Department of Pediatrics, Division of Genetics, Hasbro Children's Hospital, Providence, Rhode Island.
Warren Alpert Medical School of Brown University, Providence, Rhode Island.
JAMA. 2018 Apr 24;319(16):1687-1695. doi: 10.1001/jama.2018.3264.
Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare fatal premature aging disease. There is no approved treatment.
To evaluate the association of monotherapy using the protein farnesyltransferase inhibitor lonafarnib with mortality rate in children with HGPS.
DESIGN, SETTING, AND PARTICIPANTS: Cohort study comparing contemporaneous (birth date ≥1991) untreated patients with HGPS matched with treated patients by age, sex, and continent of residency using conditional Cox proportional hazards regression. Treatment cohorts included patients from 2 single-group, single-site clinical trials (ProLon1 [n = 27; completed] and ProLon2 [n = 36; ongoing]). Untreated patients originated from a separate natural history study (n = 103). The cutoff date for patient follow-up was January 1, 2018.
Treated patients received oral lonafarnib (150 mg/m2) twice daily. Untreated patients received no clinical trial medications.
The primary outcome was mortality. The primary analysis compared treated patients from the first lonafarnib trial with matched untreated patients. A secondary analysis compared the combined cohorts from both lonafarnib trials with matched untreated patients.
Among untreated and treated patients (n = 258) from 6 continents, 123 (47.7%) were female; 141 (54.7%) had a known genotype, of which 125 (88.7%) were classic (c.1824C>T in LMNA). When identified (n = 73), the primary cause of death was heart failure (79.4%). The median treatment duration was 2.2 years. Median age at start of follow-up was 8.4 (interquartile range [IQR], 4.8-9.5) years in the first trial cohort and 6.5 (IQR, 3.7-9.0) years in the combined cohort. There was 1 death (3.7%) among 27 patients in the first trial group and there were 9 deaths (33.3%) among 27 patients in the matched untreated group. Treatment was associated with a lower mortality rate (hazard ratio, 0.12; 95% CI, 0.01-0.93; P = .04). In the combined cohort, there were 4 deaths (6.3%) among 63 patients in the treated group and 17 deaths (27.0%) among 63 patients in the matched untreated group (hazard ratio, 0.23; 95% CI, 0.06-0.90; P = .04).
Among patients with HGPS, lonafarnib monotherapy, compared with no treatment, was associated with a lower mortality rate after 2.2 years of follow-up. Study interpretation is limited by its observational design.
Hutchinson-Gilford 早老综合征（HGPS）是一种极其罕见的致命性过早衰老疾病。目前尚无批准的治疗方法。
评估使用法尼基转移酶抑制剂 lonafarnib 进行单药治疗与 HGPS 患儿死亡率之间的关联。
设计、地点和参与者：这是一项队列研究，通过年龄、性别和居住大陆，将同时期（出生日期≥1991 年）未经治疗的 HGPS 患者与接受治疗的患者进行配对，使用条件 Cox 比例风险回归进行比较。治疗队列包括来自 2 项单组、单地点临床试验的患者（ProLon1 [n=27；已完成]和 ProLon2 [n=36；正在进行]）。未经治疗的患者来自单独的自然史研究（n=103）。患者随访的截止日期为 2018 年 1 月 1 日。
接受治疗的患者接受口服 lonafarnib（150 mg/m2），每日两次。未经治疗的患者未接受临床试验药物治疗。
主要结局是死亡率。主要分析比较了来自第一个 lonafarnib 试验的接受治疗的患者与匹配的未经治疗的患者。次要分析比较了来自 lonafarnib 两项试验的联合队列与匹配的未经治疗的患者。
在来自 6 个大陆的 258 名未经治疗和接受治疗的患者（n=258）中，123 名（47.7%）为女性；141 名（54.7%）具有已知的基因型，其中 125 名（88.7%）为经典型（LMNA 中的 c.1824C>T）。当确定（n=73）主要死因时，心力衰竭占 79.4%。在第一个试验队列中，中位治疗持续时间为 2.2 年。中位随访开始年龄为 8.4 岁（四分位距 [IQR]，4.8-9.5），在联合队列中为 6.5 岁（IQR，3.7-9.0）。在第一个试验组的 27 名患者中，有 1 例死亡（3.7%），在匹配的未经治疗组的 27 名患者中，有 9 例死亡（33.3%）。治疗与较低的死亡率相关（风险比，0.12；95%CI，0.01-0.93；P=0.04）。在联合队列中，在 63 名接受治疗的患者中，有 4 例死亡（6.3%），在 63 名匹配的未经治疗的患者中，有 17 例死亡（27.0%）（风险比，0.23；95%CI，0.06-0.90；P=0.04）。
在 HGPS 患者中，与未经治疗相比，lonafarnib 单药治疗与 2.2 年随访后的较低死亡率相关。研究解释受到其观察性设计的限制。
