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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 Q1 HEMATOLOGY 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

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.

与 B 细胞恶性肿瘤一样,在多发性骨髓瘤中,单拷贝尤其是双拷贝 TP53 基因失活是导致耐药性的高危因素,目前还没有专门针对 p53 缺失的疗法。在本研究中,我们评估了 p53 缺失的骨髓瘤细胞失去细胞周期控制是否会带来代谢上的可操作性弱点。我们发现,CTP合成酶1(CTPS1)编码淋巴细胞DNA和RNA合成所必需的CTP合成限速酶,它在骨髓瘤患者高增殖率(MKI67高表达)或低p53评分(与TP53缺失和/或突变同义)样本中过度表达。在两个队列中,CTPS1 的过表达与生存率降低有关。通过对 24 例患者样本进行 scRNA-seq 分析,我们进一步证明骨髓瘤细胞在 S 期或 G2/M 期显示 CTPS1 的高表达。在同源的 NCI-H929 或 XG7 TP53 +/+、TP53 -/-、TP53 R175H/R175H 细胞以及 TP53 -/R123STOP 患者样本中,STP-B 对 CTPS1 的药理抑制诱导细胞周期停滞在早期 S 期。对 10 个 STP-B 处理过的骨髓瘤细胞系的转录变化进行的功能注释显示,蛋白质翻译减少,并证实细胞进入 S 期受阻。在STP-B诱导的S期停滞细胞中,药理学抑制ATR(控制内在S/G2检查点)可协同诱导TP53 +/+、TP53 -/-和TP53 R175H/R175H异源细胞系(Bliss评分>15)的细胞死亡。这种组合诱导复制应激和Caspase介导的细胞死亡,对TP53缺失和/或突变的耐药/难治性患者样本以及TP53 -/- NCI-H929异种移植NOD-scid IL2Rgamma小鼠非常有效。我们的体外、体内和体外数据为联合抑制 CTPS1 和 ATR 治疗 p53 缺失患者提供了理论依据。
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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 Q1 HEMATOLOGY Pub Date : 2024-10-08 DOI: 10.1002/hem3.70011
Susanne Ghandili, Judith Dierlamm, Carsten Bokemeyer, Henrik Kusche, Frederik Peters
<p>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.<span><sup>1-6</sup></span> Possible explanations focused on barriers to care due to lack of adequate health insurance resulting in delayed or inadequate care<span><sup>1, 6</sup></span> 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.<span><sup>7</sup></span> 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.</p><p>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.<span><sup>8</sup></span> Based on the quintiles of the index score the SES was grouped into low, middle, and high and thereafter assigned to patients based on
这项流行病学研究基于癌症登记数据,其中包含患者特征和肿瘤诊断的一般信息,但缺乏更具体的预后变量,如安-阿伯分期或 IPI、治疗信息以及生活方式和合并症。总之,我们的研究结果表明,随着时间的推移,社会经济地位对生存率的影响发生了变化。在我们的观察期内,生活在高社会经济地位社区的患者的明显优势消失了。这些结果表明,治疗策略的改进,尤其是将基于利妥昔单抗的联合化疗作为一线疗法,可能已经降低了SES对DLBCL患者生存结果的影响。因此,与之前的研究结果一致,我们的研究结果支持这样一种观点,即通过在全民医疗保健环境中实施现代免疫化疗,可以有效消除社会经济地位差异。Susanne Ghandili参与了文献检索、数字、研究设计、数据分析、数据解读、写作-原稿、写作-审阅和编辑、方法论以及项目管理等工作。Judith Dierlamm 参与了监督和验证工作。Carsten Bokemeyer 参与了指导和验证工作。Henrik Kusche 参与了图表、研究设计、数据收集、数据分析、数据解释、撰写-原稿、撰写-审阅和编辑、概念化、数据整理、正式分析、方法论和项目管理等工作。弗雷德里克-彼得斯(Frederik Peters)参与了图表、研究设计、数据收集、数据分析、数据解读、撰写原稿、撰写-审阅和编辑、概念化、数据整理、正式分析、方法论和项目管理等工作。苏珊娜-甘迪里(Susanne Ghandili)、朱迪思-迪尔拉姆(Judith Dierlamm)、亨利克-库什(Henrik Kusche)和弗雷德里克-彼得斯(Frederik Peters)声明没有利益冲突。Carsten Bokemeyer 声明有以下利益冲突:发言人:AOK Germany、Bristol Myers Squibb、med update、Merck Serono、Roche Pharma,顾问委员会:阿斯利康、拜耳医药保健、BioNTech、百时美施贵宝、杨森、默克雪兰诺、肿瘤药物咨询 CRO、赛诺菲安万特。
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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 Q1 HEMATOLOGY Pub Date : 2024-10-07 DOI: 10.1002/hem3.70023

de Kanter J, Steemers A, González D, et al. Single-cell RNA sequencing of pediatric Hodgkin lymphoma to study the inhibition of T cell subtypes. HemaSphere. 2024;8:e149.

In the author listing of the manuscript, the first name of an author was incorrectly listed as Daniel Montiel Gonzalez. The correct name is Diego Montiel González.

The original publication has been corrected. We apologize for this error.

[此处更正了文章 DOI:10.1002/hem3.149.]。
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引用次数: 0
Testicular large B-cell lymphoma is genetically similar to PCNSL and distinct from nodal DLBCL 睾丸大 B 细胞淋巴瘤在基因上与 PCNSL 相似,但有别于结节性 DLBCL。
IF 7.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-07 DOI: 10.1002/hem3.70024
Alfredo Rivas-Delgado, Cristina López, Guillem Clot, Ferran Nadeu, Marta Grau, Gerard Frigola, Jan Bosch-Schips, Josefine Radke, Naveed Ishaque, Miguel Alcoceba, Gustavo Tapia, Luis Luizaga, Carmen Barcena, Nicholas Kelleher, Neus Villamor, Tycho Baumann, Ana Muntañola, Juan M. Sancho-Cia, Alejandro M. García-Sancho, Eva Gonzalez-Barca, Estella Matutes, Jordi A. Brito, Kennosuke Karube, Itziar Salaverria, Anna Enjuanes, Stefan Wiemann, Frank L. Heppner, Reiner Siebert, Fina Climent, Elías Campo, Eva Giné, Armando López-Guillermo, Silvia Beà

Testicular large B-cell lymphoma (TLBCL) is an infrequent and aggressive lymphoma arising in an immune-privileged site and has recently been recognized as a distinct entity from diffuse large B-cell lymphoma (DLBCL). We describe the genetic features of TLBCL and compare them with published series of nodal DLBCL and primary large B-cell lymphomas of the CNS (PCNSL). We collected 61 patients with TLBCL. We performed targeted next-generation sequencing, copy number arrays, and fluorescent in situ hybridization to assess chromosomal rearrangements in 40 cases with available material. Seventy percent of the cases showed localized stages. BCL6 rearrangements were detected in 36% of cases, and no concomitant BCL2 and MYC rearrangements were found. TLBCL had fewer copy number alterations (p < 0.04) but more somatic variants (p < 0.02) than nodal DLBCL and had more frequent 18q21.32-q23 (BCL2) gains and 6q and 9p21.3 (CDKN2A/B) deletions. PIM1, MYD88L265P, CD79B, TBL1XR1, MEF2B, CIITA, EP300, and ETV6 mutations were more frequent in TLBCL, and BCL10 mutations in nodal DLBCL. There were no major genetic differences between TLBCL and PCNSL. Localized or disseminated TLBCL displayed similar genomic profiles. Using LymphGen, the majority of cases were classified as MCD. However, we observed a subgroup of patients classified as BN2, both in localized and disseminated TLBCL, suggesting a degree of genetic heterogeneity in the TLBCL genetic profile. TLBCL has a distinctive genetic profile similar to PCNSL, supporting its recognition as a separate entity from DLBCL and might provide information to devise targeted therapeutic approaches.

睾丸大 B 细胞淋巴瘤(TLBCL)是一种不常见的侵袭性淋巴瘤,发生在免疫优势部位,最近被认为是与弥漫大 B 细胞淋巴瘤(DLBCL)不同的实体。我们描述了TLBCL的遗传特征,并将其与已发表的结节性DLBCL和中枢神经系统原发性大B细胞淋巴瘤(PCNSL)系列进行了比较。我们收集了61例TLBCL患者。我们对40例患者进行了有针对性的新一代测序、拷贝数阵列和荧光原位杂交,以评估染色体重排情况。70%的病例表现为局部分期。在36%的病例中检测到BCL6重排,未发现同时存在BCL2和MYC重排。TLBCL有较少的拷贝数改变(p p BCL2)增益以及6q和9p21.3(CDKN2A/B)缺失。PIM1、MYD88 L265P、CD79B、TBL1XR1、MEF2B、CIITA、EP300和ETV6突变在TLBCL中更为常见,而BCL10突变在结节性DLBCL中更为常见。TLBCL和PCNSL在基因上没有重大差异。局部或播散的TLBCL显示出相似的基因组特征。利用 LymphGen,大多数病例被归类为 MCD。然而,我们观察到,在局部性和播散性TLBCL中,都有一个亚组的患者被归类为BN2,这表明TLBCL的基因图谱存在一定程度的遗传异质性。TLBCL具有与PCNSL相似的独特遗传特征,支持将其视为独立于DLBCL的实体,并可能为设计靶向治疗方法提供信息。
{"title":"Testicular large B-cell lymphoma is genetically similar to PCNSL and distinct from nodal DLBCL","authors":"Alfredo Rivas-Delgado,&nbsp;Cristina López,&nbsp;Guillem Clot,&nbsp;Ferran Nadeu,&nbsp;Marta Grau,&nbsp;Gerard Frigola,&nbsp;Jan Bosch-Schips,&nbsp;Josefine Radke,&nbsp;Naveed Ishaque,&nbsp;Miguel Alcoceba,&nbsp;Gustavo Tapia,&nbsp;Luis Luizaga,&nbsp;Carmen Barcena,&nbsp;Nicholas Kelleher,&nbsp;Neus Villamor,&nbsp;Tycho Baumann,&nbsp;Ana Muntañola,&nbsp;Juan M. Sancho-Cia,&nbsp;Alejandro M. García-Sancho,&nbsp;Eva Gonzalez-Barca,&nbsp;Estella Matutes,&nbsp;Jordi A. Brito,&nbsp;Kennosuke Karube,&nbsp;Itziar Salaverria,&nbsp;Anna Enjuanes,&nbsp;Stefan Wiemann,&nbsp;Frank L. Heppner,&nbsp;Reiner Siebert,&nbsp;Fina Climent,&nbsp;Elías Campo,&nbsp;Eva Giné,&nbsp;Armando López-Guillermo,&nbsp;Silvia Beà","doi":"10.1002/hem3.70024","DOIUrl":"10.1002/hem3.70024","url":null,"abstract":"<p>Testicular large B-cell lymphoma (TLBCL) is an infrequent and aggressive lymphoma arising in an immune-privileged site and has recently been recognized as a distinct entity from diffuse large B-cell lymphoma (DLBCL). We describe the genetic features of TLBCL and compare them with published series of nodal DLBCL and primary large B-cell lymphomas of the CNS (PCNSL). We collected 61 patients with TLBCL. We performed targeted next-generation sequencing, copy number arrays, and fluorescent <i>in situ</i> hybridization to assess chromosomal rearrangements in 40 cases with available material. Seventy percent of the cases showed localized stages. <i>BCL6</i> rearrangements were detected in 36% of cases, and no concomitant <i>BCL2</i> and <i>MYC</i> rearrangements were found. TLBCL had fewer copy number alterations (<i>p </i>&lt; 0.04) but more somatic variants (<i>p </i>&lt; 0.02) than nodal DLBCL and had more frequent 18q21.32-q23 (<i>BCL2</i>) gains and 6q and 9p21.3 (<i>CDKN2A/B</i>) deletions. <i>PIM1</i>, <i>MYD88</i><sup><i>L265P</i></sup>, <i>CD79B</i>, <i>TBL1XR1</i>, <i>MEF2B</i>, <i>CIITA</i>, <i>EP300,</i> and <i>ETV6</i> mutations were more frequent in TLBCL, and <i>BCL10</i> mutations in nodal DLBCL. There were no major genetic differences between TLBCL and PCNSL. Localized or disseminated TLBCL displayed similar genomic profiles. Using LymphGen, the majority of cases were classified as MCD. However, we observed a subgroup of patients classified as BN2, both in localized and disseminated TLBCL, suggesting a degree of genetic heterogeneity in the TLBCL genetic profile. TLBCL has a distinctive genetic profile similar to PCNSL, supporting its recognition as a separate entity from DLBCL and might provide information to devise targeted therapeutic approaches.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":null,"pages":null},"PeriodicalIF":7.6,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11456803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390137","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
Safe and potent anti-CD19 CAR T-cells with shRNA-IL-6 gene silencing element in patients with refractory or relapsed B-cell acute lymphoblastic leukemia 带有 shRNA-IL-6 基因沉默元件的安全有效的抗 CD19 CAR T 细胞用于难治或复发 B 细胞急性淋巴细胞白血病患者。
IF 7.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-07 DOI: 10.1002/hem3.70007
Jin-Feng Ma, Jia-Wei Yan, Mei-Jing Liu, Chun-Long Yan, Xiao-Wen Tang, Hui-Ying Qiu, Miao Miao, Yue Han, Li-Min Li, Li-Qing Kang, Nan Xu, Zhou Yu, Jing-Wen Tan, Hong-Jia Zhu, Xu Jia, Zhi-Zhi Zhang, Miao Wang, Hai-Ping Dai, Lei Yu, Sheng-Li Xue, De-Pei Wu, Wen-Jie Gong

Severe cytokine release syndrome (sCRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) have limited the widespread use of chimeric antigen receptor T (CAR T)-cell therapy. We designed a novel anti-CD19 CAR (ssCART-19) with a small hairpin RNA (shRNA) element to silence the interleukin-6 (IL-6) gene, hypothesizing it could reduce sCRS and ICANS by alleviating monocyte activation and proinflammatory cytokine release. In a post hoc analysis of two clinical trials, we compared ssCART-19 with common CAR T-cells (cCART-19) in relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). Among 87 patients, 47 received ssCART-19 and 40 received cCART-19. Grade ≥3 CRS occurred in 14.89% (7/47) of the ssCART-19 group versus 37.5% (15/40) in the cCART-19 group (p = 0.036). ICANS occurred in 4.26% (2/47) of the ssCART-19 group (all grade 1) compared to 15% (2/40) of the cCART-19 group. Patients in the ssCART-19 group showed comparable rates of treatment response (calculated with rates of complete remission and incomplete hematological recovery) were 91.49% (43/47) for ssCART-19 and 85% (34/40) for cCART-19 (p = 0.999). With a median follow-up of 21.9 months, cumulative nonrelapse mortality was 10.4% for ssCART-19 and 13.6% for cCART-19 (p = 0.33). Median overall survival was 37.17 months for ssCART-19 and 32.93 months for cCART-19 (p = 0.40). Median progression-free survival was 24.17 months for ssCART-19 and 9.33 months for cCART-19 (p = 0.23). These data support the safety and efficacy of ssCART-19 for r/r B-ALL, suggesting its potential as a promising therapy.

严重细胞因子释放综合征(sCRS)和免疫效应细胞相关神经毒性综合征(ICANS)限制了嵌合抗原受体T(CAR T)细胞疗法的广泛应用。我们设计了一种新型抗 CD19 CAR(ssCART-19),它带有小发夹 RNA(shRNA)元件以沉默白细胞介素-6(IL-6)基因,并假设它可以通过减轻单核细胞活化和促炎细胞因子释放来减轻 sCRS 和 ICANS。在对两项临床试验进行的事后分析中,我们对复发/难治性 B 细胞急性淋巴细胞白血病(r/r B-ALL)的 ssCART-19 和普通 CAR T 细胞(cCART-19)进行了比较。在87名患者中,47人接受了ssCART-19治疗,40人接受了cCART-19治疗。ssCART-19组有14.89%(7/47)发生≥3级CRS,而cCART-19组为37.5%(15/40)(p = 0.036)。ssCART-19组有4.26%(2/47)的患者发生ICANS(均为1级),而cCART-19组为15%(2/40)。ssCART-19组患者的治疗反应率(以完全缓解率和不完全血液学恢复率计算)相当,ssCART-19组为91.49%(43/47),cCART-19组为85%(34/40)(P = 0.999)。中位随访时间为 21.9 个月,ssCART-19 的累积非复发死亡率为 10.4%,cCART-19 为 13.6%(p = 0.33)。ssCART-19的中位总生存期为37.17个月,cCART-19为32.93个月(p = 0.40)。ssCART-19 的中位无进展生存期为 24.17 个月,cCART-19 为 9.33 个月(p = 0.23)。这些数据支持ssCART-19治疗r/r B-ALL的安全性和有效性,表明它有可能成为一种前景广阔的疗法。
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引用次数: 0
Activating mutations remodel the chromatin accessibility landscape to drive distinct regulatory networks in KMT2A-rearranged acute leukemia 激活突变重塑染色质可及性景观,驱动 KMT2A 重组急性白血病中的不同调控网络
IF 7.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-26 DOI: 10.1002/hem3.70006
Qirui Zhang, Ton Falqués-Costa, Mattias Pilheden, Helena Sturesson, Tina Ovlund, Vendela Rissler, Anders Castor, Hanne V. H. Marquart, Birgitte Lausen, Thoas Fioretos, Axel Hyrenius-Wittsten, Anna K. Hagström-Andersson

Activating FLT3 and RAS mutations commonly occur in leukemia with KMT2A-gene rearrangements (KMT2A-r). However, how these mutations cooperate with the KMT2A-r to remodel the epigenetic landscape is unknown. Using a retroviral acute myeloid leukemia (AML) mouse model driven by KMT2A::MLLT3, we show that FLT3ITD, FLT3N676K, and NRASG12D remodeled the chromatin accessibility landscape and associated transcriptional networks. Although the activating mutations shared a common core of chromatin changes, each mutation exhibits unique profiles with most opened peaks associating with enhancers in intronic or intergenic regions. Specifically, FLT3N676K and NRASG12D rewired similar chromatin and transcriptional networks, distinct from those mediated by FLT3ITD. Motif analysis uncovered a role for the AP-1 family of transcription factors in KMT2A::MLLT3 leukemia with FLT3N676K and NRASG12D, whereas Runx1 and Stat5a/Stat5b were active in the presence of FLT3ITD. Furthermore, transcriptional programs linked to immune cell regulation were activated in KMT2A-r AML expressing NRASG12D or FLT3N676K, and the expression of NKG2D-ligands on KMT2A-r cells rendered them sensitive to CAR T cell-mediated killing. Human KMT2A-r AML cells could be pharmacologically sensitized to NKG2D-CAR T cells by treatment with the histone deacetylase inhibitor LBH589 (panobinostat) which caused upregulation of NKG2D-ligand levels. Co-treatment with LBH589 and NKG2D-CAR T cells enabled robust AML cell killing, and the strongest effect was observed for cells expressing NRASG12D. Finally, the results were validated and extended to acute leukemia in infancy. Combined, activating mutations induced mutation-specific changes in the epigenetic landscape, leading to changes in transcriptional programs orchestrated by specific transcription factor networks.

激活FLT3和RAS突变通常发生在伴有KMT2A基因重排(KMT2A-r)的白血病中。然而,这些突变是如何与 KMT2A-r 相互配合重塑表观遗传景观的还不清楚。利用 KMT2A::MLLT3 驱动的逆转录病毒急性髓性白血病(AML)小鼠模型,我们发现 FLT3ITD、FLT3N676K 和 NRASG12D 重塑了染色质可及性景观和相关转录网络。虽然活化突变具有共同的染色质变化核心,但每个突变都表现出独特的特征,大多数开放峰与内含子或基因间区域的增强子相关。具体来说,FLT3N676K和NRASG12D重新连接了类似的染色质和转录网络,与FLT3ITD介导的网络不同。动因分析发现了AP-1家族转录因子在FLT3N676K和NRASG12D的KMT2A::MLLT3白血病中的作用,而Runx1和Stat5a/Stat5b在FLT3ITD存在的情况下也很活跃。此外,在表达 NRASG12D 或 FLT3N676K 的 KMT2A-r AML 中,与免疫细胞调控有关的转录程序被激活,KMT2A-r 细胞上 NKG2D 配体的表达使它们对 CAR T 细胞介导的杀伤敏感。组蛋白去乙酰化酶抑制剂 LBH589(panobinostat)可导致 NKG2D 配体水平上调,从而使人类 KMT2A-r AML 细胞对 NKG2D-CAR T 细胞产生药理敏感性。LBH589和NKG2D-CAR T细胞联合处理能强效杀伤AML细胞,对表达NRASG12D的细胞效果最强。最后,研究结果得到了验证,并扩展到婴幼儿急性白血病。综合来看,激活性突变诱导了表观遗传景观中突变特异性的变化,导致由特定转录因子网络协调的转录程序发生变化。
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引用次数: 0
NUP98 oncofusions in myeloid malignancies: An update on molecular mechanisms and therapeutic opportunities 髓系恶性肿瘤中的 NUP98 融合:分子机制和治疗机会的最新进展
IF 7.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-25 DOI: 10.1002/hem3.70013
Milad Rasouli, Selina Troester, Florian Grebien, Bianca F. Goemans, C. Michel Zwaan, Olaf Heidenreich

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a heterogeneous molecular landscape. In the pediatric context, the NUP98 gene is a frequent target of chromosomal rearrangements that are linked to poor prognosis and unfavorable treatment outcomes in different AML subtypes. The translocations fuse NUP98 to a diverse array of partner genes, resulting in fusion proteins with novel functions. NUP98 fusion oncoproteins induce aberrant biomolecular condensation, abnormal gene expression programs, and re-wired protein interactions which ultimately cause alterations in the cell cycle and changes in cellular structures, all of which contribute to leukemia development. The extent of these effects is steered by the functional domains of the fusion partners and the influence of concomitant somatic mutations. In this review, we discuss the complex characteristics of NUP98 fusion proteins and potential novel therapeutic approaches for NUP98 fusion-driven AML.

急性髓性白血病(AML)是一种侵袭性血液恶性肿瘤,具有异质性分子特征。在儿科,NUP98 基因是染色体重排的一个常见靶点,在不同的急性髓性白血病亚型中,染色体重排与预后不良和治疗效果不佳有关。这些易位将 NUP98 与一系列不同的伙伴基因融合,从而产生具有新功能的融合蛋白。NUP98 融合肿瘤蛋白会诱发异常的生物分子凝聚、异常的基因表达程序和重新配线的蛋白质相互作用,最终导致细胞周期的改变和细胞结构的变化,所有这些都会导致白血病的发展。这些影响的程度取决于融合伙伴的功能域以及伴随的体细胞突变的影响。在这篇综述中,我们将讨论 NUP98 融合蛋白的复杂特性以及 NUP98 融合驱动的急性髓细胞性白血病的潜在新型治疗方法。
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引用次数: 0
Comprehensive sequential genetic analysis delineating frequency, patterns, and prognostic impact of genomic dynamics in a real-world cohort of patients with lower-risk MDS 在低风险 MDS 患者的真实世界队列中进行全面的序列遗传分析,确定基因组动态的频率、模式和对预后的影响。
IF 7.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-23 DOI: 10.1002/hem3.70014
Paolo Mazzeo, Christina Ganster, John Wiedenhöft, Katayoon Shirneshan, Katharina Rittscher, Elzbieta B. Brzuszkiewicz, Doris Steinemann, Maximilian Schieck, Catharina Müller-Thomas, Hannes Treiber, Friederike Braulke, Ulrich Germing, Katja Sockel, Ekaterina Balaian, Julie Schanz, Uwe Platzbecker, Katharina S. Götze, Detlef Haase

The acquisition of subsequent genetic lesions (clonal evolution, CE) and/or the expansion of existing clones (CEXP) contributes to clonal dynamics (CD) in myelodysplastic syndromes (MDS). Although CD plays an important role in high-risk patients in disease progression and transformation into acute myeloid leukemia (AML), knowledge about CD in lower-risk MDS (LR-MDS) patients is limited due to lack of robust longitudinal data considering the long clinically stable courses of the disease. In this retrospective analysis, we delineate the frequency and the prognostic impact of CD in an unselected real-world cohort of LR-MDS patients. We screened 68 patients with a median follow-up of 40.5 months and a median of 7.5 (range: 2–22) timepoints for CE and CEXP detected by chromosomal banding analysis, fluorescence in situ hybridization, sequencing, and molecular karyotyping. In 30/68 patients, 47 CE events and a CD rate of 1 event per 4 years were documented. Of note, patients with at least 1 CE event had an increased probability for subsequent treatment. Unexpectedly, CE did not correlate with inferior outcomes, which could be reasonably explained by CD detection triggering the subsequent start of a disease-modifying therapy.

骨髓增生异常综合征(MDS)的后续遗传病变(克隆进化,CE)和/或现有克隆的扩增(CEXP)促成了克隆动态(CD)。虽然克隆动态变化在高危患者的疾病进展和转化为急性髓性白血病(AML)过程中起着重要作用,但由于缺乏可靠的纵向数据,对低危 MDS(LR-MDS)患者克隆动态变化的了解十分有限,因为这种疾病的临床病程较长,病情稳定。在这项回顾性分析中,我们描述了未经筛选的 LR-MDS 患者真实世界队列中 CD 的发生频率及其对预后的影响。我们对 68 例患者进行了筛查,中位随访时间为 40.5 个月,中位时间点为 7.5 个(范围:2-22),通过染色体条带分析、荧光原位杂交、测序和分子核型分析检测出 CE 和 CEXP。在 30/68 例患者中,有 47 例 CE 事件记录在案,CD 发生率为每 4 年 1 例。值得注意的是,至少发生过一次 CE 事件的患者接受后续治疗的概率增加。出乎意料的是,CE 并不与较差的预后相关,这可以合理地解释为 CD 检测触发了随后开始的疾病改变疗法。
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引用次数: 0
Characterization of myeloid-derived suppressor cells in the peripheral blood and bone marrow of patients with chronic idiopathic neutropenia 慢性特发性中性粒细胞减少症患者外周血和骨髓中髓源性抑制细胞的特征。
IF 7.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-23 DOI: 10.1002/hem3.70005
Nikoleta Bizymi, Athina Damianaki, Nikoletta Aresti, Anastasios Karasachinidis, Zacharenia Vlata, Matthieu Lavigne, Emmanuel Dialynas, Niki Gounalaki, Irene Stratidaki, Grigorios Tsaknakis, Aristea Batsali, Irene Mavroudi, Maria Velegraki, Ioannis Sperelakis, Charalampos Pontikoglou, Panayotis Verginis, Helen A. Papadaki
<p>Chronic idiopathic neutropenia (CIN) is characterized by the persistent and unexplained reduction of peripheral blood (PB) absolute neutrophil counts (ANCs).<span><sup>1, 2</sup></span> The pathogenesis of CIN has been associated with increased apoptosis of the granulocytic progenitor cells due to an inflammatory bone marrow (BM) microenvironment consisting of activated T lymphocytes, proinflammatory monocytes, and proapoptotic cytokines.<span><sup>3-5</sup></span> The myeloid-derived suppressor cells (MDSCs) are immature myeloid cells, deviating from the standard differentiation pathway during emergency myelopoiesis, that display immunomodulatory properties mainly by suppressing T-cell responses. They are recognized by the immunophenotype CD11b<sup>+</sup>CD33<sup>+</sup>HLA-DR<sup>–/low</sup> and further characterized as CD14<sup>+</sup> (monocytic, M-MDSCs) and CD15<sup>+</sup> (polymorphonuclear, PMN-MDSCs) subpopulations.<span><sup>6-13</sup></span></p><p>In the present study, we explore, for the first time, the possible involvement of MDSCs in the pathophysiology of CIN by investigating their number, functional characteristics, and transcriptome profile in a group of patients (<i>n</i> = 102) and age- and sex-matched healthy controls (<i>n</i> = 77). The patients fulfilled the previously described diagnostic criteria for CIN (File S1).<span><sup>2, 14, 15</sup></span> Sixteen patients had clonal hematopoiesis identified by next-generation sequencing analysis of 40 recurrently mutated myeloid genes.<span><sup>15</sup></span> The clinical and laboratory data of the patients are presented in Supporting Information S1: Tables 1 and 2. The study was approved by the Institutional Review Board of the University Hospital of Heraklion and informed consent was obtained from all subjects.</p><p>MDSC subsets were quantitated and sorted by flow cytometry in the PB mononuclear cell (PBMC) and BM mononuclear cell (BMMC) fractions according to the recommended protocol.<span><sup>6</sup></span> The gating strategies for MDSC quantification and sorting are presented in Figure 1A,B respectively. The methodology of the T-cell suppression assay to evaluate the function of MDSCs was performed according to the recommended standards (File S1).<span><sup>6, 18, 19</sup></span> In brief, the suppression of normal T cells was demonstrated in a heterologous system including co-culture of immunomagnetically sorted carboxy-fluorescein succinimidyl ester (CFSE)-stained T cells with PMN-MDSCs or M-MDSCs (Figure 1C) and an autologous system including cultures of CFSE-stained PBMCs versus CD33-immunomagnetically depleted PBMCs (Figure 1D). To identify the biochemical and molecular parameters associated with MDSC characterization,<span><sup>6</sup></span> we performed transcriptional profiling of MDSCs from patients (<i>n</i> = 6) and healthy controls (<i>n</i> = 5) using RNA sequencing (File S1 and Supporting Information S1: Table 3). The data were analyzed using the Gra
MDSCs数量少、特性改变,可能导致对CIN已知的异常炎症过程抑制不足,从而导致循环炎性细胞因子和趋化因子水平升高。我们的研究结果首次描述了MDSCs在CIN中的变化,并引发了未来更多的机理研究,以进一步探索这些细胞在疾病中的确切作用。Athina Damianaki、Anastasios Karasachinidis、Nikoletta Aresti、Grigorios Tsaknakis、Aristea Batsali和Irene Mavroudi负责实验室工作。Maria Velegraki 参与了研究设计和研究工作。Zacharenia Vlata、Ioannis Sperelakis、Matthieu Lavigne、Emmanuel Dialynas、Niki Gounalaki 和 Irene Stratidaki 从事研究和数据分析工作。Charalampos Pontikoglou 和 Panayotis Verginis 参与了研究设计。海伦-帕帕达基(Helen A. Papadaki)设计并指导了研究,提供了患者样本,分析并解释了数据,并撰写了论文。本研究得到了希腊亚历山大-奥纳西斯公益基金会(Alexander S. Onassis Public Benefit Foundation in Greece)GZ 035-1/2017-2018奖学金的支持,N. B.获得了该奖学金以攻读硕士学位,N. B.获得了克里特大学玛丽亚-米夏埃尔-马纳萨基(Maria Michail Manassaki)奖学金以攻读博士学位。该研究还基于COST行动BM1404--欧洲髓系调节细胞探索性研究研究者网络(Mye-EUNITER)和CA18233--欧洲慢性中性粒细胞减少症创新诊断和治疗网络(EuNet-INNOCHRON)的工作。
{"title":"Characterization of myeloid-derived suppressor cells in the peripheral blood and bone marrow of patients with chronic idiopathic neutropenia","authors":"Nikoleta Bizymi,&nbsp;Athina Damianaki,&nbsp;Nikoletta Aresti,&nbsp;Anastasios Karasachinidis,&nbsp;Zacharenia Vlata,&nbsp;Matthieu Lavigne,&nbsp;Emmanuel Dialynas,&nbsp;Niki Gounalaki,&nbsp;Irene Stratidaki,&nbsp;Grigorios Tsaknakis,&nbsp;Aristea Batsali,&nbsp;Irene Mavroudi,&nbsp;Maria Velegraki,&nbsp;Ioannis Sperelakis,&nbsp;Charalampos Pontikoglou,&nbsp;Panayotis Verginis,&nbsp;Helen A. Papadaki","doi":"10.1002/hem3.70005","DOIUrl":"10.1002/hem3.70005","url":null,"abstract":"&lt;p&gt;Chronic idiopathic neutropenia (CIN) is characterized by the persistent and unexplained reduction of peripheral blood (PB) absolute neutrophil counts (ANCs).&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; The pathogenesis of CIN has been associated with increased apoptosis of the granulocytic progenitor cells due to an inflammatory bone marrow (BM) microenvironment consisting of activated T lymphocytes, proinflammatory monocytes, and proapoptotic cytokines.&lt;span&gt;&lt;sup&gt;3-5&lt;/sup&gt;&lt;/span&gt; The myeloid-derived suppressor cells (MDSCs) are immature myeloid cells, deviating from the standard differentiation pathway during emergency myelopoiesis, that display immunomodulatory properties mainly by suppressing T-cell responses. They are recognized by the immunophenotype CD11b&lt;sup&gt;+&lt;/sup&gt;CD33&lt;sup&gt;+&lt;/sup&gt;HLA-DR&lt;sup&gt;–/low&lt;/sup&gt; and further characterized as CD14&lt;sup&gt;+&lt;/sup&gt; (monocytic, M-MDSCs) and CD15&lt;sup&gt;+&lt;/sup&gt; (polymorphonuclear, PMN-MDSCs) subpopulations.&lt;span&gt;&lt;sup&gt;6-13&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;In the present study, we explore, for the first time, the possible involvement of MDSCs in the pathophysiology of CIN by investigating their number, functional characteristics, and transcriptome profile in a group of patients (&lt;i&gt;n&lt;/i&gt; = 102) and age- and sex-matched healthy controls (&lt;i&gt;n&lt;/i&gt; = 77). The patients fulfilled the previously described diagnostic criteria for CIN (File S1).&lt;span&gt;&lt;sup&gt;2, 14, 15&lt;/sup&gt;&lt;/span&gt; Sixteen patients had clonal hematopoiesis identified by next-generation sequencing analysis of 40 recurrently mutated myeloid genes.&lt;span&gt;&lt;sup&gt;15&lt;/sup&gt;&lt;/span&gt; The clinical and laboratory data of the patients are presented in Supporting Information S1: Tables 1 and 2. The study was approved by the Institutional Review Board of the University Hospital of Heraklion and informed consent was obtained from all subjects.&lt;/p&gt;&lt;p&gt;MDSC subsets were quantitated and sorted by flow cytometry in the PB mononuclear cell (PBMC) and BM mononuclear cell (BMMC) fractions according to the recommended protocol.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; The gating strategies for MDSC quantification and sorting are presented in Figure 1A,B respectively. The methodology of the T-cell suppression assay to evaluate the function of MDSCs was performed according to the recommended standards (File S1).&lt;span&gt;&lt;sup&gt;6, 18, 19&lt;/sup&gt;&lt;/span&gt; In brief, the suppression of normal T cells was demonstrated in a heterologous system including co-culture of immunomagnetically sorted carboxy-fluorescein succinimidyl ester (CFSE)-stained T cells with PMN-MDSCs or M-MDSCs (Figure 1C) and an autologous system including cultures of CFSE-stained PBMCs versus CD33-immunomagnetically depleted PBMCs (Figure 1D). To identify the biochemical and molecular parameters associated with MDSC characterization,&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; we performed transcriptional profiling of MDSCs from patients (&lt;i&gt;n&lt;/i&gt; = 6) and healthy controls (&lt;i&gt;n&lt;/i&gt; = 5) using RNA sequencing (File S1 and Supporting Information S1: Table 3). The data were analyzed using the Gra","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":null,"pages":null},"PeriodicalIF":7.6,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11417472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307651","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
Therapeutic strategies and treatment sequencing in patients with chronic lymphocytic leukemia: An international study of ERIC, the European Research Initiative on CLL 慢性淋巴细胞白血病患者的治疗策略和治疗顺序:欧洲慢性淋巴细胞白血病研究倡议 ERIC 的一项国际研究
IF 7.6 2区 医学 Q1 HEMATOLOGY Pub Date : 2024-09-17 DOI: 10.1002/hem3.70004
Thomas Chatzikonstantinou, Lydia Scarfò, Eva Minga, Georgios Karakatsoulis, Dimitra Chamou, Jana Kotaskova, Gloria Iacoboni, Christos Demosthenous, Elisa Albi, Miguel Alcoceba, Salem Al-Shemari, Thérèse Aurran-Schleinitz, Francesca Bacchiarri, Sofia Chatzileontiadou, Rosa Collado, Zadie Davis, Marcos Daniel de Deus Santos, Maria Dimou, Elena Dmitrieva, David Donaldson, Gimena Dos Santos, Barbara Dreta, Maria Efstathopoulou, Shaimaa El-Ashwah, Alicia Enrico, Andrzej Frygier, Sara Galimberti, Andrea Galitzia, Eva Gimeno, Valerio Guarente, Romain Guieze, Sean Harrop, Eleftheria Hatzimichael, Yair Herishanu, José-Ángel Hernández-Rivas, Ozren Jaksic, Elżbieta Kalicińska, Kamel Laribi, Volkan Karakus, Arnon P. Kater, Bonnie Kho, Maria Kislova, Εliana Konstantinou, Maya Koren-Michowitz, Ioannis Kotsianidis, Zuzana Kubova, Jorge Labrador, Deepesh Lad, Luca Laurenti, Thomas Longval, Alberto Lopez-Garcia, Juan Marquet, Stanislava Maslejova, Carlota Mayor-Bastida, Biljana Mihaljevic, Ivana Milosevic, Fatima Miras, Riccardo Moia, Marta Morawska, Uttam K. Nath, Almudena Navarro-Bailón, Jacopo Olivieri, Irina Panovska-Stavridis, Maria Papaioannou, Cheyenne Pierie, Anna Puiggros, Gianluigi Reda, Gian M. Rigolin, Rosa Ruchlemer, Mattia Schipani, Annett Schiwitza, Yandong Shen, Tereza Shokralla, Martin Simkovic, Svetlana Smirnova, Dina S. A. Soliman, Stephan Stilgenbauer, Tamar Tadmor, Kristina Tomic, Eric Tse, Theodoros Vassilakopoulos, Andrea Visentin, Candida Vitale, George Vrachiolias, Vojin Vukovic, Renata Walewska, Zhenshu Xu, Munci Yagci, Lucrecia Yañez, Mohamed Yassin, Jana Zuchnicka, David Oscier, Alessandro Gozzetti, Panagiotis Panagiotidis, Francesc Bosch, Paolo Sportoletti, Blanca Espinet, Gerassimos A. Pangalis, Viola M. Popov, Stephen Mulligan, Maria Angelopoulou, Fatih Demirkan, Tomas Papajík, Bella Biderman, Roberta Murru, Marta Coscia, Constantine Tam, Antonio Cuneo, Gianluca Gaidano, Rainer Claus, Niki Stavroyianni, Livio Trentin, Darko Antic, Lukas Smolej, Olga B. Kalashnikova, Mark Catherwood, Martin Spacek, Sarka Pospisilova, Michael Doubek, Eugene Nikitin, Anastasia Chatzidimitriou, Paolo Ghia, Kostas Stamatopoulos
<p>Novel small molecule inhibitors have revolutionized the treatment of chronic lymphocytic leukemia (CLL). Indeed, BTK (BTKi) and BCL2 inhibitors (BCL2i) alone or in combination with each other or other compounds have proven superior to chemoimmunotherapy (CIT) in both the frontline and the relapsed/refractory (R/R) setting.<span><sup>1</sup></span></p><p>ERIC, the European Research Initiative on CLL, conducted this international multicenter retrospective study focused on the era of CIT, aiming to (i) reveal the treatment patterns in the “real world” and (ii) assess the outcomes of patients who received frontline treatment between 2000 and 2016. Overall, 7382 patients with CLL (7134, 96.6%) or SLL (248, 3.4%) from 76 centers in 25 countries in five continents were included. The median age at diagnosis was 64 (interquartile range [IQR]: 56–71) years and the median age at first treatment was 66 (IQR: 58–74) years. The median follow-up was 7.33 (IQR: 4.56–10.81) years from diagnosis and 5.27 (IQR: 3.04–7.99) from first treatment. The vast majority of patients (6873/7134, 93.2%) received at least one line of chemotherapy or CIT; only 197/7134 (2.7%) received exclusively novel agents. Baseline characteristics and disease-specific biomarkers are listed in Supporting Information Material.</p><p>The most common first-line regimen was FCR (2609, 35.3%), mostly in young patients (median age at first treatment: 60 years, IQR: 54–66), followed by chlorambucil monotherapy (1293, 17.5%), mostly in older patients (median age at first treatment: 74 years, IQR: 65–80). BTKis as first-line treatment were used in 149/7134 (2%) patients who either participated in clinical trials and/or had <i>TP53</i> aberrations; 20/7134 (0.3%) received frontline venetoclax-based regimens, all in the context of clinical trials (Figure 1). Detailed outcomes for the most common frontline regimens are provided in Supporting Information Material.</p><p>BTKis were the most common type of R/R treatment (1581/8145, 19.4%). Reflecting the approval of novel agents for patients with R/R CLL, the use of all types of chemotherapy and CIT decreased after 2014, except bendamustine plus rituximab (Figure 2).</p><p>There were 387 patients with an early (<24 months) need for second-line treatment after 2016: 203/387 (52.4%) received chemotherapy and CIT, 147/387 (38%) novel agents (108/387 [27.9%] BTKi, 24/387 [6.2%] PI3Ki, and 15/387 [3.9%] venetoclax-based treatments), and 37/387 (9.6%) other treatments (Figure 2 & File S1). ORR and discontinuation rates due to progression of patients treated with novel agents are given in the File S1.</p><p>Among patients treated with BTKi with or without anti-CD20 monoclonal antibodies (Mab), 55/567 (9.7%) discontinued treatment due to toxicity in second and 120/1014 (11.8%) in later lines. The median time to discontinuation was 5 months (95% confidence interval [CI]: 3.7–12.5) for patients treated in second line and 14 months (95% CI: 8–20.9) for patie
Georgios Karakatsoulis, Eva Minga, Dimitra Chamou, Jana Kotaskova, Christos Demosthenous, Elisa Albi, Miguel Alcoceba, Salem Al-Shemari, Thérèse Aurran-Schleinitz, Francesca Bacchiarri、Sofia Chatzileontiadou, Zadie Davis, Marcos Daniel de Deus Santos, Maria Dimou, Elena Dmitrieva, David Donaldson, Gimena Dos Santos, Barbara Dreta, Maria Efstathopoulou, Shaimaa El-Ashwah, Alicia Enrico、Andrzej Frygier, Andrea Galitzia, Eva Gimeno, Valerio Guarente, Sean Harrop, Elżbieta Kalicińska, Volkan Karakus, Bonnie Kho, Maria Kislova, Εliana Konstantinou, Zuzana Kubova, Jorge Labrador、Deepesh Lad、Luca Laurenti、Thomas Longval、Alberto Lopez-Garcia、Juan Marquet、Stanislava Maslejova、Carlota Mayor-Bastida、Biljana Mihaljevic、Fatima Miras、Riccardo Moia、Marta Morawska、Uttam K.Nath、Irina Panovska-Stavridis、Maria Papaioannou、Cheyenne Pierie、Anna Puiggros、Rosa Ruchlemer、Annett Schiwitza、Yandong Shen、Tereza Shokralla、Martin Simkovic、Svetlana Smirnova、Dina S. A.Soliman、Tamar Tadmor、Kristina Tomic、Andrea Visentin、George Vrachiolias、Vojin Vukovic、Zhenshu Xu、Munci Yagci、Mohamed Yassin、Jana Zuchnicka、David Oscier、Alessandro Gozzetti、Panagiotis Panagiotidis、Blanca Espinet、Paolo Sportoletti、Gerassimos A.Pangalis, Viola M. Popov, Bella Biderman, Roberta Murru, Rainer Claus, Livio Trentin, Darko Antic, Olga B. Kalashnikova, Mark Catherwood, Sarka Pospisilova, and Anastasia Chatzidimitriou 没有需要披露的利益冲突。本项目部分由艾伯维支持;AIRC 根据 5 per Mille 2018-ID.21198计划(给PG和GG);PNRR-MAD-2022-12375673(下一代欧盟,M6/C2_CALL 2022),意大利卫生部,意大利罗马;捷克共和国卫生部提供的研究组织概念开发(FNBr 65269705);以及欧盟-下一代欧盟资助的国家癌症研究所(EXCELLES计划,ID项目编号LX22NPO5102)。
{"title":"Therapeutic strategies and treatment sequencing in patients with chronic lymphocytic leukemia: An international study of ERIC, the European Research Initiative on CLL","authors":"Thomas Chatzikonstantinou,&nbsp;Lydia Scarfò,&nbsp;Eva Minga,&nbsp;Georgios Karakatsoulis,&nbsp;Dimitra Chamou,&nbsp;Jana Kotaskova,&nbsp;Gloria Iacoboni,&nbsp;Christos Demosthenous,&nbsp;Elisa Albi,&nbsp;Miguel Alcoceba,&nbsp;Salem Al-Shemari,&nbsp;Thérèse Aurran-Schleinitz,&nbsp;Francesca Bacchiarri,&nbsp;Sofia Chatzileontiadou,&nbsp;Rosa Collado,&nbsp;Zadie Davis,&nbsp;Marcos Daniel de Deus Santos,&nbsp;Maria Dimou,&nbsp;Elena Dmitrieva,&nbsp;David Donaldson,&nbsp;Gimena Dos Santos,&nbsp;Barbara Dreta,&nbsp;Maria Efstathopoulou,&nbsp;Shaimaa El-Ashwah,&nbsp;Alicia Enrico,&nbsp;Andrzej Frygier,&nbsp;Sara Galimberti,&nbsp;Andrea Galitzia,&nbsp;Eva Gimeno,&nbsp;Valerio Guarente,&nbsp;Romain Guieze,&nbsp;Sean Harrop,&nbsp;Eleftheria Hatzimichael,&nbsp;Yair Herishanu,&nbsp;José-Ángel Hernández-Rivas,&nbsp;Ozren Jaksic,&nbsp;Elżbieta Kalicińska,&nbsp;Kamel Laribi,&nbsp;Volkan Karakus,&nbsp;Arnon P. Kater,&nbsp;Bonnie Kho,&nbsp;Maria Kislova,&nbsp;Εliana Konstantinou,&nbsp;Maya Koren-Michowitz,&nbsp;Ioannis Kotsianidis,&nbsp;Zuzana Kubova,&nbsp;Jorge Labrador,&nbsp;Deepesh Lad,&nbsp;Luca Laurenti,&nbsp;Thomas Longval,&nbsp;Alberto Lopez-Garcia,&nbsp;Juan Marquet,&nbsp;Stanislava Maslejova,&nbsp;Carlota Mayor-Bastida,&nbsp;Biljana Mihaljevic,&nbsp;Ivana Milosevic,&nbsp;Fatima Miras,&nbsp;Riccardo Moia,&nbsp;Marta Morawska,&nbsp;Uttam K. Nath,&nbsp;Almudena Navarro-Bailón,&nbsp;Jacopo Olivieri,&nbsp;Irina Panovska-Stavridis,&nbsp;Maria Papaioannou,&nbsp;Cheyenne Pierie,&nbsp;Anna Puiggros,&nbsp;Gianluigi Reda,&nbsp;Gian M. Rigolin,&nbsp;Rosa Ruchlemer,&nbsp;Mattia Schipani,&nbsp;Annett Schiwitza,&nbsp;Yandong Shen,&nbsp;Tereza Shokralla,&nbsp;Martin Simkovic,&nbsp;Svetlana Smirnova,&nbsp;Dina S. A. Soliman,&nbsp;Stephan Stilgenbauer,&nbsp;Tamar Tadmor,&nbsp;Kristina Tomic,&nbsp;Eric Tse,&nbsp;Theodoros Vassilakopoulos,&nbsp;Andrea Visentin,&nbsp;Candida Vitale,&nbsp;George Vrachiolias,&nbsp;Vojin Vukovic,&nbsp;Renata Walewska,&nbsp;Zhenshu Xu,&nbsp;Munci Yagci,&nbsp;Lucrecia Yañez,&nbsp;Mohamed Yassin,&nbsp;Jana Zuchnicka,&nbsp;David Oscier,&nbsp;Alessandro Gozzetti,&nbsp;Panagiotis Panagiotidis,&nbsp;Francesc Bosch,&nbsp;Paolo Sportoletti,&nbsp;Blanca Espinet,&nbsp;Gerassimos A. Pangalis,&nbsp;Viola M. Popov,&nbsp;Stephen Mulligan,&nbsp;Maria Angelopoulou,&nbsp;Fatih Demirkan,&nbsp;Tomas Papajík,&nbsp;Bella Biderman,&nbsp;Roberta Murru,&nbsp;Marta Coscia,&nbsp;Constantine Tam,&nbsp;Antonio Cuneo,&nbsp;Gianluca Gaidano,&nbsp;Rainer Claus,&nbsp;Niki Stavroyianni,&nbsp;Livio Trentin,&nbsp;Darko Antic,&nbsp;Lukas Smolej,&nbsp;Olga B. Kalashnikova,&nbsp;Mark Catherwood,&nbsp;Martin Spacek,&nbsp;Sarka Pospisilova,&nbsp;Michael Doubek,&nbsp;Eugene Nikitin,&nbsp;Anastasia Chatzidimitriou,&nbsp;Paolo Ghia,&nbsp;Kostas Stamatopoulos","doi":"10.1002/hem3.70004","DOIUrl":"https://doi.org/10.1002/hem3.70004","url":null,"abstract":"&lt;p&gt;Novel small molecule inhibitors have revolutionized the treatment of chronic lymphocytic leukemia (CLL). Indeed, BTK (BTKi) and BCL2 inhibitors (BCL2i) alone or in combination with each other or other compounds have proven superior to chemoimmunotherapy (CIT) in both the frontline and the relapsed/refractory (R/R) setting.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;ERIC, the European Research Initiative on CLL, conducted this international multicenter retrospective study focused on the era of CIT, aiming to (i) reveal the treatment patterns in the “real world” and (ii) assess the outcomes of patients who received frontline treatment between 2000 and 2016. Overall, 7382 patients with CLL (7134, 96.6%) or SLL (248, 3.4%) from 76 centers in 25 countries in five continents were included. The median age at diagnosis was 64 (interquartile range [IQR]: 56–71) years and the median age at first treatment was 66 (IQR: 58–74) years. The median follow-up was 7.33 (IQR: 4.56–10.81) years from diagnosis and 5.27 (IQR: 3.04–7.99) from first treatment. The vast majority of patients (6873/7134, 93.2%) received at least one line of chemotherapy or CIT; only 197/7134 (2.7%) received exclusively novel agents. Baseline characteristics and disease-specific biomarkers are listed in Supporting Information Material.&lt;/p&gt;&lt;p&gt;The most common first-line regimen was FCR (2609, 35.3%), mostly in young patients (median age at first treatment: 60 years, IQR: 54–66), followed by chlorambucil monotherapy (1293, 17.5%), mostly in older patients (median age at first treatment: 74 years, IQR: 65–80). BTKis as first-line treatment were used in 149/7134 (2%) patients who either participated in clinical trials and/or had &lt;i&gt;TP53&lt;/i&gt; aberrations; 20/7134 (0.3%) received frontline venetoclax-based regimens, all in the context of clinical trials (Figure 1). Detailed outcomes for the most common frontline regimens are provided in Supporting Information Material.&lt;/p&gt;&lt;p&gt;BTKis were the most common type of R/R treatment (1581/8145, 19.4%). Reflecting the approval of novel agents for patients with R/R CLL, the use of all types of chemotherapy and CIT decreased after 2014, except bendamustine plus rituximab (Figure 2).&lt;/p&gt;&lt;p&gt;There were 387 patients with an early (&lt;24 months) need for second-line treatment after 2016: 203/387 (52.4%) received chemotherapy and CIT, 147/387 (38%) novel agents (108/387 [27.9%] BTKi, 24/387 [6.2%] PI3Ki, and 15/387 [3.9%] venetoclax-based treatments), and 37/387 (9.6%) other treatments (Figure 2 &amp; File S1). ORR and discontinuation rates due to progression of patients treated with novel agents are given in the File S1.&lt;/p&gt;&lt;p&gt;Among patients treated with BTKi with or without anti-CD20 monoclonal antibodies (Mab), 55/567 (9.7%) discontinued treatment due to toxicity in second and 120/1014 (11.8%) in later lines. The median time to discontinuation was 5 months (95% confidence interval [CI]: 3.7–12.5) for patients treated in second line and 14 months (95% CI: 8–20.9) for patie","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":null,"pages":null},"PeriodicalIF":7.6,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142244977","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}
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