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

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