帕博利珠单抗致剥脱性皮炎1例的临床诊治并同期应用帕博利珠单抗44例皮肤毒性分析

doi:10.3969/j.issn.1004-583X.2022.02.011

摘要/Abstract

摘要：

目的随着免疫治疗在临床的推广及使用,免疫相关不良反应的伴随发生获得越来越多的关注。控制免疫相关皮肤不良反应可有效改善治疗耐受性,提高疗效。方法本文报道了近期1例严重免疫相关不良皮肤毒性患者的临床诊治经过,同时对同期本院应用帕博利珠单抗的44例患者进行皮肤毒性分析及相关文献复习。结果 44例应用帕博利珠单抗治疗患者中仅少数表现为皮肤瘙痒、皮疹,予激素对症治疗效果良好,不影响帕博利珠单抗的继续使用。1例严重剥脱性皮炎,积极治疗后好转,停用免疫治疗。结论免疫相关皮肤不良反应发生率低,合理干预为临床诊治免疫相关不良反应提供了理论依据及实践策略。

关键词: 免疫检查点抑制剂, 免疫相关性皮肤不良反应

Abstract:

Objective Clinically, increasing immune-related adverse events cause concern with the promotion and application of immunotherapy. The tolerability profile could be effectively improved by controlling immune-related skin adverse reactions to enhance efficacy.Methods In this article regarding the diagnosis and treatment of severe immune-related adverse skin toxicity in a recent patient was reported. Meanwhile, a skin toxicity analysis were performed on 44 patients who received pembrolizumab in our hospital with a review of the related literature.Results Among 44 patients received pembrolizumab, only a few patients presented itchy skin and rash. The symptomatic treatment effect of hormone was good not affecting the continued use pembrolizumab. One case with severe exfoliative dermatitis withdrew immunotherapy although which resolved by active treatment.Conclusion Although the incidence of immune-related skin adverse reactions is low, it is essential to provide reasonable intervention theoretical basis and practical strategy regarding the diagnosis and treatment of immune-related adverse reactions.

Key words: immune checkpoint inhibitors, immune-related skin adverse reactions

中图分类号:

R979.5

黄佳圆, 潘半舟, 纪红, 梅静峰, 范朝晖, 周云. 帕博利珠单抗致剥脱性皮炎1例的临床诊治并同期应用帕博利珠单抗44例皮肤毒性分析[J]. 临床荟萃, 2022, 37(2): 150-154.

Huang Jiayuan, Pan Banzhou, Ji Hong, Mei Jingfeng, Fan Zhaohui, Zhou Yun. Clinical diagnosis and treatment in 1 case of exfoliative dermatitis caused by Pembrolizumab as well as cutaneous toxicity analysis of 44 cases treated with Pembrolizumab contemporaneously[J]. Clinical Focus, 2022, 37(2): 150-154.

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链接本文: https://huicui.hebmu.edu.cn/CN/10.3969/j.issn.1004-583X.2022.02.011

https://huicui.hebmu.edu.cn/CN/Y2022/V37/I2/150

图/表 2

参考文献 19

[1]	Gong J, Chehrazi-Raffle A, Reddi S, et al. Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: A comprehensive review of registration trials and future considerations[J]. J Immunother Cancer, 2018,6(1):8. doi: 10.1186/s40425-018-0316-z pmid: 29357948
[2]	Hayashi H, Nakagawa K. Combination therapy with PD-1 or PD-L1 inhibitors for cancer[J]. Int J Clin Oncol, 2020,25(5):818-830. doi: 10.1007/s10147-019-01548-1 URL
[3]	Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade[J]. New Engl J Med, 2018,378(2):158-168. doi: 10.1056/NEJMra1703481 URL
[4]	Haanen J, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[J]. Ann Oncol, 2018,29(Suppl 4):iv264-iv266. doi: 10.1093/annonc/mdy162 URL
[5]	Sibaud V. Dermatologic reactions to immune checkpoint inhibitors: Skin toxicities and immunotherapy[J]. Am J Clin Dermatol, 2018,19(3):345-361. doi: 10.1007/s40257-017-0336-3 URL
[6]	Collins LK, Chapman MS, Carter JB, et al. Cutaneous adverse effects of the immune checkpoint inhibitors[J]. Curr Probl Cancer, 2017,41(2):125-128. doi: 10.1016/j.currproblcancer.2016.12.001 URL
[7]	Kwok G, Yau TC, Chiu JW, et al. Pembrolizumab (Keytruda)[J]. Hum Vacc Immunother, 2016,12(11):2777-2789.
[8]	Kojima T, Shah MA, Muro K, et al. Randomized phase Ⅲ KEYNOTE-181 study of pembrolizumab versus chemotherapy in advanced esophageal cancer[J]. J Clin Oncol, 2020,38(35):4138-4148. doi: 10.1200/JCO.20.01888 URL
[9]	Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial[J]. Lancet, 2016,387(10027):1540-1550. doi: S0140-6736(15)01281-7 pmid: 26712084
[10]	Schachter J, Ribas A, Long GV, et al. Pembrolizumab versus ipilimumab for advanced melanoma: Final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006)[J]. Lancet, 2017,390(10105):1853-1862. doi: S0140-6736(17)31601-X pmid: 28822576
[11]	Garassino MC, Gadgeel S, Esteban E, et al. Patient-reported outcomes following pembrolizumab or placebo plus pemetrexed and platinum in patients with previously untreated, metastatic, non-squamous non-small-cell lung cancer (KEYNOTE-189): A multicentre, double-blind, randomised, placebo-controlled, phase 3 trial[J]. Lancet Oncol, 2020,21(3):387-397. doi: S1470-2045(19)30801-0 pmid: 32035514
[12]	Gravalos C, Sanmartin O, Gurpide A, et al. Clinical management of cutaneous adverse events in patients on targeted anticancer therapies and immunotherapies: A national consensus statement by the Spanish Academy of Dermatology and Venereology and the Spanish Society of Medical Oncology[J]. Clin Transl Oncol, 2019,21(5):556-571. doi: 10.1007/s12094-018-1953-x
[13]	Shimabukuro-Vornhagen A, Godel P, Subklewe M, et al. Cytokine release syndrome[J]. J Immunother Cancer, 2018,6(1):56. doi: 10.1186/s40425-018-0343-9 pmid: 29907163
[14]	Naing A, Hajjar J, Gulley JL, et al. Strategies for improving the management of immune-related adverse events[J]. J Immunother Cancer, 2020,8(2):e001754. doi: 10.1136/jitc-2020-001754 URL
[15]	Joseph RW, Cappel M, Goedjen B, et al. Lichenoid dermatitis in three patients with metastatic melanoma treated with anti-PD-1 therapy[J]. Cancer Immunol Res, 2015,3(1):18-22. doi: 10.1158/2326-6066.CIR-14-0134 URL
[16]	Hofmann L, Forschner A, Loquai C, et al. Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy[J]. Eur J Cancer, 2016,60:190-209. doi: 10.1016/j.ejca.2016.02.025 pmid: 27085692
[17]	Kyllo RL, Parker MK, Rosman I, et al. Ipilimumab-associated Sweet syndrome in a patient with high-risk melanoma[J]. J Am Acad Dermatol, 2014,70(4):e85-e86. doi: 10.1016/j.jaad.2013.11.022 URL
[18]	Postow MA, Knox SJ, Goldman DA, et al. A prospective, phase 1 trial of nivolumab, ipilimumab, and radiotherapy in patients with advanced melanoma[J]. Clin Cancer Res, 2020,26(13):3193-3201. doi: 10.1158/1078-0432.CCR-19-3936 URL
[19]	Phillips GS, Wu J, Hellmann MD, et al. Treatment outcomes of immune-related cutaneous adverse events[J]. J Clin Oncol, 2019,37(30):2746-2758. doi: 10.1200/JCO.18.02141 pmid: 31216228

免疫相关性皮肤反应	例数	症状	治疗	转归
斑丘疹/皮疹
G1	2	斑疹/丘疹区域<10%全身体表面积(BSA),伴或不伴全身症状(例如:瘙痒、灼痛或紧绷)	复方曲安奈德乳膏、抗敏止痒水、氯雷他定片	好转,继续应用免疫治疗
G2	2	斑疹/丘疹区域占10%~30%全身BSA,伴或不伴全身症状(例如:瘙痒、灼痛或紧绷);日常使用工具受限	复方曲安奈德乳膏、抗敏止痒水、氯雷他定片和(或)泼尼松0.5~1 mg/(kg·d)	好转,继续应用免疫治疗
G3	0	斑疹/丘疹区域占>30%全身BSA,伴或不伴全身症状(例如:红斑、紫癜或表皮脱落);日常生活受限
瘙痒
G1	5	轻微或局限	硅油乳膏、复方曲安奈德乳膏、抗敏止痒水	好转,继续应用免疫治疗
G2	3	强烈或广泛;间歇性;抓挠致皮肤受损(如水肿、丘疹、脱屑、苔藓化、渗出/结痂);日常使用工具受限	硅油乳膏复方曲安奈德乳膏、抗敏止痒水、氯雷他定片和(或)泼尼松0.5~1 mg/(kg·d)	好转,继续应用免疫治疗
G3	0	强烈或广泛;持续性;日常生活自理明显受限或影响睡眠
大泡性皮炎/Stevens-Johnson综合征(SJS)/中毒性表皮坏死松解症(TEN)
G1	0	无症状,水疱区域<10%全身BSA,
G2	0	水疱覆盖占10%~30%伴疼痛;日常使用工具受限
G3	0	水疱覆盖BSA>30%,日常生活自理明显受限SJS或者TEN
G4	1	水疱覆盖BSA>30%;合并水电解质紊乱致死性SJS或者TEN	住院,起始甲基泼尼松龙2.7 mg/(kg·d)(后逐步减量),同时头孢曲松钠他唑巴坦钠抗感染,后加用氟康唑抗真菌,保持水电解质平衡,局部皮肤护理	好转,永久停用ICIs治疗

免疫相关性皮肤反应	例数	症状	治疗	转归
斑丘疹/皮疹
G1	2	斑疹/丘疹区域<10%全身体表面积(BSA),伴或不伴全身症状(例如:瘙痒、灼痛或紧绷)	复方曲安奈德乳膏、抗敏止痒水、氯雷他定片	好转,继续应用免疫治疗
G2	2	斑疹/丘疹区域占10%~30%全身BSA,伴或不伴全身症状(例如:瘙痒、灼痛或紧绷);日常使用工具受限	复方曲安奈德乳膏、抗敏止痒水、氯雷他定片和(或)泼尼松0.5~1 mg/(kg·d)	好转,继续应用免疫治疗
G3	0	斑疹/丘疹区域占>30%全身BSA,伴或不伴全身症状(例如:红斑、紫癜或表皮脱落);日常生活受限
瘙痒
G1	5	轻微或局限	硅油乳膏、复方曲安奈德乳膏、抗敏止痒水	好转,继续应用免疫治疗
G2	3	强烈或广泛;间歇性;抓挠致皮肤受损(如水肿、丘疹、脱屑、苔藓化、渗出/结痂);日常使用工具受限	硅油乳膏复方曲安奈德乳膏、抗敏止痒水、氯雷他定片和(或)泼尼松0.5~1 mg/(kg·d)	好转,继续应用免疫治疗
G3	0	强烈或广泛;持续性;日常生活自理明显受限或影响睡眠
大泡性皮炎/Stevens-Johnson综合征(SJS)/中毒性表皮坏死松解症(TEN)
G1	0	无症状,水疱区域<10%全身BSA,
G2	0	水疱覆盖占10%~30%伴疼痛;日常使用工具受限
G3	0	水疱覆盖BSA>30%,日常生活自理明显受限SJS或者TEN
G4	1	水疱覆盖BSA>30%;合并水电解质紊乱致死性SJS或者TEN	住院,起始甲基泼尼松龙2.7 mg/(kg·d)(后逐步减量),同时头孢曲松钠他唑巴坦钠抗感染,后加用氟康唑抗真菌,保持水电解质平衡,局部皮肤护理	好转,永久停用ICIs治疗