Nash Richard A, Bowen James D, McSweeney Peter A, Pavletic Steven Z, Maravilla Kenneth R, Park Man-soo, Storek Jan, Sullivan Keith M, Al-Omaishi Jinan, Corboy John R, DiPersio John, Georges George E, Gooley Theodore A, Holmberg Leona A, LeMaistre C Fred, Ryan Kate, Openshaw Harry, Sunderhaus Julie, Storb Rainer, Zunt Joseph, Kraft George H
Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, D1-100, PO Box 19024, Seattle, WA 98109-1024, USA.
Blood. 2003 Oct 1;102(7):2364-72. doi: 10.1182/blood-2002-12-3908. Epub 2003 May 22.
There were 26 patients enrolled in a pilot study of high-dose immunosuppressive therapy (HDIT) for severe multiple sclerosis (MS). Median baseline expanded disability status scale (EDSS) was 7.0 (range, 5.0-8.0). HDIT consisted of total body irradiation, cyclophosphamide, and antithymocyte globulin (ATG) and was followed by transplantation of autologous, granulocyte colony-stimulating factor (G-CSF)-mobilized CD34-selected stem cells. Regimen-related toxicities were mild. Because of bladder dysfunction, there were 8 infectious events of the lower urinary tract. One patient died from Epstein-Barr virus (EBV)-related posttransplantation lymphoproliferative disorder (PTLD) associated with a change from horse-derived to rabbit-derived ATG in the HDIT regimen. An engraftment syndrome characterized by noninfectious fever with or without rash developed in 13 of the first 18 patients and was associated in some cases with transient worsening of neurologic symptoms. There were 2 significant adverse neurologic events that occurred, including a flare of MS during mobilization and an episode of irreversible neurologic deterioration after HDIT associated with fever. With a median follow-up of 24 (range, 3-36) months, the Kaplan-Meier estimate of progression (>/= 1.0 point EDSS) at 3 years was 27%. Of 12 patients who had oligoclonal bands in the cerebrospinal fluid at baseline, 9 had persistence after HDIT. After HDIT, 4 patients developed new enhancing lesions on magnetic resonance imaging of the brain. The estimate of survival at 3 years was 91%. Important clinical issues in the use of HDIT and stem cell transplantation for MS were identified; however, modifications of the initial approaches appear to reduce treatment risks. This was a heterogeneous high-risk group, and a phase 3 study is planned to fully assess efficacy.
有26名患者参与了一项针对严重多发性硬化症（MS）的大剂量免疫抑制疗法（HDIT）的初步研究。基线扩展残疾状态量表（EDSS）中位数为7.0（范围为5.0 - 8.0）。HDIT包括全身照射、环磷酰胺和抗胸腺细胞球蛋白（ATG），随后进行自体、粒细胞集落刺激因子（G-CSF）动员的CD34选择干细胞移植。与治疗方案相关的毒性较轻。由于膀胱功能障碍，发生了8例下尿路感染事件。1例患者死于与HDIT方案中从马源ATG改为兔源ATG相关的爱泼斯坦 - 巴尔病毒（EBV）相关移植后淋巴细胞增生性疾病（PTLD）。在前18例患者中有13例出现了以非感染性发热伴或不伴皮疹为特征的植入综合征，在某些情况下与神经症状的短暂恶化有关。发生了2起严重的不良神经事件，包括动员期间MS病情加重以及HDIT后与发热相关的不可逆神经功能恶化发作。中位随访24（范围为3 - 36）个月，3年时根据Kaplan-Meier估计的病情进展（EDSS增加≥1.0分）为27%。基线时脑脊液中有寡克隆带的12例患者中，9例在HDIT后仍持续存在。HDIT后，4例患者脑部磁共振成像出现新的强化病灶。3年生存率估计为91%。确定了在MS治疗中使用HDIT和干细胞移植的重要临床问题；然而，对初始方法的修改似乎降低了治疗风险。这是一个异质性高风险组，计划进行3期研究以全面评估疗效。
