Division of Immunotherapy, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
JAMA. 2019 Jan 15;321(2):165-174. doi: 10.1001/jama.2018.18743.
Hematopoietic stem cell transplantation (HSCT) represents a potentially useful approach to slow or prevent progressive disability in relapsing-remitting multiple sclerosis (MS).
To compare the effect of nonmyeloablative HSCT vs disease-modifying therapy (DMT) on disease progression.
DESIGN, SETTING, AND PARTICIPANTS: Between September 20, 2005, and July 7, 2016, a total of 110 patients with relapsing-remitting MS, at least 2 relapses while receiving DMT in the prior year, and an Expanded Disability Status Scale (EDSS; score range, 0-10 [10 = worst neurologic disability]) score of 2.0 to 6.0 were randomized at 4 US, European, and South American centers. Final follow-up occurred in January 2018 and database lock in February 2018.
Patients were randomized to receive HSCT along with cyclophosphamide (200 mg/kg) and antithymocyte globulin (6 mg/kg) (n = 55) or DMT of higher efficacy or a different class than DMT taken during the previous year (n = 55).
The primary end point was disease progression, defined as an EDSS score increase after at least 1 year of 1.0 point or more (minimal clinically important difference, 0.5) on 2 evaluations 6 months apart, with differences in time to progression estimated as hazard ratios.
Among 110 randomized patients (73 [66%] women; mean age, 36 [SD, 8.6] years), 103 remained in the trial, with 98 evaluated at 1 year and 23 evaluated yearly for 5 years (median follow-up, 2 years; mean, 2.8 years). Disease progression occurred in 3 patients in the HSCT group and 34 patients in the DMT group. Median time to progression could not be calculated in the HSCT group because of too few events; it was 24 months (interquartile range, 18-48 months) in the DMT group (hazard ratio, 0.07; 95% CI, 0.02-0.24; P < .001). During the first year, mean EDSS scores decreased (improved) from 3.38 to 2.36 in the HSCT group and increased (worsened) from 3.31 to 3.98 in the DMT group (between-group mean difference, -1.7; 95% CI, -2.03 to -1.29; P < .001). There were no deaths and no patients who received HSCT developed nonhematopoietic grade 4 toxicities (such as myocardial infarction, sepsis, or other disabling or potential life-threatening events).
In this preliminary study of patients with relapsing-remitting MS, nonmyeloablative HSCT, compared with DMT, resulted in prolonged time to disease progression. Further research is needed to replicate these findings and to assess long-term outcomes and safety.
ClinicalTrials.gov Identifier: NCT00273364.
重要性：造血干细胞移植（HSCT）代表了一种减缓或预防复发缓解型多发性硬化（MS）进行性残疾的潜在有效方法。
目的：比较非清髓性 HSCT 与疾病修正疗法（DMT）对疾病进展的影响。
设计、地点和参与者：2005 年 9 月 20 日至 2016 年 7 月 7 日期间，共有 110 名复发缓解型 MS 患者参与了本研究，这些患者在过去一年中至少有 2 次复发，扩展残疾状况量表（EDSS；评分范围，0-10 [10 表示最严重的神经残疾]）评分在 2.0 至 6.0 之间，他们在 4 个美国、欧洲和南美中心被随机分组。最终随访时间为 2018 年 1 月，数据库锁定时间为 2018 年 2 月。
干预措施：患者被随机分为接受 HSCT 联合环磷酰胺（200mg/kg）和抗胸腺细胞球蛋白（6mg/kg）（n=55）或前一年接受的疗效更高或类别不同的 DMT（n=55）。
主要终点和测量指标：主要终点是疾病进展，定义为在至少 1 年的 2 次评估中，EDSS 评分增加至少 1.0 点（最小临床重要差异，0.5），差异在进展时间估计为风险比。
结果：在 110 名随机患者（73 名[66%]女性；平均年龄，36[SD，8.6]岁）中，有 103 名患者继续参与试验，98 名患者在 1 年后接受评估，23 名患者每年评估 5 年（中位随访时间，2 年；平均，2.8 年）。在 HSCT 组中有 3 名患者和 DMT 组中有 34 名患者发生疾病进展。由于事件太少，无法计算 HSCT 组的中位进展时间；DMT 组为 24 个月（18-48 个月）（风险比，0.07；95%CI，0.02-0.24；P<0.001）。在第一年，HSCT 组的平均 EDSS 评分从 3.38 降至 2.36，DMT 组从 3.31 升至 3.98（组间平均差异，-1.7；95%CI，-2.03 至-1.29；P<0.001）。没有死亡，也没有接受 HSCT 的患者发生非造血性 4 级毒性（如心肌梗死、脓毒症或其他致残或潜在威胁生命的事件）。
结论和相关性：在这项对复发缓解型 MS 患者的初步研究中，与 DMT 相比，非清髓性 HSCT 可延长疾病进展时间。需要进一步研究来复制这些发现，并评估长期结果和安全性。
试验注册：ClinicalTrials.gov 标识符：NCT00273364。
