Letermovir for Cytomegalovirus Prophylaxis in Hematopoietic-Cell Transplantation
Letermovir for Cytomegalovirus Prophylaxis in Hematopoietic-Cell Transplantation
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DOI：
10.1056/nejmoa1309533
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发表时间：
2014-05-08
影响因子：
158.5
通讯作者：
Ehninger, Gerhard
中科院分区：
文献类型：
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作者：
Chemaly, Roy F.;Ullmann, Andrew J.;Ehninger, Gerhard
背景巨细胞病毒（CMV）感染是异基因造血细胞移植后患者发病和死亡的主要原因。可用的治疗受到限制的临床显着的毒性作用和drugresistance.MethodsIn这个阶段2 study，我们评估的效果letermovir（也称为AIC246），一种新的抗CMV药物与一种新的作用机制，对发病率和时间的预防失败CMV血清阳性受体的异基因造血细胞移植从匹配的相关或无关的捐助者。从2010年3月到2011年10月，我们根据双盲设计将131名移植受者以3：1的比例随机分配到三个连续的研究队列。患者在移植后接受口服莱特莫韦（剂量为每天60，120或240 mg，或匹配的安慰剂）12周。主要终点是全因预防失败，定义为由于CMV抗原或DNA检测、终末器官疾病或任何其他原因而停用研究药物。患者每周进行监测CMV infection.ResultsThe减少全因预防失败的发生率是剂量依赖性的。与安慰剂相比，莱特莫韦预防失败的发生率为48%，每日剂量为60 mg的莱特莫韦为64%（P = 0.32），120 mg剂量为32%（P = 0.01），240 mg剂量为29%（P = 0.007）。预防失败的Kaplan-Meier至发作时间曲线显示，在240 mg/天剂量的莱特莫韦与安慰剂的比较中存在显著差异（P = 0.002）。莱特莫韦的安全性与安慰剂相似，没有血液学毒性或肾毒性的迹象。ConclusionsLetermovir，与安慰剂相比，是有效的异基因造血细胞移植的受者CMV感染的发病率降低。最高剂量（240 mg/天）具有最大的抗CMV活性，具有可接受的安全性特征。（由AiCuris资助; www.example.com编号，NCT 01063829。莱特莫韦是一种抗病毒药物，具有抗CMV活性。在接受异基因造血细胞移植的患者中，莱特莫韦（每日240 mg）预防失败率为29%，而安慰剂为64%。莱特莫韦和安慰剂的毒性相似。巨细胞病毒（CMV）疾病是由CMV通过再激活或新感染复制引起的，是免疫功能低下患者的一种严重的、可能危及生命的疾病。对于异基因造血细胞移植的接受者尤其如此（1），（2）;这些患者中有50 - 60%发生CMV病毒血症，并可能进展为CMV疾病。(3)治疗CMV感染或疾病的标准护理通常是静脉内更昔洛韦或其口服前药缬更昔洛韦，或者静脉内膦甲酸或西多福韦。(4)虽然有效，但这些疗法与临床显著的药物特异性效应相关，包括骨髓抑制（更昔洛韦，缬更昔洛韦和西多福韦的中性粒细胞减少症或血小板减少症）和肾功能衰竭。
BackgroundCytomegalovirus (CMV) infection is a leading cause of illness and death in patients who have undergone allogeneic hematopoietic-cell transplantation. Available treatments are restricted by clinically significant toxic effects and drug resistance.MethodsIn this phase 2 study, we evaluated the effect of letermovir (also known as AIC246), a new anti-CMV drug with a novel mechanism of action, on the incidence and time to onset of prophylaxis failure in CMV-seropositive recipients of allogeneic hematopoietic-cell transplants from matched related or unrelated donors. From March 2010 through October 2011, we randomly assigned 131 transplant recipients in a 3:1 ratio to three sequential study cohorts according to a double-blind design. Patients received oral letermovir (at a dose of 60, 120, or 240 mg per day, or matching placebo) for 12 weeks after engraftment. The primary end point was all-cause prophylaxis failure, defined as discontinuation of the study drug because of CMV antigen or DNA detection, end-organ disease, or any other cause. Patients underwent weekly surveillance for CMV infection.ResultsThe reduction in the incidence of all-cause prophylaxis failure was dose-dependent. The incidence of prophylaxis failure with letermovir, as compared with placebo, was 48% versus 64% at a daily letermovir dose of 60 mg (P=0.32), 32% at a dose of 120 mg (P=0.01), and 29% at a dose of 240 mg (P=0.007). Kaplan-Meier time-to-onset profiles for prophylaxis failure showed a significant difference in the comparison of letermovir at a dose of 240 mg per day with placebo (P=0.002). The safety profile of letermovir was similar to placebo, with no indication of hematologic toxicity or nephrotoxicity.ConclusionsLetermovir, as compared with placebo, was effective in reducing the incidence of CMV infection in recipients of allogeneic hematopoietic-cell transplants. The highest dose (240 mg per day) had the greatest anti-CMV activity, with an acceptable safety profile. (Funded by AiCuris; ClinicalTrials.gov number, NCT01063829.)Letermovir is an antiviral with activity against CMV. In patients undergoing allogeneic hematopoietic-cell transplantation, the rate of prophylaxis failure with letermovir (240 mg per day) was 29%, as compared with 64% with placebo. Toxicity was similar for letermovir and placebo. Cytomegalovirus (CMV) disease that results from CMV replication through reactivation or new infection is a serious, potentially life-threatening condition in immunocompromised patients. This is especially true for recipients of allogeneic hematopoietic-cell transplants(1),(2); CMV viremia occurs in 50 to 60% of these patients and may progress to CMV disease.(3) The standard of care for treatment of CMV infection or disease has typically been intravenous ganciclovir or its oral prodrug, valganciclovir, or alternatively, intravenous foscarnet or cidofovir.(4) Although efficacious, these therapies are associated with clinically significant drug-specific effects, including myelosuppression (neutropenia or thrombocytopenia with ganciclovir, valganciclovir, and cidofovir) and renal ...