Background

Enzyme replacement therapy (ERT) with alglucosidase alfa has been found to improve outcomes in patients with classic infantile Pompe disease, who without treatment typically die before the age of 1 year. Variable responses to the standard recommended dosage have led to alternative dosing strategies. We aimed to assess the effect of real-world ERT regimens on survival and walking ability in these patients.

Methods

In this observational cohort study, we obtained data collected as part of a collaborative study within the European Pompe Consortium on patients with classic infantile Pompe disease from France, Germany, Italy, and the Netherlands diagnosed between Oct 26, 1998 and March 8, 2019. Eligible patients had classic infantile Pompe disease with a disease onset and proven diagnosis before age 12 months, and a hypertrophic cardiomyopathy. A proven diagnosis of classic infantile Pompe disease was defined as a confirmed deficiency of α-glucosidase in leukocytes or lymphocytes, fibroblasts or muscle, or two pathogenic GAA variants in trans, or both. We collected data on demographics, GAA variants, ERT dosage, age at death, and walking ability. We analysed the effects of ERT dosage on survival and walking ability using Cox regression, Kaplan-Meier curves, and log-rank tests.

Findings

We included 124 patients with classic infantile Pompe disease, of whom 116 were treated with ERT (median age at start of treatment 3·3 months [IQR 1·8–5·0, range 0·03–11·8]). During follow-up (mean duration 60·1 months [SD 57·3]; n=115), 36 (31%) of 116 patients died. 39 different ERT dosing regimens were applied. Among the 64 patients who remained on the same dosage, 16 (52%) of 31 patients on the standard dosage (20 mg/kg every other week), 12 (80%) of 15 patients on an intermediate dosage (20 mg/kg per week or 40 mg/kg every other week), and 16 (89%) of 18 patients on the high dosage (40 mg/kg per week) were alive at last follow-up. Survival was significantly improved in the high dosage group compared with the standard dosage group (hazard ratio [HR] 0·17 [95% CI 0·04–0·76], p=0·02). No significant difference in survival was identified between the intermediate dosage group and the standard dosage group (HR 0·44 [0·13–1·51], p=0·19). Of the 86 patients who reached 18 months of age, 44 (51%) learned to walk. Ten (53%) of 19 patients on the standard dosage regimen, six (67%) of nine patients on intermediate dosage regimens, and 14 (93%) of 15 patients on high dosage regimens learnt to walk, but the differences between groups were not statistically significant.

Interpretation

Patients with classic infantile Pompe disease treated with the high ERT dosage of 40 mg/kg per week had significantly improved survival when compared with patients treated with the standard recommended ERT dosage of 20 mg/kg every other week. Based on these results, we suggest that the currently registered dosage should be reconsidered.

Funding

Prinses Beatrix Spierfonds and Wishdom Foundation.

中文翻译：

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阿糖苷酶 α 剂量对经典婴儿庞贝病患者生存和行走能力的影响：来自欧洲庞贝联盟的多中心观察性队列研究

背景

已发现使用阿糖苷酶 α 的酶替代疗法 (ERT) 可改善典型婴儿庞贝病患者的预后，这些患者未经治疗通常会在 1 岁之前死亡。对标准推荐剂量的不同反应导致了替代给药策略。我们旨在评估真实世界的 ERT 方案对这些患者的生存和行走能力的影响。

方法

在这项观察性队列研究中，我们获得了作为欧洲庞贝联盟合作研究的一部分收集的数据，这些数据来自法国、德国、意大利和荷兰在 1998 年 10 月 26 日至 2019 年 3 月 8 日期间诊断出的经典婴儿庞贝病患者。符合条件的患者患有典型的婴儿庞贝病，在 12 个月前发病并确诊，以及肥厚型心肌病。经证实的经典婴儿庞贝病诊断被定义为白细胞或淋巴细胞、成纤维细胞或肌肉中确认缺乏 α-葡萄糖苷酶，或两种反式致病性GAA变体，或两者兼有。我们收集了人口统计数据，GAA变体、ERT 剂量、死亡年龄和行走能力。我们使用 Cox 回归、Kaplan-Meier 曲线和对数秩检验分析了 ERT 剂量对生存和行走能力的影响。

发现

我们纳入了 124 名经典婴儿庞贝病患者，其中 116 名接受了 ERT 治疗（治疗开始时的中位年龄 3·3 个月 [IQR 1·8-5·0，范围 0·03-11·8]）。在随访期间（平均持续时间 60·1 个月 [SD 57·3]；n=115），116 名患者中有 36 名（31%）死亡。应用了 39 种不同的 ERT 给药方案。在保持相同剂量的 64 名患者中，31 名患者中的 16 名（52%）使用标准剂量（每隔一周 20 mg/kg），15 名患者中的 12 名（80%）使用中间剂量（20 mg/kg）每周或每两周一次 40 mg/kg），18 名高剂量（每周 40 mg/kg）的患者中有 16 名（89%）在最后一次随访时存活。与标准剂量组相比，高剂量组的存活率显着提高（风险比 [HR] 0·17 [95% CI 0·04–0·76]，p=0·02）。中间剂量组和标准剂量组的生存率没有显着差异（HR 0·44 [0·13–1·51]，p=0·19）。在达到 18 个月大的 86 名患者中，44 名 (51%) 学会了走路。标准剂量方案的 19 名患者中有 10 名 (53%)、中剂量方案的 9 名患者中有 6 名 (67%) 和高剂量方案的 15 名患者中有 14 名 (93%) 学会了走路，但组间差异显着没有统计学意义。

解释

与每周使用标准推荐剂量 20 mg/kg ERT 治疗的患者相比，使用每周 40 mg/kg 高剂量 ERT 治疗的经典婴儿庞贝病患者的生存率显着提高。基于这些结果，我们建议重新考虑目前登记的剂量。

资金

Prinses Beatrix Spierfonds 和 Wishdom Foundation。