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 letermovir group and 75 [34%] in the placebo group). Between randomisation and week 28, four (3%) of 144 participants in the letermovir group and 14 (19%) of 74 in the placebo group developed clinically significant cytomegalovirus infection (treatment difference −16·1% [95% CI −25·8 to −6·5]; p=0·0005). The most common adverse events among participants in the letermovir group versus the placebo group were graft-versus-host disease (43 [30%] vs 23 [31%]), diarrhoea (17 [12%] vs nine [12%]), nausea (16 [11%] vs 13 [18%]), pyrexia (13 [9%] vs nine [12%]), and decreased appetite (six [4%] vs nine [12%]). The most frequently reported serious adverse events were recurrent acute myeloid leukaemia (six [4%] vs none) and pneumonia (three [2%] vs two [3%]). No deaths were considered to be drug-related by the investigator.

Interpretation

Extending the duration of letermovir prophylaxis to 200 days following HSCT is efficacious and safe in reducing the incidence of late clinically significant cytomegalovirus infection in patients at risk.

Funding

Merck Sharp & Dohme LLC.

中文翻译：

---

延长莱特莫韦预防治疗对有巨细胞病毒感染风险的造血干细胞移植受者的疗效和安全性：一项多中心、随机、双盲、安慰剂对照 3 期试验

背景

在同种异体造血干细胞移植 (HSCT) 后使用莱特莫韦预防巨细胞病毒长达 100 天的关键 3 期试验中，12% 的参与者在停用莱特莫韦后出现了临床上显着的巨细胞病毒感染。我们的目的是评估将莱特莫韦预防临床上显着的巨细胞病毒感染的持续时间从 HSCT 后 100 天延长至 200 天的有效性和安全性。

方法

我们在 6 个国家（法国、德国、意大利、日本、英国和美国）的 32 个地点进行了一项多中心、随机、双盲、安慰剂对照的 3 期试验。巨细胞病毒血清阳性 HSCT 受者（年龄≥18 岁）在 HSCT 后接受莱特莫韦预防长达 100 天，且仍处于晚期临床显着巨细胞病毒感染的高风险（既往无临床显着巨细胞病毒感染史，定义为开始针对已记录的巨细胞病毒病毒血症、巨细胞病毒终末器官疾病的发作或两者的先发制人治疗是合格的。参与者被随机分配 (2:1) 接受额外 100 天（即总共 200 天；莱特莫韦组）口服或静脉注射莱特莫韦 480 mg 每天一次，环孢素 A 参与者调整为 240 mg 每天一次，或 HSCT 后使用 100 天的莱特莫韦安慰剂对照药物（即总共 100 天的莱特莫韦；安慰剂组）。随机化是使用中央交互式响应技术系统完成的，按研究中心和半相合供体（是或否）分层。参与者、研究人员和申办者人员对治疗分配情况不知情。主要疗效终点是从随机分组到第 28 周（HSCT 后 200 天）患有临床显着巨细胞病毒感染的参与者比例，使用完整分析集人群（即接受至少一剂研究干预的参与者）进行分析。对所有接受治疗的参与者（即根据分配的研究干预至少接受一剂的参与者）进行安全性分析。本研究已在ClinicalTrials.gov注册（ NCT03930615），并且已完成。

发现

2019年6月21日至2022年3月16日期间，对255名患者进行了资格筛查，其中220名患者（86%）被随机分配（莱特莫韦组145名[66%]，安慰剂组75名[34%]）。在随机分组和第 28 周之间，莱特莫韦组 144 名参与者中的 4 名 (3%) 和安慰剂组 74 名参与者中的 14 名 (19%) 出现了临床上显着的巨细胞病毒感染（治疗差异 -16·1% [95% CI -25· 8至-6·5]；p=0·0005)。莱特莫韦组与安慰剂组参与者中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（六例 [4%]对无）和肺炎（三例 [2%]对二例 [3%]）。调查人员认为没有死亡与毒品有关。

解释

将莱特莫韦预防治疗的持续时间延长至 HSCT 后 200 天，可以有效且安全地降低高危患者晚期临床显着巨细胞病毒感染的发生率。

资金

默克·夏普·多姆有限责任公司。