A phase 1 clinical trial of long-term, low-dose treatment of WHIM syndrome with the CXCR4 antagonist plerixafor
A phase 1 clinical trial of long-term, low-dose treatment of WHIM syndrome with the CXCR4 antagonist plerixafor
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DOI：
10.1182/blood-2013-09-527226
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发表时间：
2014-04-10
期刊：
影响因子：
20.3
通讯作者：
Murphy, Philip M.
中科院分区：
文献类型：
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作者：
McDermott, David H.;Liu, Qian;Murphy, Philip M.
疣、低丙种球蛋白血症、感染和骨髓病变(WHIM)综合征是一种罕见的免疫缺陷疾病，由G蛋白偶联趋化因子受体CXCR4的功能获得突变引起。CXCR4拮抗剂plerixafor已被美国食品和药物管理局(FDA)批准用于癌症干细胞动员，并以0.24 mg/kg的剂量应用于该适应症，已在短期(1至2周)第一阶段剂量递增研究中被证明，以纠正突发综合征中的中性粒细胞减少症和其他细胞减少症。然而，缺乏长期安全性和长期血液学和临床疗效数据。在这里，我们报告了普利沙福治疗任何疾病的首次长期临床试验的结果，在该试验中，3名患有突发奇想综合征的成年人每天两次皮下注射0.01至0.02毫克/公斤(FDA批准剂量的4%至8%)，为期6个月。在整个试验过程中，所有患者的循环白细胞持续增加，这与联合应用咪喹莫特减少感染和改善尖锐湿疣有关；然而，免疫球蛋白水平和特异性疫苗反应并未完全恢复。未观察到与药物相关的副作用。这些结果为长期、小剂量普利沙福治疗心血来潮综合征的安全性和临床疗效提供了初步证据，并支持其作为该疾病基于机制的治疗的继续研究。本研究的ClinicalTrials.gov标识符为NCT00967785。
Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare immunodeficiency disorder caused by gain-of-function mutations in the G protein-coupled chemokine receptor CXCR4. The CXCR4 antagonist plerixafor, which is approved by the US Food and Drug Administration (FDA) for stem cell mobilization in cancer and administered for that indication at 0.24 mg/kg, has been shown in short-term (1- to 2-week) phase 1 dose-escalation studies to correct neutropenia and other cytopenias in WHIM syndrome. However, long-term safety and long-termhematologic and clinical efficacy data are lacking. Here we report results from the first long-term clinical trial of plerixafor in any disease, in which 3 adults with WHIM syndrome self-injected 0.01 to 0.02 mg/kg (4% to 8% of the FDA-approved dose) subcutaneously twice daily for 6 months. Circulating leukocytes were durably increased throughout the trial in all patients, and this was associated with fewer infections and improvement in warts in combination with imiquimod; however, immunoglobulin levels and specific vaccine responses were not fully restored. No drug-associated side effects were observed. These results provide preliminary evidence for the safety and clinical efficacy of long-term, low-dose plerixafor in WHIM syndrome and support its continued study as mechanism-based therapy in this disease. The ClinicalTrials.gov identifier for this study is NCT00967785.