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Abstract：
BACKGROUNDWarts, 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.METHODSIn 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.RESULTSPlerixafor 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.CONCLUSIONPlerixafor 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.TRIAL REGISTRATIONClinicaltrials.gov NCT02231879.FUNDINGThis study was funded by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases.
摘要：
背景：疣，低丙种球蛋白血症，感染和髓鞘综合征(WHIM)是一种由CXCR4杂合性功能获得突变引起的原发性免疫缺陷性疾病。髓核变性是由骨髓中的中性粒细胞保留引起的中性粒细胞减少症，并与淋巴细胞减少和单核细胞减少症有关。CXCR4拮抗剂plerixafor将白细胞动员到血液中；然而，WHIM综合征的安全性和有效性尚不明确.
方法：在这个研究者发起的，单中心,随机化，四重掩蔽第三阶段交叉试验，我们比较了19例接受plerixafor治疗12个月的WHIM患者与接受G-CSF治疗12个月的患者的总感染严重程度评分（TISS）作为主要终点，严重先天性中性粒细胞减少症的标准治疗.
结果：Plerixafor在TISS中不优于G-CSF（p=0.65）。在探索性终点中，plerixafor在维持中性粒细胞计数>500个细胞/微升方面不劣于G-CSF（p=0.023），在维持淋巴细胞计数>1000个细胞/微升方面优于G-CSF（p<0.0001）。基线时，在7例主要疣重患者中，有5例在plerixafor上发生了一部分大疣区域的完全消退。暂时性皮疹发生在plerixafor，骨痛更常见于G-CSF。药物偏好或生活质量无显著差异,或药物失效或严重不良事件的发生率。
结论：在WHIM患者中，Plerixafor并不优于G-CSF，主端点。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plerixafor作为WHIM综合征的潜在治疗方法.(由校内研究部资助，国家过敏和传染病研究所；clinicaltrials.gov注册号，NCT02231879).
方法：在这个研究者发起的，单中心,随机化，四重掩蔽第三阶段交叉试验，我们比较了19例接受plerixafor治疗12个月的WHIM患者与接受G-CSF治疗12个月的患者的总感染严重程度评分（TISS）作为主要终点，严重先天性中性粒细胞减少症的标准治疗.
结果：Plerixafor在TISS中不优于G-CSF（p=0.65）。在探索性终点中，plerixafor在维持中性粒细胞计数>500个细胞/微升方面不劣于G-CSF（p=0.023），在维持淋巴细胞计数>1000个细胞/微升方面优于G-CSF（p<0.0001）。基线时，在7例主要疣重患者中，有5例在plerixafor上发生了一部分大疣区域的完全消退。暂时性皮疹发生在plerixafor，骨痛更常见于G-CSF。药物偏好或生活质量无显著差异,或药物失效或严重不良事件的发生率。
结论：在WHIM患者中，Plerixafor并不优于G-CSF，主端点。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plerixafor作为WHIM综合征的潜在治疗方法.(由校内研究部资助，国家过敏和传染病研究所；clinicaltrials.gov注册号，NCT02231879).
