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Extended duration of letermovir prophylaxis: how long is long enough? 延长利特莫韦的预防期:多长时间才算足够长?
Pub Date : 2023-12-21 DOI: 10.1016/s2352-3026(23)00368-x
Abby P Douglas, Monica A Slavin
Abstract not available
无摘要
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引用次数: 0
Efficacy and safety of extended duration letermovir prophylaxis in recipients of haematopoietic stem-cell transplantation at risk of cytomegalovirus infection: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial 对有巨细胞病毒感染风险的造血干细胞移植受者进行长效特莫韦预防的有效性和安全性:一项多中心、随机、双盲、安慰剂对照的 3 期试验
Pub Date : 2023-12-21 DOI: 10.1016/s2352-3026(23)00344-7
Domenico Russo, Michael Schmitt, Sylvain Pilorge, Matthias Stelljes, Toshiro Kawakita, Valerie L Teal, Barbara Haber, Charlene Bopp, Sanjeet S Dadwal, Cyrus Badshah

Background

In a pivotal phase 3 trial of cytomegalovirus prophylaxis with letermovir for up to 100 days after allogeneic haematopoietic stem-cell transplantation (HSCT), 12% of participants developed clinically significant cytomegalovirus infection after letermovir was discontinued. We aimed to evaluate the efficacy and safety of extending the duration of letermovir prophylaxis for clinically significant cytomegalovirus infection from 100 days to 200 days following HSCT.

Methods

We conducted a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 32 sites in six countries (France, Germany, Italy, Japan, the UK, and the USA). Cytomegalovirus‑seropositive HSCT recipients (aged ≥18 years) who had received letermovir prophylaxis for up to 100 days following HSCT and who remained at high risk of late clinically significant cytomegalovirus infection (with no previous history of clinically significant cytomegalovirus infection, defined as initiation of pre-emptive therapy for documented cytomegalovirus viraemia, onset of cytomegalovirus end-organ disease, or both) were eligible. Participants were randomly assigned (2:1) to receive either an additional 100 days (ie, a total of 200 days; letermovir group) of oral or intravenous letermovir 480 mg once daily, adjusted to 240 mg once daily for participants on cyclosporin A, or 100 days of a placebo comparator for letermovir (ie, a total of 100 days of letermovir; placebo group), following HSCT. Randomisation was done using a central interactive response technology system, stratified by study centre and haploidentical donor (yes or no). Participants, investigators, and sponsor personnel were masked to the treatment allocation. The primary efficacy endpoint was the proportion of participants from randomisation to week 28 (200 days after HSCT) with clinically significant cytomegalovirus infection, analysed using the full analysis set population (ie, those who received at least one dose of study intervention). Safety was analysed in all participants as treated (ie, those who received at least one dose according to the study intervention they were assigned to). This study is registered with ClinicalTrials.gov, NCT03930615, and is complete.

Findings

Between June 21, 2019, and March 16, 2022, 255 patients were screened for eligibility and 220 (86%) were randomly assigned (145 [66%] in the

背景在一项异基因造血干细胞移植(HSCT)后100天内使用特莫维预防巨细胞病毒的关键性3期试验中,12%的参与者在停用特莫维后出现了临床症状明显的巨细胞病毒感染。方法我们在六个国家(法国、德国、意大利、日本、英国和美国)的 32 个研究机构开展了一项多中心、随机、双盲、安慰剂对照的三期试验。巨细胞病毒血清反应阳性的造血干细胞移植受者(年龄≥18 岁)在造血干细胞移植后接受了长达 100 天的来特莫韦预防治疗,且仍处于晚期临床重大巨细胞病毒感染的高风险期(既往无临床重大巨细胞病毒感染史,即因巨细胞病毒病毒血症、巨细胞病毒终末器官疾病或两者同时发生而开始接受先期治疗)。参试者被随机分配(2:1)接受造血干细胞移植后额外100天(即总共200天;letermovir组)的口服或静脉注射letermovir 480毫克,每天一次,使用环孢素A的参试者可调整为240毫克,每天一次,或者接受100天的letermovir安慰剂对比剂治疗(即总共100天的letermovir治疗;安慰剂组)。随机化是通过中央交互式响应技术系统进行的,按研究中心和单倍体供体(是或否)进行分层。参试者、研究人员和赞助商人员均对治疗分配蒙蔽。主要疗效终点为从随机化到第28周(造血干细胞移植后200天)期间出现临床意义的巨细胞病毒感染的参与者比例,采用全分析组人群(即至少接受了一剂研究干预的人群)进行分析。对所有接受治疗的参与者(即根据所分配的研究干预至少接受了一剂治疗的参与者)进行了安全性分析。该研究已在ClinicalTrials.gov上注册,编号为NCT03930615,目前已完成。研究结果在2019年6月21日至2022年3月16日期间,共筛选出255名符合条件的患者,并随机分配了220名(86%)患者(来特莫韦组145名[66%],安慰剂组75名[34%])。从随机分配到第28周期间,来特莫韦组144名参与者中有4人(3%)和安慰剂组74名参与者中有14人(19%)出现了临床上显著的巨细胞病毒感染(治疗差异-16-1% [95% CI -25-8 to -6-5];P=0-0005)。利特莫韦组与安慰剂组相比,最常见的不良事件是移植物抗宿主病(43 [30%] vs 23 [31%])、腹泻(17 [12%] vs 9 [12%])、恶心(16 [11%] vs 13 [18%])、发热(13 [9%] vs 9 [12%])和食欲下降(6 [4%] vs 9 [12%])。最常报告的严重不良事件是复发性急性髓性白血病(6[4%] vs 无)和肺炎(3[2%] vs 2[3%])。研究者认为没有死亡病例与药物有关。释义将造血干细胞移植后的利特莫韦预防期延长至 200 天,可有效、安全地降低高危患者晚期巨细胞病毒感染的发生率。
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引用次数: 0
The dawn of the CRISPR/Cas9 gene therapy era CRISPR/Cas9基因治疗时代的来临
Pub Date : 2023-12-20 DOI: 10.1016/s2352-3026(23)00372-1
Abstract not available
无摘要
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引用次数: 0
Predicting cytopenias, progression, and survival in patients with clonal cytopenia of undetermined significance: a prospective cohort study 预测意义未定的克隆性细胞减少症患者的细胞减少症、病情进展和存活率:一项前瞻性队列研究
Pub Date : 2023-12-20 DOI: 10.1016/s2352-3026(23)00340-x
Catherine Cargo, Elsa Bernard, Tumas Beinortas, Kelly L Bolton, Paul Glover, Helen Warren, Daniel Payne, Rukhsaar Ali, Alesia Khan, Mike Short, Suzan Van Hoppe, Alex Smith, Jan Taylor, Paul Evans, Elli Papaemmanuil, Simon Crouch

Background

Somatic mutations are frequently reported in individuals with cytopenia but without a confirmed haematological diagnosis (clonal cytopenia of undetermined significance; CCUS). These patients have an increased risk of progression to a myeloid malignancy and worse overall survival than those with no such mutations. To date, studies have been limited by retrospective analysis or small patient numbers. We aimed to establish the natural history of CCUS by prospectively investigating outcome in a large, well defined patient cohort.

Methods

This prospective cohort study was conducted at the Haematological Malignancy Diagnostic Service, a diagnostic laboratory in Leeds, UK. Patients aged at least 18 years who were referred for investigation of cytopenia were eligible for inclusion; those with a history of myeloid malignancy were not eligible. Targeted sequencing was conducted alongside routine clinical testing. Baseline mutation analysis was then correlated with the main study outcomes: longitudinal blood counts, disease progression to a myeloid malignancy, and overall survival with a median follow-up of 4·54 years (IQR 4·03–5·04). Data were collected manually from hospital records or extracted from laboratory or clinical outcome databases.

Findings

Bone marrow samples from 2348 patients were received at the Haematological Malignancy Diagnostic Service between July 1, 2014, and July 31, 2016. Of these, 2083 patients (median age 72 years [IQR 63–80, range 18–99]; 854 [41·0%] female and 1229 [59·0%] male) met the inclusion criteria and had samples of sufficient quality for further analysis. 598 (28·7%) patients received a diagnosis on the basis of their biopsy sample, whereas 1485 (71·3%) samples were classified as non-diagnostic; of these, CCUS was confirmed in 400 (26·9%) patients (256 [64·0%] male and 144 [36·0%] female). TET2, SRSF2, and DNMT3A were the most frequently mutated genes in patients with CCUS, with 320 (80%) of 400 patients harbouring a mutation in at least one of these genes. Age (p<0·0001), sex (p=0·0027), and mutations in ASXL1 (p=0·0009), BCOR (p=0·0056), and TP53 (p=0·0055) correlated with a worse overall survival; however, the number of mutations was the strongest predictor for progression to a myeloid malignancy (two mutations, p=0·0024; three or more mutations, p=0·0004). Extended sequencing of samples from a subgroup of patients with sequential samples and no mutations in the initial myeloid gene panel showed recurrent mutations in both DDX41 and UBA1, suggesting that these genes should be included in clinical test panels.

Interpretation

Mutation analysis is advised in patients who have undergone bone marrow examination and have an otherwise-unexplained cytopenia. High-risk genetic mutations and increa

背景据报道,在患有细胞减少症但未确诊为血液病的患者中,经常会出现基因突变(意义未定的克隆性细胞减少症;CCUS)。与没有此类突变的患者相比,这些患者进展为髓系恶性肿瘤的风险更高,总生存率更低。迄今为止,由于回顾性分析或患者人数较少,研究受到了限制。我们的目的是通过前瞻性地调查一个庞大、定义明确的患者队列的结果来确定CCUS的自然史。方法这项前瞻性队列研究在英国利兹的一个诊断实验室--血液恶性肿瘤诊断服务处进行。年龄在 18 岁以上、转诊接受细胞减少症检查的患者均符合纳入条件;有髓系恶性肿瘤病史的患者不符合纳入条件。在进行常规临床检测的同时还进行了靶向测序。基线突变分析与主要研究结果相关联:纵向血细胞计数、髓系恶性肿瘤疾病进展和中位随访 4-54 年(IQR 4-03-5-04)的总生存期。数据由人工从医院记录中收集,或从实验室或临床结果数据库中提取。研究结果血液恶性肿瘤诊断服务机构在2014年7月1日至2016年7月31日期间接收了2348名患者的骨髓样本。其中2083名患者(中位年龄72岁[IQR 63-80,范围18-99];854名[41-0%]女性和1229名[59-0%]男性)符合纳入标准,且样本质量足以进行进一步分析。598例(28-7%)患者根据活检样本获得诊断,1485例(71-3%)样本被归类为非诊断样本;其中,400例(26-9%)患者(256例[64-0%]男性和144例[36-0%]女性)确诊为CCUS。TET2、SRSF2和DNMT3A是CCUS患者中最常发生突变的基因,400名患者中有320人(80%)至少有一个基因发生了突变。年龄(p<0-0001)、性别(p=0-0027)以及ASXL1(p=0-0009)、BCOR(p=0-0056)和TP53(p=0-0055)的突变与总生存率的降低有关;然而,突变的数量是预测进展为髓系恶性肿瘤的最强因素(两个突变,p=0-0024;三个或更多突变,p=0-0004)。对具有连续样本且初始髓系基因面板中无突变的亚组患者样本进行扩展测序后发现,DDX41 和 UBA1 均存在复发性突变,这表明临床检测面板中应包括这些基因。高风险基因突变和突变数量的增加可预测发病后 5 年内的存活率和病情进展,因此需要进行临床监测,并在必要时采取干预措施。
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引用次数: 0
A comprehensive view of pregnancy in patients with sickle cell disease in high-income countries: the need for robust data and further decline in morbidity and mortality 全面了解高收入国家镰状细胞病患者的妊娠情况:需要可靠的数据并进一步降低发病率和死亡率
Pub Date : 2023-12-20 DOI: 10.1016/s2352-3026(23)00310-1
Laure Joseph, Marine Driessen

Sickle cell disease is a major public health concern due to its prevalence and associated morbidities. In high-income countries, diagnosis and treatment advancements have extended patient's lives and enabled women to embrace motherhood. Although the provision of care in specialist centres has reduced maternal–fetal complication rates, the mortality rate among pregnant women with sickle cell disease remains disproportionately high. Complications arise from vaso-occlusive events, worsening organ damage, thrombotic risks, infections, and pregnancy-related issues, such as pre-eclampsia, premature birth, small-for-gestational-age, and pregnancy loss. Effective management during pregnancy includes preconception planning, genetic counselling, education, and collaborative care. There is no consensus on the overall approach to managing pregnant women with sickle cell disease; however, fostering a collaborative relationship between health-care professionals and researchers is crucial for advancing the understanding and management of this illness. The disparities in health-care outcomes associated with ethnicity and economic insecurity affect patients with sickle cell disease but have not been examined extensively. Hence, health-care personnel need sufficient training to address these issues alongside broader societal efforts to confront racism and discrimination. Comprehensive national and global action plans are required to address the multifaceted challenges of sickle cell disease.

镰状细胞病因其发病率和相关发病率而成为一个重大的公共卫生问题。在高收入国家,诊断和治疗方面的进步延长了患者的生命,使妇女能够做母亲。虽然专科中心提供的治疗降低了母胎并发症的发生率,但患有镰状细胞病的孕妇死亡率仍然过高。并发症的原因包括血管闭塞事件、器官损伤恶化、血栓风险、感染以及与妊娠有关的问题,如先兆子痫、早产、胎儿过小和妊娠失败。孕期的有效管理包括孕前规划、遗传咨询、教育和协作护理。对于管理患有镰状细胞病的孕妇的整体方法,目前还没有达成共识;但是,促进医疗保健专业人员与研究人员之间的合作关系,对于增进对这种疾病的了解和管理至关重要。与种族和经济不安全相关的医疗结果差异影响着镰状细胞病患者,但尚未得到广泛研究。因此,医护人员需要接受足够的培训,以便在应对种族主义和歧视的更广泛社会努力的同时解决这些问题。需要制定全面的国家和全球行动计划,以应对镰状细胞病的多方面挑战。
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引用次数: 0
Lucrèce Delicat-Loembet: offering hope to young people with sickle cell disease Lucrèce Delicat-Loembet:为患有镰状细胞病的年轻人带来希望
Pub Date : 2023-12-20 DOI: 10.1016/s2352-3026(23)00374-5
Tony Kirby
Abstract not available
无摘要
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引用次数: 0
Predicting the progression of patients with CCUS to myeloid neoplasia 预测CCUS患者向髓样肿瘤发展的进程
Pub Date : 2023-12-20 DOI: 10.1016/s2352-3026(23)00361-7
Emma M Groarke
Abstract not available
无摘要
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引用次数: 0
Correction to Lancet Haematol 2023; 10: e713–34 Lancet Haematol 2023; 10: e713-34 更正
Pub Date : 2023-12-20 DOI: 10.1016/s2352-3026(23)00373-3
Abstract not available
无摘要
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引用次数: 0
Oral decitabine–cedazuridine versus intravenous decitabine for myelodysplastic syndromes and chronic myelomonocytic leukaemia (ASCERTAIN): a registrational, randomised, crossover, pharmacokinetics, phase 3 study 治疗骨髓增生异常综合征和慢性粒细胞白血病的口服地西他滨-卡达嘧啶与静脉注射地西他滨(ASCERTAIN):一项注册、随机、交叉、药代动力学 3 期研究
Pub Date : 2023-12-20 DOI: 10.1016/s2352-3026(23)00338-1
Guillermo Garcia-Manero, James McCloskey, Elizabeth A Griffiths, Karen W L Yee, Amer M Zeidan, Aref Al-Kali, H Joachim Deeg, Prapti A Patel, Mitchell Sabloff, Mary-Margaret Keating, Nancy Zhu, Nashat Y Gabrail, Salman Fazal, Joseph Maly, Olatoyosi Odenike, Hagop Kantarjian, Amy E DeZern, Casey L O’Connell, Gail J Roboz, Lambert Busque, Michael R Savona

Background

The DNA methyltransferase inhibitors azacitidine and decitabine for individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia are available in parenteral form. Oral therapy with similar exposure for these diseases would offer potential treatment benefits. We aimed to compare the safety and pharmacokinetics of oral decitabine plus the cytidine deaminase inhibitor cedazuridine versus intravenous decitabine.

Methods

We did a registrational, multicentre, open-label, crossover, phase 3 trial of individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia and individuals with acute myeloid leukaemia, enrolled as separate cohorts; results for only participants with myelodysplastic syndromes or chronic myelomonocytic leukaemia are reported here. In 37 academic and community-based clinics in Canada and the USA, we enrolled individuals aged 18 years or older who were candidates to receive intravenous decitabine, with Eastern Cooperative Oncology Group performance status 0 or 1 and a life expectancy of at least 3 months. Participants were randomly assigned (1:1) to receive 5 days of oral decitabine–cedazuridine (one tablet once daily containing 35 mg decitabine and 100 mg cedazuridine as a fixed-dose combination) or intravenous decitabine (20 mg/m2 per day by continuous 1-h intravenous infusion) in a 28-day treatment cycle, followed by 5 days of the other formulation in the next treatment cycle. Thereafter, all participants received oral decitabine–cedazuridine from the third cycle on until treatment discontinuation. The primary endpoint was total decitabine exposure over 5 days with oral decitabine–cedazuridine versus intravenous decitabine for cycles 1 and 2, measured as area under the curve in participants who received the full treatment dose in cycles 1 and 2 and had decitabine daily AUC0–24 for both oral decitabine–cedazuridine and intravenous decitabine (ie, paired cycles). On completion of the study, all patients were rolled over to a maintenance study. This study is registered with ClinicalTrials.gov, NCT03306264.

Findings

Between Feb 8, 2018, and June 7, 2021, 173 individuals were screened, 138 (80%) participants were randomly assigned to a treatment sequence, and 133 (96%) participants (87 [65%] men and 46 [35%] women; 121 [91%] White, four [3%] Black or African-American, three [2%] Asian, and fiv

背景 用于治疗骨髓增生异常综合征或慢性粒细胞白血病患者的 DNA 甲基转移酶抑制剂阿扎胞苷和地西他滨均为肠外用药。对于这些疾病,具有类似暴露的口服疗法将提供潜在的治疗优势。我们的目的是比较口服地西他滨加细胞苷脱氨酶抑制剂西达嘧啶与静脉注射地西他滨的安全性和药代动力学。方法我们对骨髓增生异常综合征或慢性粒单核细胞白血病患者和急性髓性白血病患者分别进行了注册、多中心、开放标签、交叉、3 期试验;本文仅报告骨髓增生异常综合征或慢性粒单核细胞白血病患者的试验结果。在加拿大和美国的 37 家学术和社区诊所中,我们招募了年龄在 18 岁或 18 岁以上、适合静脉注射地西他滨的患者,这些患者的东部合作肿瘤学组(Eastern Cooperative Oncology Group)表现为 0 或 1,预期寿命至少为 3 个月。受试者被随机分配(1:1),在一个为期28天的治疗周期内接受5天的地西他滨-西达嘧啶口服治疗(每天一次,每次一片,含35毫克地西他滨和100毫克西达嘧啶的固定剂量组合)或地西他滨静脉注射治疗(每天20毫克/平方米,1小时连续静脉注射),然后在下一个治疗周期接受5天的另一种制剂治疗。此后,所有参与者从第三个治疗周期开始口服地西他滨-西达脲苷,直至治疗终止。主要终点是第1和第2周期口服地西他滨-西达嘧啶与静脉注射地西他滨5天的地西他滨总暴露量,以在第1和第2周期接受全部治疗剂量且口服地西他滨-西达嘧啶和静脉注射地西他滨的地西他滨日AUC0-24(即配对周期)的参与者的曲线下面积来衡量。研究结束后,所有患者均转入维持治疗研究。该研究已在ClinicalTrials.gov注册,编号为NCT03306264.研究结果2018年2月8日至2021年6月7日期间,173人接受了筛查,138人(80%)被随机分配到治疗序列,133人(96%)接受了治疗(87名[65%]男性,46名[35%]女性;121名[91%]白人,4名[3%]黑人或非裔美国人,3名[2%]亚裔,5名[4%]未报告)。随访中位数为 966 天(IQR 为 917-1050 天)。口服地西他滨-西达脲苷与静脉注射地西他滨的主要终点总暴露率为98-93%(90% CI 92-66-105-60),表明根据曲线下面积计算的药代动力学暴露相当。口服地西他滨-卡达嘧啶和静脉注射地西他滨的安全性相似。最常见的3级或更严重的不良反应是血小板减少(133名参与者中有81名[61%])、中性粒细胞减少(76名[57%]参与者)和贫血(67名[50%]参与者)。在第1-2周期中,口服地西他滨-西达脲苷的严重不良反应发生率为31%(130名参与者中的40人),静脉注射地西他滨的严重不良反应发生率为18%(132名参与者中的24人)。有5例治疗相关死亡,其中2例与口服治疗有关(败血症和肺炎),3例与静脉治疗有关(脓毒性休克[n=2]和肺炎[n=1])。研究结果支持将口服地西他滨-卡佐尿苷作为静脉注射地西他滨的安全有效替代药物,用于治疗骨髓增生异常综合征或慢性粒细胞白血病患者。
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引用次数: 0
2023 ASH Annual Meeting 2023 ASH 年会
Pub Date : 2023-12-20 DOI: 10.1016/s2352-3026(23)00394-0
Emma Cookson
Abstract not available
无摘要
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引用次数: 0
期刊
The Lancet Haematology
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