Randomized, placebo-controlled, double-blind study of a cytomegalovirus-specific monoclonal antibody (MSL-109) for prevention of cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation
Randomized, placebo-controlled, double-blind study of a cytomegalovirus-specific monoclonal antibody (MSL-109) for prevention of cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation
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DOI：
10.1016/s1083-8791(01)80005-7
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发表时间：
2001-01-01
影响因子：
4.3
通讯作者：
Zaia, JA
中科院分区：
文献类型：
--
作者：
Boeckh, M;Bowden, RA;Zaia, JA
MSL-109是一种针对巨细胞病毒（CMV）糖蛋白H的单克隆抗体，具有高中和能力。在一项前瞻性、随机、双盲研究中，移植前供体和/或受体CMV血液学阳性的异体造血干细胞移植（HSCT）受者从移植后第1天至第84天，每2周静脉注射60mg /kg MSL-109 （n = 59）、15mg /kg MSL-109 （n = 60）或安慰剂（n = 60）。每周检测CMV pp65抗原血症、血浆CMV- dna载量和培养病毒血症。主要终点是任何水平的pp65抗原血症和/或给予更昔洛韦的病毒血症。60 mg组（pp65抗原血症，47%；病毒血症，15%）、15 mg组（52%;23%）和安慰剂组（45%;17%）患者的CMV pp65抗原血症或病毒血症无统计学差异。三组患者pp65抗原血症的最高水平、更昔洛韦开始治疗后pp65抗原血症清除时间、巨细胞病毒病、侵袭性细菌和真菌感染、中性粒细胞和血小板植入时间、急性移植物抗宿主病、住院天数和总生存率均无差异。然而，对cmv血清阴性受者与血清阳性供者（D+/R-）的亚组分析显示，MSL-109受者在第100天的存活率有短暂提高（死亡率：60 mg组，1/13；15 mg组，1/12；安慰剂组，6/10 [60 mg组与安慰剂组相比P = 0.02； 15 mg组与安慰剂组相比P = 0.08]）。随访结束时，差异不再具有统计学意义。D+/R-患者生存率的提高不能归因于巨细胞病毒疾病的减少；然而，在该亚组中，MSL-109与血小板植入改善和III至IV级急性移植物抗宿主病较少相关。在cmv血清阳性的MSL-109受体（D+/R+和D-/R+）的亚组分析中，与安慰剂组相比，总死亡率增加（60毫克组与安慰剂组相比P = 0.12, 15毫克组与安慰剂组相比P = 0.05，联合剂量水平与安慰剂相比P = 0.04）。MSL-109耐受性良好，未观察到对该药物的免疫反应。因此，MSL-109是安全的，但不能减少同种异体造血移植受者的巨细胞病毒感染。CMV D+/R-患者移植后早期的短暂生存优势以及对血清阳性患者生存的负面影响尚不清楚。因此，没有证据表明MSL-109对cmv血清阳性的HSCT接受者有益。
MSL-109 is a monoclonal antibody specific to the cytomegalovirus (CMV) glycoprotein H with high neutralizing capacity. In a prospective, randomized, double-blind study allogeneic hematopoietic stem cell transplantation (HSCT) recipients with positive donor and/or recipient serology for CMV before transplantation received either 60 mg/kg MSL-109 (n = 59), 15 mg/kg MSL-109 (n = 60), or placebo (n = 60) intravenously every 2 weeks from day -1 until day 84 after transplantation. CMV pp65 antigenemia, CMV-DNA load in plasma, and viremia by culture were tested weekly. Primary end points were development of pp65 antigenemia at any level and/or viremia for which ganciclovir was given. There was no statistically significant difference in CMV pp65 antigenemia or viremia among patients in the 60-mg group (pp65 antigenemia, 47%; viremia, 15%), the 15-mg group (52%; 23%), and the placebo group (45%; 17%). There was also no difference in maximum levels of pp65 antigenemia, time to clearance of pp65 antigenemia after start of ganciclovir, CMV disease, invasive bacterial and fungal infections, time to neutrophil and platelet engraftment, acute graft-versus-host disease, days of hospitalization, and overall survival rate among the 3 groups. However, a subgroup analysis of CMV-seronegative recipients with a seropositive donor (D+/R-) showed a transiently improved survival rate by day 100 in MSL-109 recipients (mortality: 60-mg group, 1/13; 15-mg group, 1/12; placebo group, 6/10 [P = .02 for 60-mg versus placebo groups; P = .08 for 15-mg versus placebo groups]); by the end of follow-up, the difference was no longer statistically significant. The improved survival rate in D+/R- patients could not be attributed to a reduction in CMV disease; however, MSL-109 was associated with improved platelet engraftment and less grade III to IV acute graft-versus-host disease in this subgroup. In a subgroup analysis of CMV-seropositive recipients of MSL-109 (D+/R+ and D-/R+), overall mortality was increased compared to that of the placebo group (P = .12 for the 60-mg versus placebo groups, P = .05 for the 15-mg versus placebo groups, and P = .04 for the dose levels combined versus placebo). MSL-109 was well tolerated and no immune response to the drug was observed. Thus, MSL-109 was safe but did not reduce CMV infection in allogeneic HSCT recipients. The transient survival advantage seen early after transplantation in CMV D+/R- patients and the negative effect on survival in seropositive patients remain unexplained. Thus, there is no evidence that MSL-109 is beneficial in CMV-seropositive HSCT recipients.