Abstract: Background　Treatment of refractory Langerhans cell histiocytosis（LCH）is difficult.Methotrexate，a classic antitumor drug，is commonly used at a dose of 0.5 g/m2 in the treatment of LCH.Furthermore，high-dose methotrexate（HDMTX） can cross the blood-brain barrier，and its efficacy increases with increasing concentration.So HDMTX may improve the prognosis of refractory LCH，especially with hypophysis involvement.Objective　To analyze and summarize 5 pediatric cases of refractory LCH treated with HDMTX，offering guidance for clinical treatment of LCH with this therapeutic approach.Methods　Five pediatric cases of LCH from Peking University First Hospital between 2005—2019 with multi-organ injuries and risk organ involvement（RO+）or multiple relapses were selected.Their clinical data were retrospectively collected via reviewing medical records，including general information，symptoms and signs，treatment options，prognosis and follow-up situation.Results　（1）General information，symptoms and signs：the 5 cases included 4 boys and 1 girl，with an age of onset of less than 1.Fever was an initial symptom prevalent in all cases，3 cases had rash，1 case had decreased activity of the right lower limb muscles，1 case had orbital and right lower limb masses.All cases developed multi-organ injuries，and 4 of them had RO+，but it was unclear whether the other 1 also had RO+ at the time of consultation.3 cases had pituitary involvement with diabetes insipidus as clinical manifestation.（2）Treatment：all cases received induction therapy with international standard regimen.4 patients were treated with medium-dose MTX（0.5 g/m2）firstly.Due to early onset and risk organ injury，case 1 was treated with HDMTX（1 g/m2） consolidation therapy for a course of treatment.Case 2 was treated with HDMTX（2 g/m2）for 4 courses because of two episodes of relapses and hypophysis involvement.Case 3 recurred at 6-month of treatment，as the rash did not subside after chemotherapy with the original regimen and new defects appeared at the skull，so a regimen of 6-course HDMTX（2 g/m2）was chosen for treatment.Case 4 had good response at 6-week of initial treatment，but recurred after 1 year and 2 months of discontinuation.Bone destruction increased，the pituitary involved，and central diabetes insipidus symptoms appeared.Considering the good ability of HDMTX crossing the blood-brain barrier，HDMTX（1 g/m2）combined with vinblastine and prednisone were used for two courses.In case 5，considering hypophysis involvement，two courses of HDMTX（1 g/m2）were used.（3）Follow-up and outcome：in case 1，vinblastine was used for maintenance therapy after HDMTX treatment，but has been stopped for 13 years and case 1 survives the disease.In case 2，after 4 courses of HDMTX treatment，the masses disappeared，the skull lesions were stable，the pituitary lesions were controlled，and the diabetes insipidus symptoms disappeared，the curative effect was evaluated as intermediate after 6 weeks of treatment.But the third recurrence occurred after 3 months，then clatrabine was finally used for 5 courses and has been stopped for 5 years，case 2 survives.In case 3，the skin rash was controlled，and the bone lesions stable，the curative effect was evaluated as better after 6 weeks of treatment，and then received the maintenance treatment.At present，the drug has been stopped for 3 years，and disease-free survival was achieved.In case 4，the pituitary lesions were smaller，and the diabetes insipidus symptoms were significantly improved，the curative effect was evaluated as intermediate after 6 weeks of treatment，but the scapular bone destruction was slightly deteriorated and new lesions appeared at the frontal bone and clatrabine was used.Now the drug has been stopped for two years，and disease-free survival was achieved.In case 5，the symptoms of diabetes insipidus disappeared，the curative effect was evaluated as intermediate after 6 weeks of treatment.However，due to pulmonary infection during the treatment，HDMTX treatment was discontinued，and now the case is still receiving maintenance therapy and under the follow-up.（4）Side effects：bone marrow suppression was observed in 4 cases，elevation of glutamate aminotransferase was observed in 3 cases，gastrointestinal reactions such as nausea and vomiting were observed in 3 cases，and no serious adverse reactions of grade 3 or above were observed.Conclusion　HDMTX can be used effectively in the chemotherapy for children with refractory or recurrent LCH with RO+，especially in those with pituitary involvement under the condition of ensuring medication safety.

Key words: Histiocytosis, Langerhans-cell；High-dose methotrexate；Refractory；Recurrence；Drug toxicity；Treatment outcome；Prognosis

摘要： 背景　难治性朗格汉斯细胞组织细胞增生症（LCH）治疗困难。甲氨蝶呤（MTX）作为经典抗肿瘤药物，在该病的治疗中常用剂量为0.5 g/m2，然而MTX的一个重要优势为增大剂量后可以穿透血-脑脊液屏障，并且该药物具有浓度依赖效应，因此对于难治性LCH，尤其是垂体受累，大剂量甲氨蝶呤（HDMTX）的治疗可能能够改善预后。目的　对HDMTX治疗儿童难治性LCH的5个病例进行总结和分析，为临床应用HDMTX治疗LCH提供指导。方法　选取2005—2019年就诊于北京大学第一医院儿科确诊为LCH，存在多系统受累，同时合并危险器官受累（RO+）或者多次复发的患儿5例作为研究对象。回顾性查阅患者病历，收集患者的一般资料、症状和体征、治疗方案、预后情况及随访情况。结果　（1）一般资料及症状和体征：5例LCH患儿中男4例，女1例；起病年龄均<1岁；首发症状均有发热，其中3例有皮疹，1例右下肢活动减少，1例眼眶及右下肢肿物；均进展为多系统受累，其中4例存在RO+，另1例就诊时不能明确是否存在RO+；3例患儿有垂体受累，临床表现为尿崩症状。（2）治疗方案：5例LCH患儿均采用国际常规方案进行诱导治疗，其中4例患儿治疗期间首先采用常规方案0.5 g/m2中剂量MTX治疗。例1采用HDMTX（1 g/m2）巩固治疗1个疗程；例2已复发2次，且垂体受累，采用HDMTX（2 g/m2）治疗4个疗程；例3因复发，继续采用原方案化疗后皮疹反复，颅骨出现新发缺损，遂换用HDMTX（2 g/m2）治疗6个疗程；例4在停止常规治疗1年2个月后复发，骨质破坏较前增多，并且出现垂体受累，中枢性尿崩症状，改用HDMTX（1 g/m2）联合长春花碱、泼尼松治疗2个疗程；例5合并垂体受累，采用HDMTX（1 g/m2）治疗2个疗程。（3）预后及随访情况：例1在HDMTX治疗后使用长春花碱维持治疗，目前已停药13年，无病生存；例2治疗后肿块消失、颅骨病变稳定，垂体病变得到控制，尿崩症状消失，6周时疗效评估为中度反应，第3次复发垂体未再受累，采用克拉屈滨进行治疗，5个疗程后停药观察5年，无病生存；例3治疗后皮疹得到控制，骨骼病变未再进展，6周时疗效评估为反应良好，其后进入维持治疗，目前停药3年，无病生存；例4治疗后垂体病灶较前缩小，尿崩症状明显好转，6周时疗效评估为中度反应，后续治疗中肩胛骨骨质破坏范围较前稍有增大，额骨出现新发病灶，后改用克拉屈滨治疗，目前停药2年，无病生存；例5治疗后尿崩症状消失，6周时疗效评估为中度反应，但由于治疗过程中合并肺部感染，未再继续应用HDMTX治疗，目前仍处于维持治疗阶段，还在随访当中。（4）药物毒副作用：4例患儿出现骨髓抑制，3例患儿出现谷氨酸氨基转移酶升高，3例患儿出现恶心、呕吐等胃肠道反应，5例均未出现3级及以上严重毒副作用。结论　在保证用药安全的情况下，可以调整常规化疗药物，将HDMTX用于RO+的难治性或复发性LCH患儿的化疗当中，尤其是垂体受累患儿，疗效较好。

关键词: 组织细胞增多症, 郎格尔汉斯细胞, 大剂量甲氨蝶呤, 难治性, 复发, 药物毒性, 治疗结果, 预后