应用西罗莫司安全有效治疗并发血细胞减少的儿童自身免疫性淋巴细胞增生综合征——单中心、回顾性队列研究

Effective and safe treatment of sirolimus in the childhood autoimmune lymphoproliferative syndrome with hemocytopenia-a single center,retrospective cohort study

目的:自身免疫性淋巴细胞增生综合征(ALPS)是一种常在幼年发病、并发免疫性血细胞减少而需要药物控制的遗传性免疫缺陷病。而糖皮质激素作为传统治疗药物将影响处于生长发育的患儿。西罗莫司通过精准抑制mTOR通路、诱导T细胞凋亡而成为治疗的新选择,但尚缺乏其安全性和有效性数据。本文旨在通过总结我中心伴发免疫性血细胞减少的ALPS患儿西罗莫司用药数据,为该药在ALPS患儿的应用提供数据。方法:单中心、回顾性队列研究,收集自2016年至今在我中心确诊并应用西罗莫司治疗超过1年的12例并发免疫性血细胞减少的ALPS患儿,对治疗的有效性和安全性进行评价。结果:12例患儿中位年龄3.5(110)岁,中位病程10个月(1个月3年)。12例(100%)均存在免疫性血小板减少:其中7例(58.33%)累及全血细胞,4例(33.33%)累及两系血细胞,1例(8.33%)仅累及免疫性血小板减少。12例(100%)存在中度以上脾肿大(3例达Ⅲ度),11例(91.67%)伴淋巴结肿大。疗效方面:(1)疗程3个月时,12例(100%)血细胞减少缓解,9例(75.00%)达完全缓解;10例(83.33%)淋巴组织增殖缓解,3例(25.00%)达完全缓解。(2)疗程12个月时,12例(100%)血细胞减少缓解,11例(91.67%)达完全缓解;12例(100%)淋巴组织增殖缓解,8例(66.67%)达完全缓解。(3)患儿血细胞减少先于淋巴增殖缓解:血细胞减少中位达完全缓解时间3周(150周)。(4)缓解相关因素:ALPS-FAS及ALPS-FASLG突变患儿于3个月评估点均达血常规及淋巴增殖缓解,时间早于其余ALPS患儿。应用3个月、6个月达完全缓解者病初双阴性T细胞比例明显增高。安全性方面:1例患儿服药期间谷丙转氨酶升高,2例口腔溃疡,尚无患儿因服药继发感染。结论:西罗莫司治疗儿童期并发血细胞减少的ALPS起效快、缓解率高:疗程1年时血细胞减少及淋巴增殖总有效率高达100%(血细胞减少完全缓解率91.67%、淋巴增殖完全缓解率66.67%)。患儿血细胞减少缓解早于淋巴组织增殖。ALPS-FAS及ALPS-FASLG突变患儿及用药前双阴性T细胞比例明显增高可能是更快达完全缓解的预测指标。西罗莫司不良反应较轻微,可耐受。提示西罗莫司有望成为诊断明确伴免疫性血细胞减少的ALPS患儿的首选治疗药物。

Objective: Autoimmune lymphoproliferative syndrome(ALPS) usually presents in childhood with fever, nonmalignant splenomegaly and lymphadenopathy along with cytopenia. Glucocorticoids, as a traditional therapeutic application of ALPS, will affect the growth of children. Sirolimus has become a new treatment option which accurately inhibit the mTOR pathway and induce T cell apoptosis, but its safety and effectiveness data in pediatrics still need to be investigated. This article aims to provide safety and effectiveness data for the application of sirolimus in the childhood ALPS with hemocytopenia in our center. Methods: This study was a single-center, retrospective cohort study, collected from 2016 to present, 12 pediatric ALPS with immune cytopenia diagnosed and treated with sirolimus for more than 1 year. The data of effectiveness and safety was evaluated. Results: The median age of the 12 children was 3.5(1-10) years old, and the median course of disease was 10 months(1 month to 3 years). Twelve cases(100%) all had immune thrombocytopenia: 7 cases(58.33%) had pancytopenia, 4 cases(33.33%) involved two lines hemocytopenia, and 1 case(8.33%) only had immune thrombocytopenia. Twelve cases(100%) had moderate or higher splenomegaly(3 cases reached degree Ⅲ), and 11 cases(91.67%) had lymphadenopathy. Efficacy:(1)After 3 months of treatment, 12 cases(100%) achieved remission of cytopenia, and 9 cases(75.00%) achieved complete remission. Ten cases(83.33%) achieved remission of lymphoid tissue proliferation, and 3 cases(25.00%) achieved complete remission.(2)At 12 months of treatment, 12 cases(100%) achieved remission of cytopenia, and 11 cases(91.67%) achieved complete remission. Twelve cases(100%) achieved remission of lymphoid tissue proliferation, and 8 cases(66.67%) achieved complete remission.(3)The median time to complete remission of hemacytopenia was 3 weeks(1-50 weeks), which was shorter than that of lymphatic proliferation.(4)Relation factors: All the children with ALPS-FAS and ALPS-FASLG mutations achieved hematologic remission at 3 months, which was earlier than other children with ALPS. The rate of double negative T cell at the beginning of the disease was significantly elevated in patients who achieved complete remission after 3 months and 6 months treatment. Safety: One case had transient elevation of glutamic pyruvic transaminase, 2 cases had oral ulcers, and no children had secondary infection due to application of sirolimus. Conclusion: Sirolimus treatment of childhood ALPS complicated with hemocytopenia has rapid response and high remission rate. After 12 months of treatment, the overall response rate of hemocytopenia and lymphatic proliferation is 100%(91.67% complete remission rate of hemocytopenia and 66.67% complete remission rate of lymphatic proliferation). The remission of hemocytopenia in children is earlier than that of lymphoproliferation. ALPS-FAS and ALPS-FASLG mutation and the significant increase in the proportion of double negative T cell before medication may be a predictor of faster complete remission.The adverse events of sirolimus are mild and tolerable. This study suggests that sirolimus is expected to be the first choice for the treatment of children with ALPS diagnosed with immune cytopenia.