Reduction of disease activity and disability with high-dose cyclophosphamide in patients with aggressive multiple sclerosis
Reduction of disease activity and disability with high-dose cyclophosphamide in patients with aggressive multiple sclerosis
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DOI：
10.1001/archneurol.65.8.noc80042
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发表时间：
2008-08-01
影响因子：
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通讯作者：
Kerr, Douglas A.
中科院分区：
文献类型：
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作者：
Krishnan, Chitra;Kaplin, Adam I.;Kerr, Douglas A.
目的：探讨大剂量环磷酰胺（HiCy）不进行骨髓移植治疗侵袭性多发性硬化（MS）患者的安全性和有效性。设计：一项在接受HiCy免疫清除方案的侵袭性复发缓解型多发性硬化症（RRMS）患者中进行的2年开放标签试验（50 mg/kg/d，连续4天），除非疾病活动再次出现，需要补救治疗，否则不进行后续免疫调节治疗。患者：总共筛选了21名患有RRMS的患者的合格性，并且9名患者入选试验。要求患者在2次治疗前磁共振成像扫描中有2个或更多钆增强病变，在HiCy治疗前12个月内至少有1次临床加重，或在前一年扩展残疾状态量表（EDSS）上持续增加1.0分或更高。主要结果测量：研究的主要结果是HiCy在RRMS患者中的安全性和耐受性。次要结局指标包括磁共振图像上钆增强病变的变化和残疾措施（EDSS和多发性硬化症功能复合物）的变化。结果：9例患者接受了治疗，并随访了平均23个月。8例患者常规治疗失败，1例未经治疗。入组时的中位年龄为29岁（范围：20-47岁）。所有患者均出现一过性全血细胞减少或接近全血细胞减少，随后在粒细胞集落刺激因子刺激下，造血功能在10 - 17天内恢复。未发生死亡或非预期严重不良事件。随访时残疾（EDSS）有统计学显著性降低（平均[SD]降低，2.11[1.97]; 39.4%; P = .02）。随访时，2次治疗前扫描的钆增强病变的平均（SD）数量分别为6.5（2.1）和1.2（2.3）（减少81.4%; P = 0.01）。两名患者需要抢救治疗与其他免疫调节疗法在研究期间，由于MS acquisitions.Conclusion：治疗与HiCy是安全的，耐受性良好，在我们的MS患者。患者经历了显着减少疾病活动和残疾HiCy治疗后。环磷酰胺免疫清除方案治疗侵袭性MS值得进一步研究，并可能成为骨髓移植的替代方案。
Objective: To explore the safety and effectiveness of high-dose cyclophosphamide (HiCy) without bone marrow transplantation in patients with aggressive multiple sclerosis (MS).Design: A 2-year open-label trial of patients with aggressive relapsing-remitting multiple sclerosis (RRMS) given an immunoablative regimen of HiCy ( 50 mg/kg/d for 4 consecutive days) with no subsequent immunomodulatory therapy unless disease activity reappeared that required rescue therapy.Setting: The Johns Hopkins University Multiple Sclerosis Center, Baltimore, Maryland.Patients: A total of 21 patients with RRMS were screened for eligibility and 9 patients were enrolled in the trial. Patients were required to have 2 or more gadolinium-enhancing lesions on each of 2 pretreatment magnetic resonance imaging scans, at least 1 clinical exacerbation in the 12 months prior to HiCy treatment, or a sustained increase of 1.0 point or higher on the Expanded Disability Status Scale (EDSS) in the preceding year.Main Outcome Measures: The primary outcome of the study was the safety and tolerability of HiCy in patients with RRMS. Secondary outcome measures included a change in gadolinium-enhancing lesions on magnetic resonance images and a change in disability measures (EDSS and Multiple Sclerosis Functional Composite).Results: Nine patients were treated and followed up for a mean period of 23 months. Eight patients had failed conventional therapy and 1 was treatment naive. The median age at time of entry was 29 years (range, 20-47 years). All patients developed transient total or near-total pancytopenia as expected, followed by hematopoietic recovery in 10 to 17 days, stimulated by granulocyte colony-stimulating factor. There were no deaths or unexpected serious adverse events. There was a statistically significant reduction in disability (EDSS) at follow-up (mean [SD] decrease, 2.11[1.97]; 39.4%; P = .02). The mean(SD) number of gadolinium-enhancing lesions on the 2 pretreatment scans were 6.5(2.1) and 1.2(2.3) at follow-up (81.4% reduction; P = .01). Two patients required rescue treatment with other immunomodulatory therapies during the study owing to MS exacerbations.Conclusion: Treatment with HiCy was safe and well tolerated in our patients with MS. Patients experienced a pronounced reduction in disease activity and disability after HiCy treatment. This immunoablative regimen of cyclophosphamide for patients with aggressive MS is worthy of further study and may be an alternative to bone marrow transplantation.