安罗替尼治疗难治性自然杀伤/T细胞淋巴瘤的有效性与安全性的探索性研究

doi:10.3969/j.issn.1674-8115.2021.02.011

上海交通大学学报(医学版) ›› 2021, Vol. 41 ›› Issue (2): 196-201.doi: 10.3969/j.issn.1674-8115.2021.02.011

安罗替尼治疗难治性自然杀伤/T细胞淋巴瘤的有效性与安全性的探索性研究

李高扬(), 姜霁峰, 刘传绪, 张文皓, 朱杨, 马玉杰, 陶荣()

上海交通大学医学院附属新华医院血液科，上海 200092

收稿日期:2020-06-03 出版日期:2021-02-28 发布日期:2021-02-28
通讯作者: 陶荣 E-mail:elisaLGY@126.com;taorong@xinhuamed.com.cn
作者简介:李高扬（1991—），女，博士生；电子信箱：elisaLGY@126.com。
基金资助:
上海市教育委员会高峰高原学科建设计划(20152219);上海市科学技术委员会医学引导类项目(18411968300);上海申康医院发展中心临床科技创新项目(SHDC2019X02)

A pilot study on the efficacy and safety of anlotinib in the treatment of refractory natural killer/T-cell lymphoma

Gao-yang LI(), Ji-feng JIANG, Chuan-xu LIU, Wen-hao ZHANG, Yang ZHU, Yu-jie MA, Rong TAO()

Department of Hematology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China

Received:2020-06-03 Online:2021-02-28 Published:2021-02-28
Contact: Rong TAO E-mail:elisaLGY@126.com;taorong@xinhuamed.com.cn
Supported by:
Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support(20152219);Medical Guide Project of Shanghai Science and Technology Commission(18411968300);Clinical Science and Technology Innovation Project of Shanghai Shenkang Hospital Development Center(SHDC2019X2)

摘要/Abstract

摘要：

目的·观察安罗替尼用于治疗难治性自然杀伤/T细胞淋巴瘤（natural killer/T-cell lymphoma，NKTCL）的有效性和安全性。方法·招募于2018年8月至2019年12月在上海交通大学医学院附属新华医院门诊就诊的经病理检查确诊为NKTCL，表现为门冬酰胺酶耐药，且具有可测量/可评估病灶和一定器官功能储备的患者纳入研究；患者接受安罗替尼单药（12 mg/d）或安罗替尼（10 mg/d）联合程序性死亡蛋白-1（programmed death-1，PD-1）单克隆抗体（单抗）治疗，直至疾病进展或者不能耐受不良反应，根据Lugano 2014标准评估治疗应答。不良反应按照美国国家癌症研究所常见不良反应事件评价标准4.03版进行分级评估。Kaplan-Meier法对患者进行生存分析。结果·共12例患者纳入研究，中位年龄44岁，其中男性9例；6例患者接受安罗替尼单药治疗，6例患者接受安罗替尼联合PD-1单抗治疗。所有受试者均出现了治疗相关的不良反应，3级不良反应为高血压（2例）和低钠血症（1例），无非预期的不良反应。50.0%的患者获得客观应答，安罗替尼单药的应答率为33.3%，安罗替尼联合PD-1单抗的应答率为66.7%。中位疾病无进展生存期为3.0个月，中位总生存期（overall survival，OS）为3.0个月。接受安罗替尼单药治疗患者的中位OS为2.8个月，接受安罗替尼联合PD-1单抗治疗患者的中位OS为8.0个月；应答患者的中位OS为8.0个月，无应答患者的中位OS仅2.8个月。结论·安罗替尼可能是一个治疗难治性NKTCL的潜在药物，且与PD-1单抗具有潜在协同增效作用；该药整体安全性良好，患者普遍耐受。

关键词: 自然杀伤/T细胞淋巴瘤, 安罗替尼, 程序性死亡蛋白-1单克隆抗体

Abstract:

Objective·To observe the efficacy and safety of anlotinib in the treatment of refractory natural killer/T-cell lymphoma (NKTCL).

Methods·The patients who had been pathologically diagnosed as having NKTCL with measurable/assessable lesions and some organ function reserve after failing in L-asparaginase-containing regimen were recruited in this study from August 2018 to December 2019 in the Outpatient Department of Xinhua Hospital, Shanghai Jiao Tong University School of Medicine. They were given anlotinib (12 mg/d) alone or anlotinib (10 mg/d) with programmed death-1 (PD-1) monoclonal antibody until the disease progression or intolerable adverse reactions. Responses were evaluated as per Lugano 2014 criteria. Adverse reactions were assessed according to Common Terminology Criteria for Adverse Events of National Cancer Institute, USA (version 4.03). Kaplan-Meier method was used for survival analysis.

Results·Twelve patients were included in this study with a median age of 44 years, and 9 patients were males. Among them, 6 patients received anlotinib monotherapy, and 6 patients received anlotinib combined with PD-1 monoclonal antibody therapy. Treatment-related adverse events were observed in all 12 subjects without unexpected adverse reactions. The grade 3 adverse events included hypertension (2 cases) and hyponatremia (1 case). There were 50.0% patients obtaining objective responses with 33.3% in the anlotinib monotherapy group and 66.7% in the combined treatment group. The median progression-free survival was 3.0 months and the median overall survival (OS) was 3.0 months. The median OS of the patients receiving anlotinib alone was 2.8 months, while it was 8.0 months in the patients receiving anlotinib combined with PD-1 monoclonal antibody. The median OS of the responding patients was 8.0 months, while it was 2.8 months in the non-responding patients.

Conclusion·Anlotinib may be a promising drug for the treatment of refractory NKTCL, which has a potentially synergistic effect with PD-1 monoclonal antibody; the overall safety of the drug is good, and patients generally tolerate it.

Key words: natural killer/T-cell lymphoma (NKTCL), anlotinib, programmed death-1 (PD-1) monoclonal antibody

中图分类号:

R733.4

李高扬, 姜霁峰, 刘传绪, 张文皓, 朱杨, 马玉杰, 陶荣. 安罗替尼治疗难治性自然杀伤/T细胞淋巴瘤的有效性与安全性的探索性研究[J]. 上海交通大学学报(医学版), 2021, 41(2): 196-201.

Gao-yang LI, Ji-feng JIANG, Chuan-xu LIU, Wen-hao ZHANG, Yang ZHU, Yu-jie MA, Rong TAO. A pilot study on the efficacy and safety of anlotinib in the treatment of refractory natural killer/T-cell lymphoma[J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(2): 196-201.

图/表 4

图1 安罗替尼治疗前后NKTCL患者病灶的影像学变化Note:A. A patient with stage Ⅳdisease and primary resistance to asparaginase chemotherapy showed both enlarged kidneys diffusely infiltrated by lymphoma before treatment. On the 21st day after anlotinib (12 mg·d-1) treatment, CT showed PR and both kidneys remarkably improved. B. A patient with stage Ⅱ disease and primary resistance to asparaginase chemotherapy and radiotherapy did not respond to PD-1 antibody treatment for 4 cycles, and then received PD-1 antibody combined with anlotinib (10 mg·d-1). His response was evaluated after 4 cycles (12 weeks). CT showed CR, and PET showed complete metabolic remission.

Fig 1 Imaging changes of lesions before and after treatment with anlotinib in NKTCL patients

图2 安罗替尼治疗NKTCL患者的整体PFS曲线和OS曲线Note: A. PFS curve. B. OS curve.

Fig 2 Overall PFS curve and OS curve of the patients with NKTCL treated with anlotinib

图3 接受安罗替尼单药治疗和安罗替尼联合PD-1单抗治疗患者的PFS曲线和OS曲线Note: A. PFS curves. B. OS curves.

Fig 3 PFS curves and OS curves of the patients receiving anlotinib monotherapy and anlotinib combined with PD-1 mAb

图4 接受安罗替尼治疗的应答患者和无应答患者的PFS曲线和OS曲线Note: A. PFS curves. B. OS curves.

Fig 4 PFS curves and OS curves of the responders and non-responders to anlotinib

参考文献 12

1	Fox CP, Civallero M, Ko YH, et al. Survival outcomes of patients with extranodal natural-killer T-cell lymphoma: a prospective cohort study from the international T-cell project[J]. Lancet Haematol, 2020, 7(4): e284-e294.
2	Lim SH, Hong JY, Lim ST, et al. Beyond first-line non-anthracycline-based chemotherapy for extranodal NK/T-cell lymphoma: clinical outcome and current perspectives on salvage therapy for patients after first relapse and progression of disease[J]. Ann Oncol, 2017, 28(9): 2199-2205.
3	Tao R, Fan L, Song YP, et al. Sintilimab for relapsed/refractory (r/r) extranodal NK/T cell lymphoma (ENKTL): a multicenter, single-arm, phase 2 trial (ORIENT-4)[J]. J Clin Oncol, 2019, 37(15S): 425s.
4	董一文, 金震, 丁浩, 等. 自分泌VEGF/VEGFR环路在NK/TCL中的表达及其对肿瘤迁移和侵袭的调控[J]. 临床血液学杂志, 2014, 27(3): 379-385.
5	金震, 李青, 丁浩, 等. 自分泌PDGF/PDGFR环路对NK/T细胞淋巴瘤细胞增殖的影响及其机制研究[J]. 白血病·淋巴瘤, 2014, 23(6): 325-330.
6	黄方, 丁浩, 常君, 等. 自分泌IGF-1/IGF-1R环路促进NK/T细胞淋巴瘤细胞株迁移和侵袭[J]. 白血病·淋巴瘤, 2015, 24(6): 334-340.
7	Han BH, Li K, Wang QM, et al. Effect of anlotinib as a third-line or further treatment on overall survival of patients with advanced non-small cell lung cancer: the ALTER 0303 phase 3 randomized clinical trial[J]. JAMA Oncol, 2018, 4(11): 1569-1575.
8	Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification[J]. J Clin Oncol, 2014, 32(27): 3059-3068.
9	Hoy SM. Sintilimab: first global approval[J]. Drugs, 2019, 79(3): 341-346.
10	Georganaki M, Hooren LV, Dimberg A. Vascular targeting to increase the efficiency of immune checkpoint blockade in cancer[J]. Front Immunol, 2018, 9: 3081.
11	Zhao S, Ren SX, Jiang T, et al. Low-dose apatinib optimizes tumor microenvironment and potentiates antitumor effect of PD-1/PD-L1 blockade in lung cancer[J]. Cancer Immunol Res, 2019, 7(4): 630-643.
12	Taylor MH, Lee CH, Makker V, et al. Phase ⅠB/Ⅱ trial of lenvatinib plus pembrolizumab in patients with advanced renal cell carcinoma, endometrial cancer, and other selected advanced solid tumors[J]. J Clin Oncol, 2020, 38(11): 1154-1163.

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安罗替尼治疗难治性自然杀伤/T细胞淋巴瘤的有效性与安全性的探索性研究

A pilot study on the efficacy and safety of anlotinib in the treatment of refractory natural killer/T-cell lymphoma

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