirmed the blockade of cells into the S phase. The pharmacological inhibition of ATR, which governs the intrinsic S/G2 checkpoint, in STP-B-induced S-phase arrested cells synergistically induced cell death in TP53+/+, TP53−/−, and TP53R175H/R175H isogenic cell lines (Bliss score >15). This combination induced replicative stress and caspase-mediated cell death and was highly effective in resistant/refractory patient samples with TP53 deletion and/or mutation and in TP53−/− NCI-H929 xenografted NOD-scid IL2Rgamma mice. Our in vitro, ex vivo, and in vivo data provide the rationale for combined CTPS1 and ATR inhibition for the treatment of p53-deficient patients.","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 10","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11460984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390133","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

The changing influence of neighborhood socioeconomic status on long-term survival in diffuse large B-cell lymphoma patients: A German metropolitan case-control study spanning over three decades 邻里社会经济状况对弥漫大 B 细胞淋巴瘤患者长期生存的影响不断变化：一项跨越三十年的德国大都市病例对照研究。

IF 7.6 2区医学

HemaSphere Pub Date : 2024-10-08 DOI: 10.1002/hem3.70011

Susanne Ghandili, Judith Dierlamm, Carsten Bokemeyer, Henrik Kusche, Frederik Peters

{"title":"The changing influence of neighborhood socioeconomic status on long-term survival in diffuse large B-cell lymphoma patients: A German metropolitan case-control study spanning over three decades","authors":"Susanne Ghandili, Judith Dierlamm, Carsten Bokemeyer, Henrik Kusche, Frederik Peters","doi":"10.1002/hem3.70011","DOIUrl":"10.1002/hem3.70011","url":null,"abstract":"An increasing body of evidence suggests that area-based socioeconomic status (SES) in addition to patient and disease characteristics might be viewed as a relevant prognostic factor for long-term survival in diffuse large B-cell lymphoma (DLBCL) patients.1-6 Possible explanations focused on barriers to care due to lack of adequate health insurance resulting in delayed or inadequate care1, 6 while there is also evidence that large-scale implementation of CD20-directed immunochemotherapy in the standard of care considerably affected DLBCL-specific survival at the population level.7 Here, we investigate the extent to which the introduction of rituximab-based immunochemotherapy has affected socioeconomic status (SES) disparities in all-cause overall survival (OS). This retrospective, case-control study conducts a population-based analysis in a German metropolitan area over a period of 32 years, encompassing the time before and after the introduction of up-front CD20-directed immunochemotherapy within a universal healthcare system.DLBCL cases were reported to the Hamburg Cancer Registry between January 1, 1990 and December 31, 2022, as the first occurrence of a primary diagnosis “C83.3” according to the International Statistical Classification of Diseases, German Modification (ICD-10-GM in combination with morphology “9680” or “9684” of the International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3). Patients under 18 years, without a residency in Hamburg, with an incomplete record (e.g., information only from pathology report or death certificate), with a DLBCL location at the central nervous system (ICD-O-3 “C70,” “C71,” or “C72”), a follow-up duration of less than 3 months, or incomplete information regarding sex or SES were excluded. For assessing the impact of the introduction of modern immunochemotherapy in 2003, the sample was divided into two sub-cohorts (controls diagnosed between 1990 and 2003 and thus defining the pre-rituximab era and cases diagnosed between 2004 and 2022 defining the rituximab era). Patients with a primary diagnosis of T-cell lymphoma (ICD-10-GM coding “C84.4,” “C84.6,” “C84.7,” “C86.5”) in 1990–2022 were used as negative controls, as these patients did not benefit from the breakthrough in modern immunochemotherapy as DLBCL patient did. The SES index, hereinafter “SES,” refers to the deprivation score “Sozialindex” for the City of Hamburg, which is defined for each of the 103 urban districts in Hamburg by the Social Welfare Authority of the Free and Hanseatic City of Hamburg and calculated in 2011 and 2020. The index is based on statistics related to household income, social housing, house/apartment sizes per head, and welfare reception as an indirect proxy of income.8 Based on the quintiles of the index score the SES was grouped into low, middle, and high and thereafter assigned to patients based on ","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 10","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11459230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390138","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

Correction to “Single-cell RNA sequencing of pediatric Hodgkin lymphoma to study the inhibition of T cell subtypes” 小儿霍奇金淋巴瘤单细胞 RNA 测序研究对 T 细胞亚型的抑制》的更正。

IF 7.6 2区医学

HemaSphere Pub Date : 2024-10-07 DOI: 10.1002/hem3.70023

引用次数: 0