From the Dana-Farber Cancer Institute and Brigham and Women's Hospital (F.M.M.) and Tufts Medical Center and Tufts University School of Medicine (D.R.S.), Boston; Karolinska University Hospital and Karolinska Institutet, Stockholm (P.L.); University of Texas M.D. Anderson Cancer Center, Houston (R.F.C.); Universitaire Ziekenhuizen Leuven, Leuven, Belgium (J.M.); City of Hope National Medical Center, Duarte (S.S.D.), and Stanford University School of Medicine, Palo Alto (J.B.) - both in California; Hospital Universitario Puerta de Hierro-Majadahonda, Madrid (R.F.D.); Juravinski Hospital and Cancer Center, McMaster University, Hamilton, ON, Canada (S.H.); Universitätsklinikum Würzburg, Würzburg, Germany (A.J.U., H.E.); Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital, Hiroshima (Y. Katayama), and Saitama Medical Center, Jichi Medical University, Saitama (Y. Kanda) - both in Japan; University of Chicago, Chicago (K.M.M.); Fred Hutchinson Cancer Research Center, Seattle (M.B.); Perelman School of Medicine at the University of Pennsylvania, Philadelphia (E.A.B.); and Merck, Kenilworth, NJ (M.J.D., V.L.T., H.W., Y.M., N.A.K., R.Y.L., C.B.).
N Engl J Med. 2017 Dec 21;377(25):2433-2444. doi: 10.1056/NEJMoa1706640. Epub 2017 Dec 6.
Cytomegalovirus (CMV) infection remains a common complication after allogeneic hematopoietic-cell transplantation. Letermovir is an antiviral drug that inhibits the CMV-terminase complex.
In this phase 3, double-blind trial, we randomly assigned CMV-seropositive transplant recipients, 18 years of age or older, in a 2:1 ratio to receive letermovir or placebo, administered orally or intravenously, through week 14 after transplantation; randomization was stratified according to trial site and CMV disease risk. Letermovir was administered at a dose of 480 mg per day (or 240 mg per day in patients taking cyclosporine). Patients in whom clinically significant CMV infection (CMV disease or CMV viremia leading to preemptive treatment) developed discontinued the trial regimen and received anti-CMV treatment. The primary end point was the proportion of patients, among patients without detectable CMV DNA at randomization, who had clinically significant CMV infection through week 24 after transplantation. Patients who discontinued the trial or had missing end-point data at week 24 were imputed as having a primary end-point event. Patients were followed through week 48 after transplantation.
From June 2014 to March 2016, a total of 565 patients underwent randomization and received letermovir or placebo beginning a median of 9 days after transplantation. Among 495 patients with undetectable CMV DNA at randomization, fewer patients in the letermovir group than in the placebo group had clinically significant CMV infection or were imputed as having a primary end-point event by week 24 after transplantation (122 of 325 patients [37.5%] vs. 103 of 170 [60.6%], P<0.001). The frequency and severity of adverse events were similar in the two groups overall. Vomiting was reported in 18.5% of the patients who received letermovir and in 13.5% of those who received placebo; edema in 14.5% and 9.4%, respectively; and atrial fibrillation or flutter in 4.6% and 1.0%, respectively. The rates of myelotoxic and nephrotoxic events were similar in the letermovir group and the placebo group. All-cause mortality at week 48 after transplantation was 20.9% among letermovir recipients and 25.5% among placebo recipients.
Letermovir prophylaxis resulted in a significantly lower risk of clinically significant CMV infection than placebo. Adverse events with letermovir were mainly of low grade. (Funded by Merck; ClinicalTrials.gov number, NCT02137772 ; EudraCT number, 2013-003831-31 .).
巨细胞病毒（CMV）感染仍然是异基因造血细胞移植后的常见并发症。来特莫韦是一种抑制 CMV 端酶复合物的抗病毒药物。
在这项 3 期、双盲试验中，我们将年龄为 18 岁或以上的 CMV 血清阳性移植受者以 2:1 的比例随机分配，接受来特莫韦或安慰剂口服或静脉输注，直到移植后 14 周；随机分组根据试验地点和 CMV 疾病风险分层。来特莫韦的剂量为每天 480 毫克（或每天 240 毫克，用于服用环孢素的患者）。出现临床显著 CMV 感染（CMV 疾病或导致预防性治疗的 CMV 病毒血症）的患者停止试验方案并接受抗 CMV 治疗。主要终点是在随机分组时未检测到 CMV DNA 的患者中，在移植后 24 周时有临床显著 CMV 感染的患者比例。在第 24 周时停止试验或终点数据缺失的患者被推断为发生了主要终点事件。患者在移植后 48 周时进行随访。
从 2014 年 6 月至 2016 年 3 月，共有 565 名患者接受了随机分组，并在移植后中位数为 9 天开始接受来特莫韦或安慰剂。在随机分组时未检测到 CMV DNA 的 495 名患者中，来特莫韦组比安慰剂组在移植后 24 周时有临床显著 CMV 感染或被推断为发生主要终点事件的患者更少（325 名患者中有 122 名[37.5%] vs. 170 名患者中有 103 名[60.6%]，P<0.001）。两组患者的不良事件总体发生率和严重程度相似。来特莫韦组的呕吐发生率为 18.5%，安慰剂组为 13.5%；水肿分别为 14.5%和 9.4%；心房颤动或扑动分别为 4.6%和 1.0%。来特莫韦组和安慰剂组的骨髓毒性和肾毒性事件发生率相似。移植后 48 周的全因死亡率在来特莫韦组为 20.9%，安慰剂组为 25.5%。
来特莫韦预防治疗可显著降低临床显著 CMV 感染的风险。来特莫韦的不良事件主要为低级别。（由默克公司资助；临床试验.gov 编号，NCT02137772；EudraCT 编号，2013-003831-31）。
