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Diagnostic evaluation of paediatric autoimmune lymphoproliferative immunodeficiencies (ALPID): a prospective cohort study 儿科自身免疫性淋巴细胞增生性免疫缺陷症(ALPID)的诊断评估:前瞻性队列研究
Pub Date : 2024-01-30 DOI: 10.1016/s2352-3026(23)00362-9
Pauline Hägele, Paulina Staus, Raphael Scheible, Annette Uhlmann, Maximilian Heeg, Christian Klemann, Maria Elena Maccari, Henrike Ritterbusch, Martin Armstrong, Ioana Cutcutache, Katherine S Elliott, Horst von Bernuth, Timothy Ronan Leahy, Jörg Leyh, Dirk Holzinger, Kai Lehmberg, Peter Svec, Katja Masjosthusmann, Sophie Hambleton, Marcus Jakob, Thomas Wiesel

Background

Lymphoproliferation and autoimmune cytopenias characterise autoimmune lymphoproliferative syndrome. Other conditions sharing these manifestations have been termed autoimmune lymphoproliferative syndrome-like diseases, although they are frequently more severe. The aim of this study was to define the genetic, clinical, and immunological features of these disorders to improve their diagnostic classification.

Methods

In this prospective cohort study, patients were referred to the Center for Chronic Immunodeficiency in Freiburg, Germany, between Jan 1, 2008 and March 5, 2022. We enrolled patients younger than 18 years with lymphoproliferation and autoimmune cytopenia, lymphoproliferation and at least one additional sign of an inborn error of immunity (SoIEI), bilineage autoimmune cytopenia, or autoimmune cytopenia and at least one additional SoIEI. Autoimmune lymphoproliferative syndrome biomarkers were determined in all patients. Sanger sequencing followed by in-depth genetic studies were recommended for patients with biomarkers indicative of autoimmune lymphoproliferative syndrome, while IEI panels, exome sequencing, or genome sequencing were recommended for patients without such biomarkers. Genetic analyses were done as decided by the treating physician. The study was registered on the German Clinical Trials Register, DRKS00011383, and is ongoing.

Findings

We recruited 431 children referred for autoimmune lymphoproliferative syndrome evaluation, of whom 236 (55%) were included on the basis of lymphoproliferation and autoimmune cytopenia, 148 (34%) on the basis of lymphoproliferation and another SoIEI, 33 (8%) on the basis of autoimmune bicytopenia, and 14 (3%) on the basis of autoimmune cytopenia and another SoIEI. Median age at diagnostic evaluation was 9·8 years (IQR 5·5–13·8), and the cohort comprised 279 (65%) boys and 152 (35%) girls. After biomarker and genetic assessments, autoimmune lymphoproliferative syndrome was diagnosed in 71 (16%) patients. Among the remaining 360 patients, 54 (15%) had mostly autosomal-dominant autoimmune lymphoproliferative immunodeficiencies (AD-ALPID), most commonly affecting JAK-STAT (26 patients), CTLA4-LRBA (14), PI3K (six), RAS (five), or NFκB (three) signalling. 19 (5%) patients had other IEIs, 17 (5%) had non-IEI diagnoses, 79 (22%) were unresolved despite extended genetics (ALPID-U), and 191 (53%) had insufficient genetic workup for diagnosis. 16 (10%) of 161 patients with a final diagnosis had somatic mutations. Alternative classification of patients fulfilling common variable immunodeficiency or Evans syndrome criteria did not increase the proportion of genetic diagnoses.

Interpretation

The ALPID phenotype defined in this study is enriched for patients with genetic diseases treatable with targeted therapies. The term ALPID might be useful t

背景淋巴细胞增生和自身免疫性细胞减少症是自身免疫性淋巴细胞增生综合征的特征。具有这些表现的其他疾病被称为自身免疫性淋巴细胞增生综合征样疾病,尽管它们通常更为严重。这项研究的目的是明确这些疾病的遗传、临床和免疫学特征,以改进它们的诊断分类。方法在这项前瞻性队列研究中,患者是在 2008 年 1 月 1 日至 2022 年 3 月 5 日期间转诊到德国弗莱堡慢性免疫缺陷中心的。我们招募了年龄小于 18 岁、患有淋巴细胞增生和自身免疫性全血细胞减少症、淋巴细胞增生和至少一种额外的先天性免疫错误(SoIEI)体征、双系自身免疫性全血细胞减少症或自身免疫性全血细胞减少症和至少一种额外的 SoIEI 的患者。对所有患者的自身免疫淋巴细胞增生综合征生物标记物进行了测定。对于具有自身免疫性淋巴细胞增生综合征生物标志物的患者,建议先进行桑格测序,然后再进行深入的基因研究;对于没有此类生物标志物的患者,建议进行 IEI 面板、外显子组测序或基因组测序。基因分析由主治医生决定。该研究已在德国临床试验注册中心(DRKS00011383)注册,目前仍在进行中。研究结果我们招募了 431 名转诊进行自身免疫性淋巴细胞增生综合征评估的儿童,其中 236 名(55%)因淋巴细胞增生和自身免疫性全血细胞减少症而被纳入,148 名(34%)因淋巴细胞增生和另一项 SoIEI 而被纳入,33 名(8%)因自身免疫性全血细胞减少症而被纳入,14 名(3%)因自身免疫性全血细胞减少症和另一项 SoIEI 而被纳入。诊断评估时的中位年龄为 9-8 岁(IQR 5-5-13-8),队列中有 279 名男孩(65%)和 152 名女孩(35%)。经过生物标志物和基因评估后,71 名(16%)患者被确诊为自身免疫性淋巴组织增生综合征。在其余 360 名患者中,54 人(15%)主要患有常染色体显性自身免疫性淋巴细胞增生性免疫缺陷症(AD-ALPID),最常见的是影响 JAK-STAT 信号(26 人)、CTLA4-LRBA 信号(14 人)、PI3K 信号(6 人)、RAS 信号(5 人)或 NFκB 信号(3 人)。19(5%)名患者有其他 IEI,17(5%)名患者有非 IEI 诊断,79(22%)名患者在扩展遗传学(ALPID-U)后仍无法确诊,191(53%)名患者的遗传学检查不足以确诊。在最终确诊的161名患者中,有16人(10%)出现体细胞突变。对符合常见变异性免疫缺陷或埃文斯综合征标准的患者进行替代分类并没有增加基因诊断的比例。ALPID一词可能有助于集中诊断和治疗工作,引发扩展遗传分析和考虑靶向疗法,包括目前被归类为普通可变免疫缺陷或埃文斯综合征的一些儿童。
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引用次数: 0
When cancer disguises: small-cell lung cancer masquerading as HIV-associated lymphoma in leukaemic phase 癌症的伪装:小细胞肺癌在白血病期伪装成艾滋病毒相关淋巴瘤
Pub Date : 2024-01-30 DOI: 10.1016/s2352-3026(23)00369-1
Shuhei Kurosawa, Yusuke Hamakawa, Yukihiro Yoshimura, Hiroyuki Hayashi, Tomonori Nakazato, Hiroaki Okamoto
Abstract not available
无摘要
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引用次数: 0
Elotuzumab: no additional effect in patients with newly diagnosed multiple myeloma 埃洛珠单抗:对新诊断的多发性骨髓瘤患者无额外疗效
Pub Date : 2024-01-30 DOI: 10.1016/s2352-3026(23)00376-9
Hideto Tamura
Abstract not available
无摘要
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引用次数: 0
Production and supply of blood products in Brazil 巴西血液制品的生产和供应
Pub Date : 2024-01-30 DOI: 10.1016/s2352-3026(24)00010-3
Tony Kirby
Abstract not available
无摘要
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引用次数: 0
High-dose chemotherapy and autologous haematopoietic stem-cell transplantation in older, fit patients with primary diffuse large B-cell CNS lymphoma (MARTA): a single-arm, phase 2 trial 高龄、身体健康的原发性弥漫大 B 细胞中枢神经系统淋巴瘤患者的大剂量化疗和自体造血干细胞移植(MARTA):单臂 2 期试验
Pub Date : 2024-01-29 DOI: 10.1016/s2352-3026(23)00371-x
Elisabeth Schorb, Lisa Kristina Isbell, Andrea Kerkhoff, Stephan Mathas, Friederike Braulke, Gerlinde Egerer, Alexander Röth, Simon Schliffke, Peter Borchmann, Uta Brunnberg, Frank Kroschinsky, Robert Möhle, Andreas Rank, Dominique Wellnitz, Benjamin Kasenda, Lisa Pospiech, Julia Wendler, Florian Scherer, Martina Deckert, Elina Henkes, Gerald Illerhaus

Background

Available treatments for older patients with primary diffuse large B-cell CNS lymphoma (PCNSL) offer progression-free survival of up to 16 months. We aimed to investigate an intensified treatment of high-dose chemotherapy and autologous haematopoietic stem-cell transplantation (HSCT) in older patients with PCNSL.

Methods

MARTA was a prospective, single-arm, phase 2 study done at 15 research hospitals in Germany. Patients aged 65 years or older with newly diagnosed, untreated PCNSL were enrolled if they had an Eastern Cooperative Oncology Group performance status of 0–2 and were fit for high-dose chemotherapy and autologous HSCT. Induction treatment consisted of two 21-day cycles of high-dose intravenous methotrexate 3·5 g/m2 (day 1), intravenous cytarabine 2 g/m2 twice daily (days 2 and 3), and intravenous rituximab 375 mg/m2 (days 0 and 4) followed by high-dose chemotherapy with intravenous rituximab 375 mg/m2 (day –8), intravenous busulfan 3·2 mg/kg (days –7 and –6), and intravenous thiotepa 5 mg/kg (days –5 and –4) plus autologous HSCT. The primary endpoint was progression-free survival at 12 months in all patients who met eligibility criteria and started treatment. The study was registered with the German clinical trial registry, DRKS00011932, and recruitment is complete.

Findings

Between Nov 28, 2017, and Sept 16, 2020, 54 patients started induction treatment and 51 were included in the full analysis set. Median age was 71 years (IQR 68–75); 27 (53%) patients were female and 24 (47%) were male. At a median follow-up of 23·0 months (IQR 16·8–37·4), 23 (45%) of 51 patients progressed, relapsed, or died. 12-month progression-free survival was 58·8% (80% CI 48·9–68·2; 95% CI 44·1–70·9). During induction treatment, the most common grade 3–5 toxicities were thrombocytopenia and leukopenia (each in 52 [96%] of 54 patients). During high-dose chemotherapy and autologous HSCT, the most common grade 3–5 toxicity was leukopenia (37 [100%] of 37 patients). Treatment-related deaths were reported in three (6%) of 54 patients, all due to infectious complications.

Interpretation

Although the primary efficacy threshold was not met, short induction followed by high-dose chemotherapy and autologous HSCT is active in selected older patients with PCNSL and could serve as a benchmark for comparative trials.

Funding

Else Kröner-Fresenius Foundation, Riemser Pharma, and Medical Center—University of Freiburg.

背景现有治疗原发性弥漫大B细胞中枢神经系统淋巴瘤(PCNSL)老年患者的无进展生存期长达16个月。我们的目的是研究针对老年 PCNSL 患者的高剂量化疗和自体造血干细胞移植(HSCT)强化治疗方法。方法 MARTA 是一项前瞻性、单臂、2 期研究,在德国 15 家研究医院进行。年龄在65岁或65岁以上的新确诊、未经治疗的PCNSL患者,如果其东部合作肿瘤学组(Eastern Cooperative Oncology Group)的表现状态为0-2级,且适合接受大剂量化疗和自体造血干细胞移植,均被纳入研究范围。诱导治疗包括两个 21 天周期的大剂量甲氨蝶呤静脉注射 3-5 克/平方米(第 1 天)、阿糖胞苷静脉注射 2 克/平方米,每天两次(第 2 天和第 3 天)、静脉注射利妥昔单抗 375 毫克/平方米(第 0 天和第 4 天),然后进行大剂量化疗,静脉注射利妥昔单抗 375 毫克/平方米(第 8 天),静脉注射丁硫酚 3-2 毫克/公斤(第 7 天和第 6 天),静脉注射噻替帕 5 毫克/公斤(第 5 天和第 4 天),再进行自体造血干细胞移植。主要终点是所有符合资格标准并开始治疗的患者在12个月后的无进展生存期。该研究已在德国临床试验注册机构DRKS00011932注册,招募工作已完成。研究结果2017年11月28日至2020年9月16日期间,54名患者开始诱导治疗,51名患者纳入完整分析集。中位年龄为71岁(IQR 68-75);27名(53%)患者为女性,24名(47%)患者为男性。中位随访时间为 23-0 个月(IQR 16-8-37-4),51 名患者中有 23 人(45%)病情恶化、复发或死亡。12个月无进展生存率为58-8%(80% CI 48-9-68-2; 95% CI 44-1-70-9)。在诱导治疗期间,最常见的3-5级毒性反应是血小板减少症和白细胞减少症(54名患者中有52人[96%]出现过)。在大剂量化疗和自体造血干细胞移植期间,最常见的3-5级毒性是白细胞减少症(37例患者中的37例[100%])。虽然未达到主要疗效阈值,但短期诱导后进行大剂量化疗和自体造血干细胞移植对选定的老年 PCNSL 患者有积极作用,可作为比较试验的基准。
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引用次数: 0
Extending potentially curative options for older patients with PCNSL 扩展老年 PCNSL 患者的潜在治疗方案
Pub Date : 2024-01-29 DOI: 10.1016/s2352-3026(24)00004-8
Elizabeth H Phillips, Kate Cwynarski
Abstract not available
无摘要
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引用次数: 0
Polatuzumab vedotin plus rituximab and lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma: a cohort of a multicentre, single-arm, phase 1b/2 study 波拉珠单抗韦多汀联合利妥昔单抗和来那度胺治疗复发或难治性弥漫大B细胞淋巴瘤患者:一项多中心、单臂、1b/2期研究的队列研究
Pub Date : 2024-01-05 DOI: 10.1016/s2352-3026(23)00345-9
Pau Abrisqueta, Eva González-Barca, Carlos Panizo, José María Arguiñano Pérez, Fiona Miall, Mariana Bastos-Oreiro, Ana Triguero, Lalita Banerjee, Andrew McMillan, Erlene Seymour, Jamie Hirata, Jayson de Guzman, Sunil Sharma, Hyun Yong Jin, Lisa Musick, Catherine Diefenbach

Background

Diffuse large B-cell lymphoma comprises nearly 30% of non-Hodgkin lymphoma cases and patients with relapsed or refractory diffuse large B-cell lymphoma who are ineligible for stem-cell transplantation have few treatment options and poor prognoses. We aimed to determine whether the novel combination of polatuzumab vedotin in combination with rituximab and lenalidomide (Pola+R+Len) would provide a tolerable treatment option with enhanced antitumour response in patients with relapsed or refractory diffuse large B-cell lymphoma.

Methods

This completed phase 1b/2, open-label, multicentre, single-arm study (GO29834) evaluated the safety and efficacy of Pola+R+Len in patients with relapsed or refractory diffuse large B-cell lymphoma at 19 sites in three countries (USA, Spain, and UK). Patients (≥18 years old) were eligible for inclusion if they had histologically documented CD20-positive relapsed or refractory diffuse large B-cell lymphoma and Eastern Cooperative Oncology Group performance status of 2 or lower, had received at least one previous line of chemoimmunotherapy, including an anti-CD20 agent, and were ineligible for stem-cell transplantation. The dose-escalation phase (1b) used escalating doses of lenalidomide to find the recommended phase 2 dose. Patients received six 28-day cycles of induction treatment with intravenous rituximab 375 mg/m2 and intravenous polatuzumab vedotin 1·8 mg/kg (all cohorts) plus oral lenalidomide at the following doses: 10 mg (cohort A); 15 mg (cohort B); and 20 mg (cohort C). Rituximab and polatuzumab vedotin were administered on day 1 and lenalidomide on days 1–21 of each 28-day cycle. During the dose-expansion phase (2), patients received six 28-day cycles of Pola+R+Len at the recommended phase 2 dose established during dose escalation. In both phases, patients with a complete response or partial response at the end of induction were eligible for post-induction therapy with rituximab 375 mg/m2 on day 1 and lenalidomide 10 mg/day on days 1–21 of each 28-day cycle for a maximum of 6 cycles. The primary safety objective of the dose-escalation phase was identification of the maximum tolerated dose through incidence of dose-limiting toxic effects. The primary efficacy outcome of the dose-expansion phase was Independent Review Committee-assessed complete response rate at end of induction, based on PET-CT. Analyses were conducted in the safety population, which included all patients who received at least one dose of any study drug, and the efficacy population, which included all patients who received at least one dose of any study drug at the recommended phase 2 dose. This study is registered with ClinicalTrials.gov

背景弥漫大B细胞淋巴瘤占非霍奇金淋巴瘤病例的近30%,不符合干细胞移植条件的复发或难治性弥漫大B细胞淋巴瘤患者治疗选择少且预后差。我们旨在确定波拉珠单抗韦多汀与利妥昔单抗和来那度胺(Pola+R+Len)的新型组合是否能为复发或难治性弥漫大B细胞淋巴瘤患者提供一种可耐受的治疗选择,并增强抗肿瘤反应。方法这项已完成的1b/2期、开放标签、多中心、单臂研究(GO29834)评估了Pola+R+Len在复发或难治性弥漫大B细胞淋巴瘤患者中的安全性和疗效,该研究在三个国家(美国、西班牙和英国)的19个地点进行。组织学记录为CD20阳性的复发性或难治性弥漫性大B细胞淋巴瘤患者(≥18岁)、东部合作肿瘤学组(Eastern Cooperative Oncology Group)表现状态为2级或2级以下、既往至少接受过一次化疗免疫疗法(包括抗CD20药物)且不符合干细胞移植条件的患者均可纳入研究。剂量递增阶段(1b)使用来那度胺的递增剂量,以找到第二阶段的推荐剂量。患者接受6个28天周期的诱导治疗,静脉注射利妥昔单抗375毫克/平方米和静脉注射泊拉珠单抗维多汀1-8毫克/千克(所有组别),外加口服来那度胺,剂量如下:10毫克(组别A);10毫克(组别B);10毫克(组别C);10毫克(组别D):10毫克(A组);15毫克(B组);20毫克(C组)。利妥昔单抗和泊拉珠单抗维多汀在每个28天周期的第1天给药,来那度胺在第1-21天给药。在剂量扩增阶段(2),患者按照剂量扩增期间确定的第2阶段推荐剂量接受6个28天周期的Pola+R+Len治疗。在这两个阶段中,诱导治疗结束时获得完全应答或部分应答的患者均有资格接受诱导后治疗,即在每个28天周期的第1天使用利妥昔单抗375毫克/平方米,第1-21天使用来那度胺10毫克/天,最多6个周期。剂量递增阶段的主要安全性目标是通过剂量限制性毒性反应的发生率确定最大耐受剂量。剂量扩增阶段的主要疗效结果是由独立审查委员会根据 PET-CT 评估的诱导结束时的完全反应率。分析在安全性人群和疗效人群中进行,安全性人群包括所有至少接受过一次任何研究药物治疗的患者,疗效人群包括所有至少接受过一次任何研究药物治疗且达到第二阶段推荐剂量的患者。本研究已在 ClinicalTrials.gov 注册,编号为 NCT02600897。研究结果2017 年 7 月 11 日至 2020 年 2 月 3 日期间,57 名患者入组(中位年龄 71 岁 [IQR 60-75];38 [67%] 为男性,19 (33%) 为女性;47 [82%] 不是西班牙裔或拉丁裔;既往治疗中位数为 2 [IQR 1-3])。第 1b 期纳入了 18 名参与者,第 2 期纳入了 39 名参与者。第1b期确认了来那度胺第2期的推荐剂量为20毫克。中位随访11-8个月(IQR 4-7-25-8)后,经独立评审委员会评估,完全应答率为31%(90% CI 20-43)。最常见的3-4级不良反应是中性粒细胞减少(57例中有35例[61%])和血小板减少(57例中有8例[14%])。57例患者中有23例(40%)报告了严重不良事件,1例患者因治疗相关不良事件(中性粒细胞败血症)死亡。虽然Pola+R+Len的组合未达到预设的活性阈值,但一些患者获得了临床获益,而且该方案在复发或难治性弥漫大B细胞淋巴瘤患者中具有可耐受的安全性。
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引用次数: 0
Prophylaxis and management of graft-versus-host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation 血液恶性肿瘤干细胞移植后移植物抗宿主病的预防和管理:欧洲血液和骨髓移植学会最新共识建议
Pub Date : 2024-01-03 DOI: 10.1016/s2352-3026(23)00342-3
Olaf Penack, Monia Marchetti, Mahmoud Aljurf, Mutlu Arat, Francesca Bonifazi, Rafael F Duarte, Sebastian Giebel, Hildegard Greinix, Mette D Hazenberg, Nicolaus Kröger, Stephan Mielke, Mohamad Mohty, Arnon Nagler, Jakob Passweg, Francesca Patriarca, Tapani Ruutu, Hélène Schoemans, Carlos Solano, Radovan Vrhovac, Daniel Wolff, Zinaida Peric

Graft-versus-host disease (GVHD) is a major factor contributing to mortality and morbidity after allogeneic haematopoietic stem-cell transplantation (HSCT). In the last 3 years, there has been regulatory approval of new drugs and considerable change in clinical approaches to prophylaxis and management of GVHD. To standardise treatment approaches, the European Society for Blood and Marrow Transplantation (EBMT) has updated its clinical practice recommendations. We formed a panel of one methodologist and 22 experts in the field of GVHD management. The selection was made on the basis of their role in GVHD management in Europe and their contributions to the field, such as publications, presentations at conferences, and other research. We applied the GRADE process to ten PICO (patient, intervention, comparator, and outcome) questions: evidence was searched for by the panel and graded for each crucial outcome. In two consensus meetings, we discussed the evidence and voted on the wording and strengths of recommendations. Key updates to the recommendations include: (1) primary use of ruxolitinib in steroid-refractory acute GVHD and steroid-refractory chronic GVHD as the new standard of care, (2) use of rabbit anti-T-cell (thymocyte) globulin or post-transplantation cyclophosphamide as standard GVHD prophylaxis in peripheral blood stem-cell transplantations from unrelated donors, and (3) the addition of belumosudil to the available treatment options for steroid-refractory chronic GVHD. The EBMT proposes to use these recommendations as the basis for routine management of GVHD during allogenic HSCT. The current recommendations favour European practice and do not necessarily represent global preferences.

移植物抗宿主疾病(GVHD)是异基因造血干细胞移植(HSCT)后导致死亡和发病的主要因素。在过去三年中,监管机构批准了一些新药,预防和治疗 GVHD 的临床方法也发生了很大变化。为了统一治疗方法,欧洲血液与骨髓移植学会(EBMT)更新了其临床实践建议。我们成立了一个由一名方法论专家和 22 名 GVHD 管理领域的专家组成的小组。选择专家的依据是他们在欧洲 GVHD 管理中的作用以及对该领域的贡献,如发表的论文、在会议上的发言以及其他研究。我们将 GRADE 流程应用于十个 PICO(患者、干预、比较者和结果)问题:专家组搜索证据,并对每个关键结果进行分级。在两次共识会议上,我们讨论了证据,并就建议的措辞和力度进行了投票。建议的主要更新包括(1)在类固醇难治性急性GVHD和类固醇难治性慢性GVHD中主要使用鲁索利替尼作为新的治疗标准;(2)在非亲缘供者的外周血干细胞移植中使用兔抗T细胞(胸腺细胞)球蛋白或移植后环磷酰胺作为标准的GVHD预防措施;(3)在类固醇难治性慢性GVHD的现有治疗方案中增加贝卢莫司地。EBMT 建议将这些建议作为异基因造血干细胞移植期间 GVHD 常规治疗的基础。目前的建议倾向于欧洲的做法,并不一定代表全球的偏好。
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引用次数: 0
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。
{"title":"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","authors":"Domenico Russo, Michael Schmitt, Sylvain Pilorge, Matthias Stelljes, Toshiro Kawakita, Valerie L Teal, Barbara Haber, Charlene Bopp, Sanjeet S Dadwal, Cyrus Badshah","doi":"10.1016/s2352-3026(23)00344-7","DOIUrl":"https://doi.org/10.1016/s2352-3026(23)00344-7","url":null,"abstract":"<h3>Background</h3><p>In a pivotal phase 3 trial of cytomegalovirus<span><span><span> prophylaxis with letermovir for up to 100 days after allogeneic haematopoietic stem-cell transplantation (HSCT), 12% of participants developed clinically significant </span>cytomegalovirus infection<span><span> after letermovir was discontinued. We aimed to evaluate the efficacy and safety of extending the duration of letermovir prophylaxis for clinically significant </span>cytomegalovirus infection from 100 days to 200 days following </span></span>HSCT.</span></p><h3>Methods</h3><p><span><span><span>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<span> 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 </span></span>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 </span>cyclosporin A<span>, 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 </span></span><span>ClinicalTrials.gov</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"8px\" viewbox=\"0 0 8 8\" width=\"8px\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg>, <span>NCT03930615</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"8px\" viewbox=\"0 0 8 8\" width=\"8px\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg>, and is complete.</p><h3>Findings</h3><p>Between June 21, 2019, and March 16, 2022, 255 patients were screened for eligibility and 220 (86%) were randomly assigned (145 [66%] in the","PeriodicalId":501011,"journal":{"name":"The Lancet Haematology","volume":"53 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138840637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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The Lancet Haematology
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