托法替布治疗激素抵抗型免疫检查点抑制剂相关心肌炎的临床研究

doi:10.19401/j.cnki.1007-3639.2024.04.007

摘要/Abstract

摘要：

背景与目的：激素抵抗型免疫检查点抑制剂相关心肌炎（steroid-resistant immune checkpoint inhibitor-associated myocarditis，srICIAM）是一种在接受免疫治疗后出现的心脏相关不良反应，患者总体预后较差。既往研究显示，包含Janus激酶（Janus kinase，JAK）抑制剂托法替布在内的免疫强化抑制治疗可能对srICIAM具有一定疗效。然而，由于缺乏足够的临床数据，其治疗效果及对于肿瘤病情的影响尚不明确。本研究旨在探讨托法替布对srICIAM的治疗效果。方法：本项回顾性病例对照研究连续纳入了2019年7月—2022年5月在复旦大学附属中山医院接受免疫检查点抑制剂治疗且出现srICIAM的36例恶性肿瘤患者。接受糖皮质激素联合托法替布治疗的患者被分配至托法替布组（n = 19），未使用托法替布治疗的患者被分配至对照组（n = 17）。比较两组患者在临床特征、检验指标、影像学检查结果等方面的数据。同时对这些患者进行随访以监测心血管终点事件的发生。研究方案经过复旦大学附属中山医院伦理委员会批准（批准号：B2021-275R）。本研究按照《赫尔辛基宣言》的伦理学规范进行。结果：与对照组相比，在糖皮质激素累积剂量及持续时间差异无统计学意义（P>0.05）的情况下，托法替布组的心肌炎恢复时间更短（中位恢复时间：86.5 d vs 126.5 d，P = 0.021）。托法替布组的心肌炎相关死亡率显著低于对照组（5% vs 35%，P = 0.025）。结论：托法替布可在一定程度上降低srICIAM患者的死亡率并缩短康复时间，同时对于肿瘤患者的预后未产生不良影响。其可能成为srICIAM的潜在治疗药物之一。

关键词: 免疫检查点抑制剂, 免疫疗法, 心肌炎, Janus激酶抑制剂

Abstract:

Background and purpose: Outcomes for cancer patients with steroid-resistant immune checkpoint inhibitor-associated myocarditis (srICIAM) are poor. Intensified immunosuppressive therapies, including tofacitinib, a novel Janus kinase (JAK) inhibitor, may have some therapeutic benefits. However, due to the lack of sufficient clinical data, the effectiveness of such treatments and their impact on cardiovascular outcomes remain unclear. This study aimed to investigate the therapeutic effect of tofacitinib on srICIAM. Methods: This retrospective case-control study included 36 malignant tumor patients who received immune checkpoint inhibitor treatment at Zhongshan Hospital affiliated to Fudan University from July 2019 to May 2022 and developed srICIAM. Patients receiving corticosteroids in combination with tofacitinib were assigned to the tofacitinib group (n=19), while those not treated with tofacitinib were allocated to the control group (n=17). The study compared clinical characteristics, laboratory findings, and imaging results between the two groups. Additionally, follow-up was conducted to monitor the incidence of cardiovascular endpoints in these patients. The research plan was approved by the Ethics Committee of Zhongshan Hospital Affiliated to Fudan University (Approval Number: B2021-275R). This study was conducted in accordance with the ethical guidelines of the Helsinki Declaration. Results: Compared to the control group, and with no significant difference in the cumulative dose and duration of corticosteroids (P<0.05), the tofacitinib group showed a shorter myocarditis recovery time (median recovery time: 86.5 days vs 126.5 days, P=0.021). The myocarditis-related mortality rate was significantly lower in the tofacitinib group than in the control group (5% vs 35%, P=0.025). Conclusion: Tofacitinib may reduce mortality and promote cardiac recovery in srICIAM patients without impeding the anti-tumor effect. It may become one of the potential treatment strategies in the future.

Key words: Immune checkpoint inhibitors, Immunotherapy, Myocarditis, Janus kinase inhibitor

中图分类号:

R730.6

许宇辰, 张健, 王妍, 林瑾仪, 周宇红, 程蕾蕾, 葛均波. 托法替布治疗激素抵抗型免疫检查点抑制剂相关心肌炎的临床研究[J]. 中国癌症杂志, 2024, 34(4): 400-408.

XU Yuchen, ZHANG Jian, WANG Yan, LIN Jinyi, ZHOU Yuhong, CHENG Leilei, GE Junbo. Therapeutic effects of tofacitinib on steroid-resistant immune checkpoint inhibitor-associated myocarditis[J]. China Oncology, 2024, 34(4): 400-408.

图/表 5

图1

表1

表2

对照组与托法替布组患者的临床特征及治疗信息"

Item	Comparator (n=17)	Tofacitinib (n=19)	P value	Item	Comparator (n=17)	Tofacitinib (n=19)	P value
ICI regimen n(%)				cTnT level, days following treatment
PD-1 inhibitors				cTnT of day 0^d/(ng·mL^-1)	0.55±0.44	0.30±0.26	0.043
Camrelizumab	3 (18)	6 (32)	0.35	cTnT of day 3/(ng·mL^-1)	0.50±0.51	0.29±0.33	0.16
Pembrolizumab	2 (12)	5 (43)	0.29	cTnT of day 7/(ng·mL^-1)	0.48±0.42	0.23±0.22	0.031
Toripalimab	3 (18)	2 (11)	0.56	cTnT of day 14/(ng·mL^-1)	0.42±0.36	0.16±0.17	0.008
Sintilimab	3 (18)	2 (11)	0.56	New ECG abnormality n(%)
Tislelizumab	3 (18)	0 (0)	-	Atrial fibrillation	1 (6)	1 (5)	0.97
Nivolumab	0 (0)	1 (5)	-	Supraventricular tachycardia	0 (0)	1 (5)	-
PD-L1 inhibitors				Ventricular arrhythmia	3 (18)	2 (11)	0.56
Durvalumab	1 (6)	0 (0)	-	High degree atrioventricular block	3 (18)	2 (11)	0.56
ZKAB001	0 (0)	1 (5)	-	New bundle branch block	3 (18)	3 (16)	0.90
PD-1/CTLA-4 inhibitors				T wave or ST segment abnormality	9 (53)	7 (37)	0.35
Candonilimab	1 (6)	2 (11)	0.64	Echocardiography
Unknown^a	1 (6)	0 (0)	-	LVEF (%)^e	60.6±9.4	61.5±8.1	0.79
Clinical presentation n(%)				New decline in LVEF n(%)	4 (24)	3 (16)	0.58
Chest pain	3 (18)	2 (11)	0.56	Pericardial effusion n(%)	1 (6)	0 (0)	-
Dyspnea	8 (47)	9 (47)	1.00	CMR n(%)
Palpitations	4 (24)	3 (16)	0.58	CMR performed	9 (53)	12 (63)	0.55
Myalgias	6 (35)	5 (26)	0.58	Myocarditis confirmed	2 (12)	2 (11)	0.93
Weakness	9 (53)	10 (53)	1.00	Myocarditis suggestive	7 (41)	8 (42)	0.97
Dizziness	1 (6)	3 (16)	0.37	Normal	0 (0)	2 (11)	-
Diplopia and/or ptosis	6 (35)	5 (26)	0.58	Myocardial biopsy n(%)	1 (6)	2 (11)	0.64
Concomitant irAE^b n(%)				Pharmacological management n(%)
Myositis	6 (35)	5 (26)	0.58	Intravenous steroids	17 (100)	19 (100)	1.00
Endocrine (thyroiditis or hypophysitis)	3 (18)	2 (11)	0.56	Additional immunosuppressive drugs	9 (53)	19 (100)	-
Hepatitis	4 (24)	1 (5)	0.12	Intravenous immunoglobulin	9 (53)	0 (0)	-
Pneumonitis	2 (12)	0 (0)	-	Infliximab	2 (12)	0 (0)	-
Neuritis	2 (12)	1 (5)	0.51	Plasma exchange	1 (6)	0 (0)	-
Grade of myocarditis^c n(%)				Tofacitinib	0 (0)	19 (100)	-
Grade 3	9 (53)	9 (47)	0.76
Grade 4	8 (47)	10 (53)	0.76

表2

图2

图3

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Item	Comparator (n = 17)	Tofacitinib (n = 19)	P value	Item	Comparator (n = 17)	Tofacitinib (n = 19)	P value
Patients’ characteristics				Cerebral vascular disease n(%)			0.90
Age at diagnosis/year	64.2±9.7	64.1±9.7	0.93	Yes	3 (17.6)	3 (15.8)
Gender n(%)			0.87	No	14 (82.4)	16 (84.2)
Male	13 (72.2)	14 (73.7)		Autoimmune disease n(%)			-
Female	4 (27.8)	5 (26.3)		Yes	0 (0.0)	1 (5.3)
Smoking n(%)			0.66	No	17 (100.0)	19 (94.7)
Yes	5 (29.4)	7 (36.8)		Cancer type n(%)
No	12 (70.6)	12 (63.2)		Gastroenteric cancer	9 (52.9)	7 (36.8)	0.35
Hypertension n(%)			0.97	Hepatoma	5 (29.4)	4 (21.1)	0.58
Yes	7 (41.1)	8 (42.1)		Genitourinary cancer	0 (0.0)	3 (15.8)	-
No	10 (58.9)	11 (57.9)		Skin	1 (5.9)	0 (0.0)	-
Diabetes mellitus n(%)			0.90	Other	2 (17.6)	5 (26.3)	0.29
Yes	3 (17.6)	3 (15.8)		Baseline laboratory tests
No	14 (82.4)	16 (84.2)		Neutrophil absolute value (10⁹/L)	45.4±37.3	63.4±16.6	0.63
Coronary artery disease n(%)			0.75	Lymphocyte absolute value (10⁹/L)	16.8±14.8	23.6±13.7	0.28
Yes	2 (11.8)	3 (15.8)		Albumin/(g·L^-1)	40.7±7.5	40.0±5.4	1.00
No	15 (88.2)	16 (84.2)		Platelet value (10⁹/L)	161.7±51.9	163.4±62.4	0.88
Prior history of LV systolic dysfunction n(%)			-	CRP/(mg·L^-1)	9.0±5.8	7.7±4.1	0.79
Yes	0 (0.0)	1 (5.3)		LDH/(U·L^-1)	137.3±29.7	276.0±108.8	0.057
No	17 (100.0)	19 (94.7)		TNF-α/(nmol·L^-1)	2.12±0.1	1.43±0.2	0.095