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Abstract：
BACKGROUND: The somatic BRAFV600E mutation occurs in 38-64% of pediatric cases of Langerhans cell histiocytosis (LCH). Vemurafenib (VMF), a BRAF inhibitor, was approved for refractory BRAFV600E mutated LCH. In adults, VMF causes frequent cutaneous adverse events (CAE) including skin tumors (squamous cell carcinomas, melanomas), but little is known in children. The objective of this study was to evaluate the frequency, clinical spectrum, and severity of CAEs in children treated with VMF for LCH. In addition, a correlation between CAE occurrence and VMF dose, residual plasma levels (RPLs), and efficacy was searched for.
METHODS: Multicentric retrospective observational study including patients <18 years treated with VMF alone for refractory BRAFV600E mutated LCH in 13 countries between October 1, 2013 and December 31, 2018.
RESULTS: Fifty-seven patients: 56% female, median age 2.1 years (0.2-14.6), median treatment duration 4.1 months (1.4-29.7). Forty-one patients (72%) had at least one CAE: photosensitivity (40%), keratosis pilaris (32%), rash (26%), xerosis (21%), and neutrophilic panniculitis (16%). No skin tumor was observed. Five percent of CAEs were grade 3. None were grade 4 or led to permanent VMF discontinuation. Dose reduction was necessary for 12% of patients, temporary treatment discontinuation for 16%, none leading to loss of efficacy. VMF dose, median RPL, and efficacy were not correlated with CAE occurrence.
CONCLUSIONS: At doses used for pediatric LCH, CAEs are frequent but rarely severe and have little impact on the continuation of treatment when managed appropriately. Regular dermatological follow-up is essential to manage CAEs and screen for possible induced skin tumors.
METHODS: Multicentric retrospective observational study including patients <18 years treated with VMF alone for refractory BRAFV600E mutated LCH in 13 countries between October 1, 2013 and December 31, 2018.
RESULTS: Fifty-seven patients: 56% female, median age 2.1 years (0.2-14.6), median treatment duration 4.1 months (1.4-29.7). Forty-one patients (72%) had at least one CAE: photosensitivity (40%), keratosis pilaris (32%), rash (26%), xerosis (21%), and neutrophilic panniculitis (16%). No skin tumor was observed. Five percent of CAEs were grade 3. None were grade 4 or led to permanent VMF discontinuation. Dose reduction was necessary for 12% of patients, temporary treatment discontinuation for 16%, none leading to loss of efficacy. VMF dose, median RPL, and efficacy were not correlated with CAE occurrence.
CONCLUSIONS: At doses used for pediatric LCH, CAEs are frequent but rarely severe and have little impact on the continuation of treatment when managed appropriately. Regular dermatological follow-up is essential to manage CAEs and screen for possible induced skin tumors.
摘要：
背景：38-64％的小儿朗格汉斯细胞组织细胞增生症（LCH）病例中存在体细胞BRAFV600E突变。Vemurafenib(VMF)，BRAF抑制剂，被批准用于难治性BRAFV600E突变的LCH。在成年人中,VMF引起频繁的皮肤不良事件（CAE），包括皮肤肿瘤（鳞状细胞癌，黑色素瘤)，但在儿童中鲜为人知。这项研究的目的是评估频率，临床谱，接受VMF治疗的LCH儿童CAE的严重程度。此外,CAE发生率和VMF剂量之间的相关性，残余血浆水平（RPL），并寻找功效。
方法：多中心回顾性观察性研究，包括2013年10月1日至2018年12月31日在13个国家/地区仅接受VMF治疗难治性BRAFV600E突变LCH的患者。
结果：57例患者：56%为女性，中位年龄2.1岁（0.2-14.6），中位治疗持续时间4.1个月（1.4-29.7）。41例患者（72％）至少有一种CAE：光敏性（40％），毛发角化病（32%），皮疹（26%），干燥症（21%），和中性粒细胞脂膜炎（16％）。未观察到皮肤肿瘤。百分之五的CAE是3级。没有一个是4级或导致永久停止VMF。12%的患者需要减少剂量，暂时停止治疗16％，没有导致功效丧失。VMF剂量,RPL中位数，疗效与CAE发生无关。
结论：在用于小儿LCH的剂量下，CAE是常见的，但很少严重，如果管理得当，对继续治疗的影响很小。定期的皮肤病学随访对于管理CAE和筛查可能诱发的皮肤肿瘤至关重要。
方法：多中心回顾性观察性研究，包括2013年10月1日至2018年12月31日在13个国家/地区仅接受VMF治疗难治性BRAFV600E突变LCH的患者。
结果：57例患者：56%为女性，中位年龄2.1岁（0.2-14.6），中位治疗持续时间4.1个月（1.4-29.7）。41例患者（72％）至少有一种CAE：光敏性（40％），毛发角化病（32%），皮疹（26%），干燥症（21%），和中性粒细胞脂膜炎（16％）。未观察到皮肤肿瘤。百分之五的CAE是3级。没有一个是4级或导致永久停止VMF。12%的患者需要减少剂量，暂时停止治疗16％，没有导致功效丧失。VMF剂量,RPL中位数，疗效与CAE发生无关。
结论：在用于小儿LCH的剂量下，CAE是常见的，但很少严重，如果管理得当，对继续治疗的影响很小。定期的皮肤病学随访对于管理CAE和筛查可能诱发的皮肤肿瘤至关重要。
