PDF(Pubmed)
Abstract：
UNASSIGNED: We investigated efficacy and safety of mavorixafor, an oral CXCR4 antagonist, in participants with warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, a rare immunodeficiency caused by CXCR4 gain-of-function variants. This randomized (1:1), double-blind, placebo-controlled, phase 3 trial enrolled participants aged ≥12 years with WHIM syndrome and absolute neutrophil count (ANC) ≤0.4 × 103/μL. Participants received once-daily mavorixafor or placebo for 52 weeks. The primary end point was time (hours) above ANC threshold ≥0.5 × 103/μL (TATANC; over 24 hours). Secondary end points included TAT absolute lymphocyte count ≥1.0 × 103/μL (TATALC; over 24 hours); absolute changes in white blood cell (WBC), ANC, and absolute lymphocyte count (ALC) from baseline; annualized infection rate; infection duration; and total infection score (combined infection number/severity). In 31 participants (mavorixafor, n = 14; placebo, n = 17), mavorixafor least squares (LS) mean TATANC was 15.0 hours and 2.8 hours for placebo (P < .001). Mavorixafor LS mean TATALC was 15.8 hours and 4.6 hours for placebo (P < .001). Annualized infection rates were 60% lower with mavorixafor vs placebo (LS mean 1.7 vs 4.2; nominal P = .007), and total infection scores were 40% lower (7.4 [95% confidence interval [CI], 1.6-13.2] vs 12.3 [95% CI, 7.2-17.3]). Treatment with mavorixafor reduced infection frequency, severity, duration, and antibiotic use. No discontinuations occurred due to treatment-emergent adverse events (TEAEs); no related serious TEAEs were observed. Overall, mavorixafor treatment demonstrated significant increases in LS mean TATANC and TATALC, reduced infection frequency, severity/duration, and was well tolerated. The trial was registered at www.clinicaltrials.gov as #NCT03995108.
摘要：
我们调查了mavorixafor的疗效和安全性，用于疣患者的口服CXCR4拮抗剂，低丙种球蛋白血症，感染,和髓核（WHIM）综合征，由CXCR4功能获得变体引起的罕见免疫缺陷。这个随机（1：1），双盲,安慰剂对照,3期试验纳入年龄≥12岁且中性粒细胞绝对计数(ANC)≤400/μL的WHIM综合征参与者.参与者每天接受一次mavorixafor或安慰剂，持续52周。主要终点是超过ANC阈值≥500/μL的时间（小时）（TATANC；超过24小时）。次要终点包括TAT绝对淋巴细胞计数≥1000/μL（TATALC;定义类似于TATANC）;白细胞（WBC）的绝对变化，ANC,和ALC从基线;年度感染率;感染持续时间和总感染评分（合并感染数量/严重程度）。在31名参与者中(mavorixafor，n=14；安慰剂，n=17),最小二乘(LS)平均TATANC为15.0小时，安慰剂2.8小时（P<0.001）。MavorixaforLS平均TATALC为15.8小时，安慰剂4.6小时（P<0.001）。绝对白细胞较高，ANC,在评估的每个时间点，使用mavorixafor比安慰剂观察到ALC水平。与安慰剂相比，mavorixafor的年化感染率降低了60％（LS均值为1.7比4.2；名义P=0.007），总感染评分降低了40％（7.4[95％CI，1.6-13.2]比12.3[95％CI，7.2-17.3]）。用mavorixa治疗减少感染频率，严重程度,持续时间,抗生素的使用。没有因治疗引起的不良事件（TEAE）而停药；没有观察到相关的严重TEAE。总的来说,mavorixafor治疗的参与者显示LS平均TATANC和TATALC显着增加，减少感染频率，严重性/持续时间。Mavorixafor在WHIM综合征患者中耐受性良好。试验在ClinicalTrials.govNCT03995108注册。
