A phase III randomized crossover trial of plerixafor versus G-CSF for treatment of WHIM syndrome.
A phase III randomized crossover trial of plerixafor versus G-CSF for treatment of WHIM syndrome.
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DOI：
10.1172/jci164918
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发表时间：
2023-10-02
影响因子：
15.9
通讯作者：
Murphy, Philip M.
中科院分区：
文献类型：
--
作者：
Mcdermott, David H.;Velez, Daniel;Cho, Elena;Cowen, Edward W.;Digiovanna, John J.;Pastrana, Diana V.;Buck, Christopher B.;Calvo, Katherine R.;Gardner, Pamela J.;Rosenzweig, Sergio D.;Stratton, Pamela;Merideth, Melissa A.;Kim, H. Jeffrey;Brewer, Carmen;Katz, James D.;Kuhns, Douglas B.;Malech, Harry L.;Follmann, Dean;Fay, Michael P.;Murphy, Philip M.
疣、低丙种球蛋白血症、感染和骨髓增生异常综合征（WHIM）是由杂合性功能获得性CXCR 4突变引起的原发性免疫缺陷疾病。骨髓性贫血是一种中性粒细胞滞留在骨髓中引起的中性粒细胞减少症，WHIM综合征与淋巴细胞减少和单核细胞减少有关。CXCR 4拮抗剂普乐沙福可动员白细胞进入血液;然而，其在WHIM综合征中的安全性和疗效尚不明确。在这项由药物启动的、单中心、四盲、III期交叉试验中，我们以意向治疗方式比较了19例WHIM患者的感染严重程度总评分（TISS）作为主要终点，这些患者均接受了12个月的普乐沙福治疗和12个月的粒细胞CSF（G-CSF，重度先天性中性粒细胞减少症的标准治疗）治疗。每例患者的治疗顺序随机化。对于TISS，普乐沙福不优于G-CSF（P = 0.54）。在探索性终点中，普乐沙福在维持中性粒细胞计数大于500个细胞/μL方面非劣效于G-CSF（P = 0.023），在维持淋巴细胞计数大于1，000个细胞/μL方面上级优于G-CSF（P < 0.0001）。在普乐沙福治疗期间，7例基线时有较大疣负担的患者中有5例患者的大疣面积子集完全消退。普乐沙福组发生一过性皮疹，G-CSF组骨痛更常见。在药物偏好、生活质量、药物失效或严重不良事件的发生率方面没有显著差异。在WHIM患者中，普乐沙福在TISS（主要终点）方面并不上级优于G-CSF。连同疣消退和血液学改善，感染严重程度结果支持继续研究普乐沙福作为WHIM综合征的潜在治疗。Clinicaltrials.gov NCT02231879。这项研究由国家过敏和传染病研究所校内研究部资助。
Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a primary immunodeficiency disorder caused by heterozygous gain-of-function CXCR4 mutations. Myelokathexis is a kind of neutropenia caused by neutrophil retention in bone marrow and in WHIM syndrome is associated with lymphopenia and monocytopenia. The CXCR4 antagonist plerixafor mobilizes leukocytes to the blood; however, its safety and efficacy in WHIM syndrome are undefined. In this investigator-initiated, single-center, quadruple-masked phase III crossover trial, we compared the total infection severity score (TISS) as the primary endpoint in an intent-to-treat manner in 19 patients with WHIM who each received 12 months treatment with plerixafor and 12 months treatment with granulocyte CSF (G-CSF, the standard of care for severe congenital neutropenia). The treatment order was randomized for each patient. Plerixafor was nonsuperior to G-CSF for TISS (P = 0.54). In exploratory endpoints, plerixafor was noninferior to G-CSF for maintaining neutrophil counts of more than 500 cells/μL (P = 0.023) and was superior to G-CSF for maintaining lymphocyte counts above 1,000 cells/μL (P < 0.0001). Complete regression of a subset of large wart areas occurred on plerixafor in 5 of 7 patients with major wart burdens at baseline. Transient rash occurred on plerixafor, and bone pain was more common on G-CSF. There were no significant differences in drug preference or quality of life or the incidence of drug failure or serious adverse events. Plerixafor was not superior to G-CSF in patients with WHIM for TISS, the primary endpoint. Together with wart regression and hematologic improvement, the infection severity results support continued study of plerixafor as a potential treatment for WHIM syndrome. Clinicaltrials.gov NCT02231879. This study was funded by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases.