Therapeutic effects of tofacitinib on steroid-resistant immune checkpoint inhibitor-associated myocarditis

doi:10.19401/j.cnki.1007-3639.2024.04.007

Abstract

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

CLC Number:

R730.6

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.

Figures/Tables 5

Fig. 1

Tab. 1

Tab. 2

Clinical details and management of comparator and tofacitinib group"

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

Tab. 2

Fig. 2

Fig. 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