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Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the randomized phase 3 CLL14 study. Venetoclax-Obinutuzumab 治疗既往未经治疗的慢性淋巴细胞白血病:CLL14 3 期研究的 6 年结果。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-31 DOI: 10.1182/blood.2024024631
Othman Al-Sawaf, Sandra Robrecht, Can Zhang, Stefano Olivieri, Yi Meng Chang, Anna Maria Fink, Eugen Tausch, Christof Schneider, Matthias Ritgen, Karl-Anton Kreuzer, Liliya Sivchev, Carsten Utoft Niemann, Anthony Schwarer, Javier Loscertales, Robert Weinkove, Dirk Strumberg, Allanah Kilfoyle, Beenish S Manzoor, Dureshahwar Jawaid, Nnadozie Emechebe, Jacob Devine, Michelle Boyer, Eva D Runkel, Barbara Eichhorst, Stephan Stilgenbauer, Yanwen Jiang, Michael Hallek, Kirsten Fischer

Abstract: In the CLL14 study, patients with previously untreated chronic lymphocytic leukemia (CLL) and coexisting conditions were randomized to 12 cycles of venetoclax-obinutuzumab (Ven-Obi, n = 216) or chlorambucil-obinutuzumab (Clb-Obi, n = 216). Progression-free survival (PFS) was the primary end point. Key secondary end points included time-to-next-treatment (TTNT), rates of undetectable minimal residual disease (uMRD), overall survival (OS), and rates of adverse events. Patient reported outcomes of time until definitive deterioration (TUDD) in quality of life (QoL) were analyzed. At a median observation time of 76.4 months, PFS remained superior for Ven-Obi compared with Clb-Obi (median, 76.2 vs 36.4 months; hazard ratio [HR], 0.40; 95% confidence interval [CI], 0.31-0.52; P < .0001). Likewise, TTNT was longer after Ven-Obi (6-year TTNT, 65.2% vs 37.1%; HR, 0.44; 95% CI, 0.33-0.58; P < .0001). In the Ven-Obi arm, presence of del(17p), unmutated immunoglobulin heavy-chain variable region, and lymph node size of ≥5 cm were independent prognostic factors for shorter PFS. The 6-year OS rate was 78.7% in the Ven-Obi and 69.2% in the Clb-Obi arm (HR, 0.69; 95% CI, 0.48-1.01; P = .052). A significantly longer TUDD in global health status/QoL was observed in the Ven-Obi than in the Clb-Obi arm (median, 82.1 vs 65.1 months; HR, 0.70; 95% CI, 0.51-0.97). Follow-up-adjusted second primary malignancies incidence rates were 2.3 and 1.4 per 1000 patient-months in the Ven-Obi and Clb-Obi arm, respectively. The sustained long-term survival and QoL benefits support the use of 1-year fixed-duration Ven-Obi in CLL. This trial was registered at www.ClinicalTrials.gov as #NCT02242942.

Venetoclax-obinutuzumab(Ven-Obi)是既往未经治疗的慢性淋巴细胞白血病(CLL)患者的标准疗法。在CLL14研究中,既往未经治疗的CLL合并症患者被随机分配到12个周期的Ven-Obi(n=216)或氯布嘧啶-奥比布珠单抗(Clb-Obi,n=216)治疗中。无进展生存期(PFS)是主要终点。主要次要终点包括下次治疗时间(TTNT)、检测不到的最小残留病(uMRD)率、总生存期(OS)和不良反应率。此外,还分析了患者报告的生活质量(QoL)恶化时间(TUDD)。中位观察时间为 76.4 个月时,Ven-Obi 的 PFS 仍优于 Clb-Obi(中位 76.2 个月 vs 36.4 个月;HR 0.40[95%CI 0.31-0.52], p
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引用次数: 0
Epigenetic agents plus anti-PD-1 reprogram the tumor microenvironment and restore antitumor efficacy in Hodgkin lymphoma. 表观遗传学药物加抗 PD-1 重塑肿瘤微环境并恢复霍奇金淋巴瘤的抗肿瘤疗效
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-31 DOI: 10.1182/blood.2024024487
Jing Nie, Chunmeng Wang, Liangtao Zheng, Yang Liu, Chengcheng Wang, Yixin Chang, Yudi Hu, Bing Guo, Yuting Pan, Qingming Yang, Xueda Hu, Weidong Han

Abstract: DNA methyltransferase inhibitor decitabine plus anti-programmed cell death 1 (DP) therapy was effective in relapsed/refractory classic Hodgkin lymphoma (cHL). However, a subset of patients experienced primary resistance or relapse/progression after DP therapy. In this study, we evaluated the efficacy and safety of a triplet regimen consisting of the histone deacetylase inhibitor chidamide, decitabine, and anti-PD-1 camrelizumab (CDP) in 52 patients who previously received DP therapy. CDP treatment was well tolerated and resulted in an objective response rate of 94% (95% confidence interval [CI], 84-99), with 50% (95% CI, 36-64) of patients achieving complete response (CR). Notably, all patients who were recalcitrant to previous DP treatment exhibited therapeutic responses after CDP therapy, although their CR rate was lower than patients responsive to prior DP. Overall, the median progression-free survival was 29.4 months. Through single-cell RNA sequencing of pretreatment and on-treatment cHL tumor biopsy samples, we observed the heterogeneity of rare malignant Hodgkin Reed/Sternberg (HRS)-like cells. The classical CD30+ HRS-like cells interacted with abundant immunosuppressive IL21+CD4+ T helper cells, forming a positive feedback loop that supported their survival. While the CD30- HRS-like cell population showed potential resistance to anti-PD-1 immunotherapy. CDP treatment promoted the activation of diverse tumor-reactive CD8+ T cells and suppressed the proliferation of IL21+CD4+ T cells by inhibiting STAT1/3 signaling, thereby alleviating their immunosuppressive effects. These findings provide insights into the cHL microenvironment that contributes to anti-PD-1 resistance and highlight the therapeutic effectiveness of dual epi-immunotherapy in overcoming immunotherapy resistance. This trial was registered at www.clinicaltrials.gov as #NCT04233294.

DNA甲基转移酶抑制剂地西他滨+抗PD-1(DP)联合疗法对复发/难治性典型霍奇金淋巴瘤(cHL)有效。然而,一部分患者在接受DP治疗后出现了原发性耐药或复发/进展。在这项研究中,我们评估了由组蛋白去乙酰化酶抑制剂奇达胺、地西他滨和抗PD-1康瑞珠单抗(CDP)组成的三联疗法在52例既往接受过DP治疗的复发/难治性cHL患者中的疗效和安全性(NCT04233294)。CDP治疗效果良好,客观反应率为94%(95% CI,84-99%),其中50%(95% CI,36-64%)的患者获得了完全反应(CR)。值得注意的是,所有对既往DP治疗不耐受的患者在接受CDP治疗后都表现出了治疗反应,尽管与对既往DP治疗有反应的患者相比,他们的CR率较低。总体而言,CDP疗法后的中位无进展生存期为29.4个月。通过对治疗前和治疗中的cHL肿瘤活检组织进行单细胞RNA测序,我们观察到了罕见恶性霍奇金里德/斯特恩伯格(HRS)样细胞的异质性。典型的CD30+ HRS样细胞与大量免疫抑制性IL21+CD4+ T辅助细胞相互作用,形成正反馈循环,支持其生存。相比之下,CD30- HRS样细胞群对抗PD-1免疫疗法表现出潜在的抵抗力。CDP治疗可促进多种肿瘤反应性CD8+ T细胞的活化,并通过抑制STAT1/3信号传导抑制IL21+CD4+ T细胞的增殖,从而减轻它们的免疫抑制作用。这些发现深入揭示了导致抗PD-1耐药的cHL微环境,并凸显了双重外免疫疗法在克服免疫疗法耐药方面的疗效。
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引用次数: 0
Longitudinal detection of prion infection in preclinical sheep blood samples compared using 3 assays. 使用 3 种检测方法比较临床前绵羊血液样本中朊病毒感染的纵向检测。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-31 DOI: 10.1182/blood.2024024649
Charlotte M Thomas, M Khalid F Salamat, Florian Almela, Jillian K Cooper, Kaetan Ladhani, Mark E Arnold, Daisy Bougard, Olivier Andréoletti, E Fiona Houston

Abstract: Variant Creutzfeldt-Jakob disease (vCJD) is a devastating disease caused by transmission of bovine spongiform encephalopathy to humans. Although vCJD cases are now rare, evidence from appendix surveys suggests that a small proportion of the United Kingdom population may be infected without showing signs of disease. These "silent" carriers could present a risk of iatrogenic vCJD transmission through medical procedures or blood/organ donation, and currently there are no validated tests to identify infected asymptomatic individuals using easily accessible samples. To address this issue, we evaluated the performance of 3 blood-based assays in a blinded study, using longitudinal sample series from a well-established large animal model of vCJD. The assays rely on amplification of misfolded prion protein (PrPSc; a marker of prion infection) and include real-time quaking-induced conversion (RT-QuIC), and 2 versions of protein misfolding cyclic amplification (PMCA). Although diagnostic sensitivity was higher for both PMCA assays (100%) than RT-QuIC (61%), all 3 assays detected prion infection in blood samples collected 26 months before the onset of clinical signs and gave no false-positive results. Parallel estimation of blood prion infectivity titers in a sensitive transgenic mouse line showed positive correlation of infectivity with PrPSc detection by the assays, suggesting that they are suitable for detection of asymptomatic vCJD infection in the human population. This study represents, to our knowledge, the largest comparison to date of preclinical prion detection in blood samples from a relevant animal model. The outcomes will guide efforts to improve early detection of prion disease and reduce infection risks in humans.

变异型克雅氏病(vCJD)是一种毁灭性疾病,由牛海绵状脑病(BSE)传播给人类引起。虽然 vCJD 病例现在已经很少见了,但阑尾调查的证据表明,英国人口中可能有一小部分人受到感染,但没有表现出疾病的症状。这些 "沉默 "的携带者可能会通过医疗程序或献血/器官捐献造成 vCJD 的先天性传播风险,而目前还没有有效的检测方法可以利用容易获得的样本来识别受感染的无症状个体。为了解决这个问题,我们在一项盲法研究中,使用一种成熟的大型 vCJD 动物模型的纵向样本系列,对三种基于血液的检测方法的性能进行了评估。这些检测方法依赖于错误折叠的朊病毒蛋白(PrPSc;朊病毒感染的标志物)的扩增,包括实时震荡诱导转换(RT-QuIC)和两种蛋白质错误折叠循环扩增(PMCA)。虽然两种 PMCA 检测法的诊断灵敏度(100%)高于 RT-QuIC 检测法(61%),但所有这三种检测法都能检测出临床症状出现前 26 个月采集的血液样本中的朊病毒感染,而且不会出现假阳性结果。在敏感的转基因小鼠品系中对血液朊病毒感染性滴度的平行估计显示,感染性与检测方法检测到的PrPSc呈正相关,这表明它们适用于检测人类中无症状的vCJD感染。这项研究是迄今为止对相关动物模型血液样本中临床前朊病毒检测进行的最大规模比较。研究结果将为改善朊病毒疾病的早期检测和降低人类感染风险提供指导。
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引用次数: 0
A modern view of LGL leukemia. 低密度粒细胞白血病的现代观点。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-31 DOI: 10.1182/blood.2023021790
Tony Marchand, Thierry Lamy, Thomas P Loughran

Abstract: Large granular lymphocytic leukemia (LGLL) is a rare lymphoproliferative chronic disorder characterized by expansion of either T or natural killer (NK) cytotoxic cells. In contrast to Epstein-Barr virus-induced aggressive NK-LGLL, chronic T-LGLL and NK-LGLL are indolent diseases affecting older patients with a median age of 66.5 years. LGLL is frequently associated with autoimmune disorders, most frequently rheumatoid arthritis. An auto-/alloantigen is tentatively implicated in disease initiation. Large granular lymphocyte expansion is then triggered by proinflammatory cytokines such as interleukin-15, macrophage inflammatory protein 1 (MIP-1), and RANTES (regulated upon activation, normal T cell expressed, and secreted). This proinflammatory environment contributes to deregulation of proliferative and apoptotic pathways. After the initial description of the JAK-STAT pathway signaling activation in the majority of patients, recurrent STAT3 gain-of-function mutations have been reported. The JAK-STAT pathway plays a key role in LGL pathogenesis by promoting survival, proliferation, and cytotoxicity. Several recent advances have been made toward understanding the molecular landscapes of T- and NK-LGLL, identifying multiple recurrent mutations affecting the epigenome, such as TET2 or KMT2D, and cross talk with the immune microenvironment, such as CCL22. Despite an indolent course, published series suggest that the majority of patients eventually need treatment. However, it is noteworthy that many patients may have a long-term observation period without ever requiring therapy. Treatments rely upon immunosuppressive drugs, namely cyclophosphamide, methotrexate, and cyclosporine. Recent advances have led to the development of targeted approaches, including JAK-STAT inhibitors, cytokine targeting, and hypomethylating agents, opening new developments in a still-incurable disease.

大颗粒淋巴细胞(LGL)白血病是一种罕见的淋巴细胞增生性慢性疾病,其特点是T细胞或NK细胞毒性扩增。与EBV诱导的侵袭性NK-LGL白血病相反,慢性T淋巴细胞白血病和NK-LGL白血病是一种不严重的疾病,多发于中位年龄为66.5岁的老年患者。LGL 白血病经常与自身免疫性疾病相关,最常见的是类风湿性关节炎。一种自身/类风湿性关节炎抗原被初步认为与疾病的发生有关。白细胞介素(IL)IL-15、MIP-1 和 RANTES 等促炎细胞因子会诱发 LGLs 扩增。这种促炎环境导致增殖和凋亡途径失调。继最初描述大多数患者的 JAK-STAT 通路信号激活后,又有报道称 STAT3 功能增益突变反复发生。JAK-STAT 通路通过促进生存、增殖和细胞毒性,在 LGL 发病机制中发挥着关键作用。最近在了解T和NK LGL白血病的分子图谱方面取得了一些进展,发现了影响表观基因组(如TET2或KMT2D)的多种复发性突变,以及与免疫微环境(如CCL22)的串联。尽管病程缓慢,但已发表的系列研究表明,大多数患者最终都需要接受治疗。但值得注意的是,许多患者可能需要长期观察而无需治疗。治疗依赖于免疫抑制剂,即环磷酰胺、甲氨蝶呤和环孢素。最近的进展导致了靶向治疗方法的开发,包括 JAK-STAT 抑制剂、细胞因子靶向治疗和低甲基化药物,为这一仍无法治愈的疾病开辟了新的治疗途径。
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引用次数: 0
A practical approach to the modern diagnosis and classification of T- and NK-cell lymphomas. T- NK 细胞淋巴瘤的现代诊断和分类实用方法。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-31 DOI: 10.1182/blood.2023021786
Laurence de Leval, Philippe Gaulard, Ahmet Dogan

Abstract: T- and natural killer (NK)-cell lymphomas are neoplasms derived from immature T cells (lymphoblastic lymphomas), or more commonly, from mature T and NK cells (peripheral T-cell lymphomas, PTCLs). PTCLs are rare but show marked biological and clinical diversity. They are usually aggressive and may present in lymph nodes, blood, bone marrow, or other organs. More than 30 T/NK-cell-derived neoplastic entities are recognized in the International Consensus Classification and the classification of the World Health Organization (fifth edition), both published in 2022, which integrate the most recent knowledge in hematology, immunology, pathology, and genetics. In both proposals, disease definition aims to integrate clinical features, etiology, implied cell of origin, morphology, phenotype, and genetic features into biologically and clinically relevant clinicopathologic entities. Cell derivation from innate immune cells or specific functional subsets of CD4+ T cells such as follicular helper T cells is a major determinant delineating entities. Accurate diagnosis of T/NK-cell lymphoma is essential for clinical management and mostly relies on tissue biopsies. Because the histological presentation may be heterogeneous and overlaps with that of many benign lymphoid proliferations and B-cell lymphomas, the diagnosis is often challenging. Disease location, morphology, and immunophenotyping remain the main features guiding the diagnosis, often complemented by genetic analysis including clonality and high-throughput sequencing mutational studies. This review provides a comprehensive overview of the classification and diagnosis of T-cell lymphoma in the context of current concepts and scientific knowledge.

T细胞淋巴瘤和NK细胞淋巴瘤是由未成熟T细胞(淋巴母细胞淋巴瘤)或更常见的成熟T细胞和NK细胞(外周T细胞淋巴瘤,PTCLs)演变而来的肿瘤。PTCLs 很罕见,但在生物和临床上表现出明显的多样性。它们通常具有侵袭性,可能出现在淋巴结、血液、骨髓或其他器官中。国际共识分类》(International Consensus Classification)和《世界卫生组织分类(第五版)》(World Health Organization,均于 2022 年出版)整合了血液学、免疫学、病理学和遗传学方面的最新知识,确认了 30 多种由 T/NK 细胞衍生的肿瘤实体。在这两份提案中,疾病定义旨在将临床特征、病因学、隐含的起源细胞、形态学、表型和遗传学特征整合为生物学和临床相关的临床病理学实体。细胞来源于先天性免疫细胞或 CD4+ T 细胞的特定功能亚群(如滤泡辅助性 T 细胞)是划分实体的主要决定因素。T/NK细胞淋巴瘤的准确诊断对临床治疗至关重要,主要依赖于组织活检。由于组织学表现可能是异质性的,并与许多良性淋巴细胞增生和B细胞淋巴瘤重叠,因此诊断往往具有挑战性。疾病位置、形态学和免疫分型仍是指导诊断的主要特征,通常辅以基因分析,包括克隆性和高通量测序突变研究。本综述结合当前的概念和科学知识,全面概述了 T 细胞淋巴瘤的分类和诊断。
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引用次数: 0
Forimtamig, a novel GPRC5D-targeting T-cell bispecific antibody with a 2+1 format, for the treatment of multiple myeloma. 用于治疗多发性骨髓瘤的新型 GPRC5D 靶向 T 细胞双特异性抗体 Forimtamig(2+1 型)。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-30 DOI: 10.1182/blood.2024025987
Jan Eckmann, Tanja Fauti, Marlene Biehl, Aintzane Zabaleta, Laura Blanco, Iva Lelios, Stefan Gottwald, Richard Rae, Stefanie Lechner, Christa Bayer, Quincy Dekempe, Franz Osl, Nadège Carrié, Sahar Kassem, Stefan Lorenz, Tony Christopeit, Alejandro Carpy, Alexander Bujotzek, Ann-Marie E Bröske, Iryna Dekhtiarenko, Jan Attig, Leo Kunz, Floriana Cremasco, Roberto Adelfio, Georg Fertig, Stefan Dengl, Christian Gassner, Felix Bormann, Claudia Kirstenpfad, Thomas Emanuel Kraft, Sarah Diggelmann, Melanie Knobloch, Carina Hage, Romi Feddersen, Gordon Heidkamp, Thomas Pöschinger, Maud Lea Mayoux, Luise Bernasconi, Charles Dumontet, Felipe Prosper, Ludovic Martinet, Stephane Leclair, Wei Xu, Bruno Paiva, Christian Klein, Pablo Umaña

Despite several approved therapies, multiple myeloma (MM) remains an incurable disease with high unmet medical need. "Off-the-shelf" T-cell bispecific antibodies (TCBs) targeting BCMA and GPRC5D have demonstrated high objective response rates (ORR) in heavily pre-treated MM patients, however, primary resistance, short duration of response and relapse driven by antigen shift frequently occurs. Although GPRC5D represents the most selective target in MM, recent findings indicate antigen loss occurs more frequently than with BCMA. Thus, anti-GPRC5D immunotherapies must hit hard during a short period of time to kill as many myeloma cells as possible. Here, we characterize forimtamig, a novel GPRC5D-targeting TCB with 2+1 format, using preclinical models of MM. Bivalent binding of forimtamig to the N-terminus of GPRC5D confers higher affinity as compared to classical 1+1 TCB formats correlating with formation of more stable immunological synapses and higher potency in tumor cell killing and T cell activation. Using an orthotopic mouse model of MM, forimtamig recruited T effector cells to the bone marrow and induced rapid tumor killing even after the introduction of step-up dosing to mitigate cytokine release. Combination of forimtamig with standard-of-care (SoC) agents including anti-CD38 antibodies, immunomodulatory drugs and proteasome inhibitors improved depth and duration of response. The combination of forimtamig with novel therapeutic agents including BCMA-TCB and Cereblon E3 Ligase Modulatory Drugs (CELMoDs) was potent and prevented occurrence of GPRC5D-negative tumor relapse. Forimtamig is currently being evaluated in Phase 1 clinical trials in relapsed and refractory myeloma (RRMM) patients for monotherapy and in combination treatments. NCT04557150.

尽管有多种疗法获得批准,但多发性骨髓瘤(MM)仍是一种无法治愈的疾病,有大量医疗需求尚未得到满足。以 BCMA 和 GPRC5D 为靶点的 "现成 "T 细胞双特异性抗体(TCBs)已在接受过大量预处理的 MM 患者中显示出较高的客观反应率(ORR),但由于抗原转移而导致的原发性耐药、反应持续时间短和复发的情况时有发生。虽然 GPRC5D 是 MM 中最具选择性的靶点,但最近的研究结果表明,抗原丢失比 BCMA 更常发生。因此,抗 GPRC5D 免疫疗法必须在短时间内重创尽可能多的骨髓瘤细胞。在这里,我们利用MM的临床前模型对forimtamig进行了表征,它是一种新型的GPRC5D靶向TCB,具有2+1形式。与传统的 1+1 TCB 形式相比,forimtamig 与 GPRC5D N 端的二价结合具有更高的亲和力,这与形成更稳定的免疫突触以及更高的肿瘤细胞杀伤力和 T 细胞活化能力相关。通过使用正位小鼠 MM 模型,forimtamig 将 T 效应细胞招募到骨髓中,并诱导快速杀伤肿瘤,即使在采用阶梯剂量以减少细胞因子释放之后也是如此。forimtamig与标准治疗(SoC)药物(包括抗CD38抗体、免疫调节药物和蛋白酶体抑制剂)联用可提高反应的深度和持续时间。forimtamig与新型治疗药物(包括BCMA-TCB和脑龙E3连接酶调节药物(CELMoDs))的联合治疗效果显著,可防止GPRC5D阴性的肿瘤复发。目前,Forimtamig正在复发性和难治性骨髓瘤(RRMM)患者的单药治疗和联合治疗的1期临床试验中接受评估。NCT04557150。
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引用次数: 0
Genetic and Clinical Spectrum of SAMD9 and SAMD9L Syndromes: from Variant Interpretation to Patient Management. SAMD9 和 SAMD9L 综合征的遗传和临床谱系:从变异解释到患者管理。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-30 DOI: 10.1182/blood.2022017717
Sushree S Sahoo, Miriam Erlacher, Marcin W Wlodarski

SAMD9 and SAMD9L (SAMD9/9L) are paralogous genes encoding antiviral proteins that negatively regulate cell proliferation. Heterozygous germline gain-of-function (GoF) SAMD9/9L variants cause multisystem syndromes with variable manifestations. The unifying features are cytopenia, immunodeficiency, infections, bone marrow failure (BMF), myelodysplasia (MDS) and monosomy 7. Non-hematopoietic presentations can affect almost every organ system. Growth impairment and adrenal insufficiency are typical in SAMD9, while progressive neurologic deficits characterize SAMD9L. Most patients (>90%) carry germline missense GoF variants. A subgroup of patients presenting with SAMD9L-associated inflammatory disease (SAAD) carry frameshift truncating variants that are also GoF. Somatic genetic rescue occurs in >2/3 of patients and involves monosomy 7, which may spontaneously disappear (transient monosomy 7) or progress to MDS/leukemia, and adaptive clones with somatic SAMD9/9L compensatory mutations or uniparental disomy 7q (UPD7q), both associated with remission. This manuscript examines the clinical and genetic spectrum, therapies and outcome based on 243 published patients compiled in our registry with additional genetic information on 62 unpublished cases. We consolidate the diverse clinical manifestations and diagnostic challenges of SAMD9/9L syndromes to enhance recognition and improve patient care. We highlight the knowledge gaps in pathomechanisms and emphasize the importance of genetic surveillance assessing disease remission versus disease progression. Insights are provided into variant curation and the necessity of testing for somatic SAMD9/9L mutations and UPD7q. Multidisciplinary care in specialized centers is critical to manage these complex disorders. Future natural history studies, especially in patients with monosomy 7, will help formulate evidence-based surveillance protocols and optimize transplant timing and outcomes.

SAMD9 和 SAMD9L(SAMD9/9L)是编码抗病毒蛋白的旁系基因,可对细胞增殖进行负向调节。杂合子种系功能增益(GoF)SAMD9/9L 变体会导致表现各异的多系统综合征。统一的特征是全血细胞减少、免疫缺陷、感染、骨髓衰竭(BMF)、骨髓增生异常(MDS)和单体 7。生长障碍和肾上腺功能不全是 SAMD9 的典型表现,而进行性神经功能缺损则是 SAMD9L 的特征。大多数患者(大于 90%)携带种系错义 GoF 变异。SAMD9L相关炎症性疾病(SAAD)患者中有一个亚群携带也是GoF的框架移位截断变体。2/3以上的患者会出现体细胞遗传救援,包括可能自发消失(一过性单体7)或进展为MDS/白血病的单体7,以及具有体细胞SAMD9/9L代偿突变或单亲7q断裂(UPD7q)的适应性克隆,两者均与病情缓解有关。本手稿以我们登记的 243 名已发表患者为基础,结合 62 例未发表病例的其他基因信息,对临床和基因谱、疗法和预后进行了研究。我们整合了 SAMD9/9L 综合征的各种临床表现和诊断难题,以提高识别能力并改善患者护理。我们强调了病理机制方面的知识差距,并强调了评估疾病缓解与疾病进展的遗传监测的重要性。我们还深入探讨了变异整理以及检测体细胞SAMD9/9L突变和UPD7q的必要性。专科中心的多学科治疗对于管理这些复杂的疾病至关重要。未来的自然史研究,尤其是针对单体7型患者的研究,将有助于制定循证监控方案,优化移植时机和结果。
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引用次数: 0
Long term follow-up of the STOPAGO study. STOPAGO 研究的长期跟踪。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-30 DOI: 10.1182/blood.2024025707
Adrien Cottu, Stéphanie Guillet, Jean-François Viallard, Etienne Riviere, Stéphane Cheze, Delphine Gobert, Antoine Neel, Julie Graveleau, Jean-Pierre Marolleau, François Lefrere, Guillaume Moulis, Jean-Christophe Lega, Aline Moignet, Ailsa Robbins, Etienne Crickx, Emmanuelle Boutin, Nicolas Noel, Marion Malphettes, Lionel Galicier, Sylvain Audia, Bernard Bonnotte, Olivier Lambotte, Olivier Fain, Mathieu Gerfaud-Valentin, Louis Terriou, Nihal Martis, Anne-Sophie Morin, Antoinette Perlat, Thomas Le Gallou, Frédérique Roy-Peaud, Matthieu Puyade, Thibault Comont, Nicolas Limal, Laetitia Languille, Marc Michel, Bertrand Godeau, Matthieu Mahevas

An open prospective, multicenter study enrolled 48 selected patients with chronic immune thrombocytopenia who achieved complete response for 1 year on thrombopoietin receptor agonists, half of the patients maintained a sustained response off treatment 4 years after treatment discontinuation. NCT03119974.

一项开放性前瞻性多中心研究入选了 48 例慢性免疫性血小板减少症患者,这些患者在服用促血小板生成素受体激动剂 1 年后获得了完全应答,其中一半患者在停药 4 年后仍保持了持续应答。NCT03119974。
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引用次数: 0
Current myeloproliferative neoplasm scoring systems for clinical practice. 目前用于临床实践的骨髓增生性肿瘤评分系统。
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-30 DOI: 10.1182/blood.2024025459
Hélène Pasquer, Jean-Jacques Kiladjian, Lina Benajiba

BCR::ABL1-negative myeloproliferative neoplasms (MPN) are clonal hematological malignancies resulting from the proliferation of myeloid cells harboring a JAK-STAT pathway activating driver mutation. MPN management recommendations are based on the evaluation of different risks to prevent disease evolution associated events while preserving patients' quality of life. Such risks can be common across all MPN or specific to each subtype (polycythemia vera (PV), essential thrombocythemia (ET), prefibrotic myelofibrosis (pre-MF), primary myelofibrosis (PMF)). MF-patients harbor the worse prognosis and hematopoietic stem cell transplantation (HSCT) is the only curative treatment, at the expense of a high morbi-mortality. Therefore, accurate scoring systems to estimate overall survival are crucial for MF patients' management and selection for HSCT. In PV and ET, vascular events prediction is prioritized given their higher incidence and related morbi-mortality. Finally, quality of life evaluation is important for all subtypes. To predict these risks and adapt MPN therapeutic strategies, clinical risk scores have been developed over the past decades, more recently including molecular risk factors for more accurate risk stratification. The large number of scoring systems available in combination with disease heterogeneity and the necessity to predict diverse outcomes, make it difficult for clinicians to choose the most appropriate score to evaluate their patients' risk in 2024. Here, we provide an overview of MPN disease evolution associated events incidence and conduct an exhaustive comparative review of the scoring systems currently available for each risk. Finally, we propose an algorithm for the use of these scores in clinical practice in each MPN subtype.

BCR::ABL1阴性骨髓增殖性肿瘤(MPN)是一种克隆性血液恶性肿瘤,由携带JAK-STAT通路激活驱动突变的骨髓细胞增殖引起。MPN 的管理建议基于对不同风险的评估,以预防疾病演变相关事件的发生,同时保护患者的生活质量。这些风险可能是所有骨髓增生性疾病的共同风险,也可能是各亚型(真性红细胞增多症(PV)、原发性血小板增多症(ET)、骨髓纤维化前期(Pre-MF)、原发性骨髓纤维化(PMF))的特有风险)的共同风险。骨髓纤维化患者的预后较差,造血干细胞移植(HSCT)是唯一可治愈的治疗方法,但死亡率较高。因此,估算总生存期的精确评分系统对中风患者的管理和造血干细胞移植的选择至关重要。在血管性白血病和白血病中,由于血管事件的发生率较高,相关死亡率也较高,因此血管事件的预测应优先考虑。最后,生活质量评估对所有亚型都很重要。为了预测这些风险并调整骨髓增生性疾病的治疗策略,过去几十年来人们开发了临床风险评分,最近又增加了分子风险因素,以进行更准确的风险分层。大量的评分系统加上疾病的异质性和预测不同结果的必要性,使得临床医生很难选择最合适的评分来评估患者在 2024 年的风险。在此,我们概述了与事件发生率相关的 MPN 疾病演变,并对目前可用于各种风险的评分系统进行了详尽的比较审查。最后,我们提出了在临床实践中针对每种 MPN 亚型使用这些评分的算法。
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引用次数: 0
Venetoclax Dose Escalation Rapidly Activates a BAFF/BCL-2 Survival Axis in Chronic Lymphocytic Leukemia. Venetoclax剂量递增可快速激活慢性淋巴细胞白血病的BAFF/BCL-2生存轴
IF 21 1区 医学 Q1 HEMATOLOGY Pub Date : 2024-10-29 DOI: 10.1182/blood.2024024341
Meng-Xiao Luo, Tania Tan, Marie Trussart, Annika Poch, Minh-Hanh Thi Nguyen, Terence P Speed, Damien G Hicks, Esther Bandala-Sanchez, Hongke Peng, Stephane Chappaz, Charlotte Slade, Daniel T Utzschneider, Rachel M Koldej, David Ritchie, Andreas Strasser, Rachel Thijssen, Matthew E Ritchie, Constantine Si Lun Tam, Geoffrey J Lindeman, David Ching Siang Huang, Thomas E Lew, Mary Ann Anderson, Andrew W Roberts, Charis E Teh, Daniel H D Gray

Venetoclax, a first-in-class BH3 mimetic drug targeting BCL-2, has improved outcomes for patients with chronic lymphocytic leukemia (CLL). Early measurements of the depth of the venetoclax treatment response, assessed by minimal residual disease, are strong predictors of long-term clinical outcomes. Yet, there are limited data concerning the early changes induced by venetoclax treatment that might inform strategies to improve responses. To address this gap, we conducted longitudinal mass cytometric profiling of blood cells from patients with CLL during the first five weeks of venetoclax monotherapy. At baseline, we resolved CLL heterogeneity at the single-cell level to define multiple subpopulations in all patients distinguished by proliferative, metabolic and cell survival proteins. Venetoclax induced significant reduction in all CLL subpopulations coincident with rapid upregulation of pro-survival BCL-2, BCL-XL and MCL-1 proteins in surviving cells, which had reduced sensitivity to the drug. Mouse models recapitulated the venetoclax-induced elevation of survival proteins in B cells and CLL-like cells that persisted in vivo, with genetic models demonstrating that extensive apoptosis and access to the B cell cytokine, BAFF, were essential. Accordingly, analysis of patients with CLL that were treated with venetoclax or the anti-CD20 antibody obinutuzumab exhibited marked elevation of BAFF and increased pro-survival proteins in leukemic cells that persisted. Overall, these data highlight the rapid adaptation of CLL cells to targeted therapies via homeostatic factors and support co-targeting of cytokine signals to achieve deeper and more durable long-term responses.

Venetoclax是一种靶向BCL-2的首创BH3模拟药物,它能改善慢性淋巴细胞白血病(CLL)患者的治疗效果。通过最小残留病来评估 Venetoclax 治疗反应的深度,是预测长期临床疗效的有力指标。然而,有关 Venetoclax 治疗引起的早期变化的数据却很有限,而这些数据可能为改善反应的策略提供依据。为了填补这一空白,我们在 Venetoclax 单药治疗的前五周对 CLL 患者的血细胞进行了纵向质谱分析。在基线阶段,我们在单细胞水平上解决了 CLL 的异质性,在所有患者中定义了多个亚群,这些亚群由增殖蛋白、代谢蛋白和细胞存活蛋白区分。Venetoclax 能显著减少所有 CLL 亚群的数量,同时存活细胞中促进存活的 BCL-2、BCL-XL 和 MCL-1 蛋白迅速上调,从而降低了对药物的敏感性。小鼠模型再现了 Venetoclax 诱导的 B 细胞和 CLL 样细胞中存活蛋白的升高,这种升高在体内持续存在,基因模型表明,广泛的细胞凋亡和获得 B 细胞细胞因子 BAFF 至关重要。因此,对接受 Venetoclax 或抗 CD20 抗体 obinutuzumab 治疗的 CLL 患者进行的分析表明,BAFF 明显升高,持续存在的白血病细胞中的促生存蛋白也有所增加。总之,这些数据突显了CLL细胞通过同源因子对靶向疗法的快速适应,并支持联合靶向细胞因子信号以获得更深入、更持久的长期应答。
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引用次数: 0
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