Three Cases of Immune Myocarditis Associated with Camrelizumab Use

Camrelizumab, which was launched in China on May 29, 2019, is a humanized anti-programmed cell death-1 (PD-1) antibody. It is used for the treatment of complicated or refractory classic Hodgkin’s lymphoma with at least second-line chemotherapy. Upon administration, the antibody binds to and blocks the binding of PD-1 (expressed on activated T lymphocytes, B cells, and natural killer cells) to its ligands programmed cell death ligand 1 (PD-L1), overexpressed on certain cancer cells, and programmed cell death ligand 2 (PD-L2), which is primarily expressed on antigen-presenting cells. This prevents the activation of PD-1 and its downstream signaling pathways and restores immune function through the activation of cytotoxic T lymphocytes and cell-mediated immune responses against tumor cells or pathogens [1]. The PD-1 binding epitope of camrelizumab is different from that of pembrolizumab and nivolumab. Its heavy chain CDRH2 region has a unique interaction with the N-glycosylated molecule at position ASN58 of the PD-1 molecule [2]. China has approved the drug for four indications due to its good antitumor activity: advanced hepatocellular carcinoma, advanced nasopharyngeal carcinoma, advanced non-small cell lung cancer, and advanced esophageal squamous carcinoma. Clinical trials have confirmed camrelizumab’s significant efficacy in gastric, pancreatic, renal, cervical, and numerous other cancers [3]. The most common adverse reaction of camrelizumab was reactive capillary endothelial proliferation, in addition to hepatic adverse reactions, endocrine disorders, pulmonary inflammation/interstitial lung disease, and other immune-related adverse events [2]. Similar to other immune checkpoint inhibitors, immune-associated myocarditis, with its low incidence and high mortality rate of 50% in clinical studies, is the most mortality-prone adverse event among immune-related adverse events [4]. Several cases of immune-associated myocarditis have been reported in the literature following the drug’s marketing [4‒8]. In this article, we report three cases of immune myocarditis caused by camrelizumab, discuss the clinical features and laboratory test changes associated with ICI-induced myocarditis, and analyze immunosuppressive treatment strategies.

A 44-year-old male with nasopharyngeal squamous cell carcinoma (stage T2N3M0 IVA) diagnosed in January 2023 was admitted to the Oncology Center of Shandong Provincial Hospital on April 24, 2023, for his 4th cycle of treatment. CT scan and pathological specimens from a nasal endoscopy showed nasopharyngeal occupancy.

The patient received three cycles of chemotherapy plus immunotherapy from February 1 to April 6, 2023. The regimen consisted of cisplatin 60 mg, gemcitabine 1.6 g, and camrelizumab 200 mg, administered in 21-day cycles. He was discharged with normal laboratory results but developed an itchy head rash after discharge. He denied any other discomfort and reported no prior medical history of hypertension, coronary atherosclerotic heart disease, or chronic diseases. He also denied allergies to medications or foods.

Physical examination on admission revealed a temperature of 36.0°C, heart rate of 102 beats/min, respiration of 20 beats/min, and blood pressure of 122/100 mm Hg. He appeared well nourished, clear, and cooperative, and reported no obvious discomfort. Examination of the precordium showed no bulge, apical beat diffusion, tremor, or enlarged cardiac borders. Auscultation revealed rhythmic heart sounds without pathological murmurs.

An electrocardiogram showed sinus rhythm with a normal tracing, and a cardiac ultrasound showed no abnormalities of intracardiac structures. Laboratory tests revealed elevated levels of ultrasensitive troponin T (hs-TnT) at 653.00 pg/mL (reference value: 0–14 pg/mL), creatine kinase isoenzyme mass (CK-MB) at 22.60 ng/mL (reference value: 0.1–4.94 ng/mL), and myoglobin (Mb) at 142.00 ng/mL (reference value: 28–72 ng/mL).

Eighteen days after his last dose, the patient was diagnosed with immune myocarditis caused by camrelizumab. He was immediately started on intravenous methylprednisolone sodium succinate 500 mg daily. After 4 days of treatment, he reported no significant discomfort, and follow-up laboratory results showed improvement: hs-TnT decreased to 125.00 pg/mL, CK-MB to 2.96 ng/mL, and Mb to 29.2 ng/mL. Brain natriuretic peptide (NT-proBNP) remained elevated at 798.00 pg/mL (reference value: 0–125 pg/mL).

The methylprednisolone dose was reduced to 240 mg for 2 days on the fourth day of treatment. With continued improvement in his condition and declining cardiac biomarkers, the dosage was gradually tapered to 40 mg once daily. The patient was discharged on May 9 with instructions to continue prednisone acetate 40 mg orally once daily.

During follow-up, the patient reported good general health with no significant abnormalities in laboratory tests. The prednisone dosage was gradually reduced and eventually discontinued.

A 69-year-old male with progressive dysphagia and occasional chest pain for over 2 months was admitted to the Shandong Provincial Hospital Oncology Center. Based on CT and pathological tests on April 17, 2023, he was diagnosed with squamous esophageal carcinoma of the middle and lower thoracic esophagus with metastasis to the omental bursa, retroperitoneal lymph nodes, left adrenal gland, and pancreatic invasion. The large tumor invaded the stomach fundus, posing a risk for hemorrhage. Past medical history included coronary artery disease for 3 months with no significant symptoms and no medications. He denied hypertension, diabetes mellitus, other systemic diseases, and food/drug allergies.

On admission, physical examination revealed a temperature of 36.5°C, heart rate of 88 beats/min, respiratory rate of 21 breaths/min, and blood pressure of 135/85 mm Hg. He appeared wasted and malnourished but had clear mentation. No precordial bulge was noted. Heart sounds were normal with no murmurs. ECG showed sinus rhythm with complete right bundle branch block. Cardiac ultrasound revealed segmental ventricular wall dyskinesia and a small pericardial effusion.

Laboratory tests indicated esophageal obstruction, poor nutrition, moderate anemia, and hypoproteinemia. To ensure nutrition, a gastric tube was placed on April 21. Albumin supplementation and treatment for anemia were initiated. After cardiology consultation, a single cycle of antitumor therapy was administered on April 24. The regimen included 400 mg of albumin paclitaxel, 60 mg of cisplatin, and 200 mg of camrelizumab intravenously every 21 days.

On the night of chemotherapy, the patient developed diarrhea and a fever of 38.4°C. He received diosmectite for diarrhea and levofloxacin for suspected infection. Cardiac biomarkers rechecked on April 25 showed significant elevations (hs-TnT 575.00 pg/mL, CK-MB 33.90 ng/mL, and NT-proBNP 15,497.00 pg/mL). ECG demonstrated sinus rhythm with right bundle branch block, left anterior branch block, and nonspecific ST-T segment abnormalities in the lower leads. Cardiac ultrasound remained consistent with segmental ventricular wall dyskinesia but showed thickening of both left and right ventricles. Despite these findings, the patient reported no chest tightness, shortness of breath, chest pain, or other discomfort, and his vital signs were stable. After a day of observation, immune myocarditis secondary to camrelizumab was suspected, and methylprednisolone sodium succinate injection 500 mg intravenously daily was initiated.

High-dose corticosteroids resulted in a significant decrease in cardiac biomarkers. After 3 days of treatment, the patient appeared drowsy but had stable vital signs. Laboratory results showed hs-TnT 211 pg/mL, CK-MB 10.40 ng/mL, procalcitonin (PCT) 0.51 ng/mL (reference: 0–0.05 ng/mL), and NT-proBNP 2,379.00 pg/mL. On the 5th day, he developed gastrointestinal bleeding of approximately 500 mL. Methylprednisolone was reduced to 240 mg daily on April 30.

A rebound in cardiac biomarkers was observed, prompting the addition of immunoglobulin 10 g daily on April 30. Due to severe anemia, he received blood transfusion, acid suppression, and hemostatic medications. An examination on May 2 revealed poor mentation, persistent vomiting of blood with black stools. Laboratory tests showed hs-TnT 364 pg/mml, CK-MB2.1 ng/mml, Mb 39 ng/mml, NT-proBNP 12,570.00 pg/mml. Methylprednisolone sodium succinate was reduced to 180 mg/dd and immunoglobulin to 180 mg/d, and immunoglobulin dosage was increased to 20 g/d. The patient died on May 2 due to advanced age, many underlying diseases, a high tumor load, combined immune myocarditis, recurrent gastrointestinal hemorrhage, and heart failure.

A male, 53 years old, was admitted to the Oncology Center of Shandong Provincial Hospital due to feeling of food obstruction for more than 9 months, chest tightness, and breath-holding for 4 days. He was diagnosed with cervical esophageal squamous carcinoma (cT3N2M0 stage III) and hypopharyngeal carcinoma (cT4aN2M0 stage IVA) according to CT and pathological specimens on May 24, 2023. The family refused surgery, and the patient had locally advanced esophageal cancer. After excluding contraindications to treatment, 3 cycles of chemotherapy combined with immunotherapy were given from 30 May to 20 July: the specific regimen was cisplatin 60 mg + paclitaxel (albumin-bound) 400 mg + camrelizumab 200 mg, intravenously, with a cycle of 21 days. The patient was discharged from the hospital at the end of the day with normal results from relevant laboratory tests.

The patient developed chest tightness and shortness of breath that had been present for 2 days by August 2, 2023. In order to alleviate the symptoms of breathlessness, he was treated with an infusion of fluids in the emergency clinic. After the completion of the infusion, he suddenly had dyspnea, accompanied by profuse sweating, and his oxygen saturation level was measured at 85%. He was admitted to the oncology center for 1 day and given symptomatic supportive treatments, including tracheotomy, nebulization, and rehydration.

The patient had no special medical history, a history of hypertension, heart disease, and other chronic diseases, and a history of drug and food allergies. Physical examination on admission revealed a temperature of 36.0°C, heart rate of 96 beats/min, respiration of 24 beats/min, blood pressure of 110/91 mm Hg (1 mm Hg = 0.133 kPa). Heart rate of 98 beats per minute; rhythm; heart sounds were normal; and there was no pathological murmur in each valvular auscultation area. An electrocardiogram showed sinus rhythm, borderline QT interval prolongation, extensive ST-T segment changes; a cardiac ultrasound showed myocardial thinning in the middle and lower left ventricular anterior wall, middle segment of the lower posterior wall, loss of motility, left ventricular systolic function: LVEF 54%, myocardial infarction or necrosis in the left ventricular anterior wall and lower posterior wall. Laboratory tests showed hs-TnT 174.00 pg/mL, PCT 6.81 ng/mL, interleukin-6 (IL-6) 43.10 pg/mL (reference value: 0–7 pg/mL), NT-proBNP 10,117.00 pg/mL. After a cardiology consultation, myocardial damage was suspected to be related to immunotherapy. Methylprednisolone sodium succinate (240 mg) was given on August 3.

Laboratory tests were repeated on August 5. The patient was alert and oriented, with improved chest tightness and wheezing compared to previously. The laboratory results showed improvement: hs-TnT 73.10 pg/mL, PCT 1.74 ng/mL, and NT-proBNP 2,565.00 pg/mL.

Despite 7 days of treatment, hs-TnT and NT-proBNP remained higher than the reference range and showed an upward trend on August 12. Laboratory tests revealed hs-TnT 67.60 pg/mL, Mb 23.50 ng/mL, NT-proBNP 5,841.00 pg/mL. An electrocardiogram review showed extensive ST-T segment abnormalities. Immunoglobulin (20 g/day) was added for 3 days, resulting in a decrease in cardiac biomarkers compared to the previous values. On August 16, the dose of (medication name) was reduced to 160 mg/day. Hs-TnT and NT-proBNP slowly decreased. After switching to prednisone acetate 60 mg orally once daily, the medication was gradually reduced to 80 mg/day. The patient’s condition stabilized, and they were discharged from the hospital on August 21.

During the follow-up period, the patient’s general condition remained good, with no significant abnormalities found in any subsequent laboratory tests. The medication was gradually reduced and eventually discontinued.

In this paper, 3 patients were suspected to have ICI-associated myocarditis due to elevated cardiac biomarkers (CK, CK-MB, hs-TnT, etc.) after treatment with camrelizumab. The cardiac biomarkers of the 3 patients were in the normal range before the administration of the drug, and the association between immune-associated myocarditis and camrelizumab was evaluated to be “very likely.”

The incidence of adverse cardiac events was reported in the literature [9] to be 69.4% in patients treated with PD-1, which was higher than in patients treated with CTLA-4 and PD-L1. A risk prediction model developed by Oren et al. [10] showed that patients with a history of heart failure, a history of acute coronary syndromes, and an age greater than 80 years were at a higher risk of developing ICI-associated myocarditis. These clinical factors may help identify patients at higher risk of ICI-induced myocarditis who may benefit from more rigorous cardiac monitoring.

The clinical manifestations of ICI-associated myocarditis may present as asymptomatic, mildly symptomatic, progressive, or fulminant myocarditis with cardiovascular symptoms such as shortness of breath, chest pain, syncope, heart failure, and arrhythmias, and may be combined with myositis and myasthenia gravis [11]. About 90% of patients have abnormal electrocardiograms, which may present as various types of arrhythmias [12], with relative specificity for atrioventricular block [13]. Cardiac biomarkers, elevated troponin I (cTnI) levels, are seen in about 94% of patients, usually significantly elevated in patients with clinical symptoms, and elevated BNP or NT-proBNP levels are seen in about 70% (13), while others, such as Mb, CK and CK-MB, aspartate aminotransferase, and lactate dehydrogenase, may be elevated [14, 15].

Vasbinder et al. [15] showed that in addition to hs-TnT, ICI-associated myocarditis is associated with changes in aspartate aminotransferase, alanine aminotransferase, and creatine phosphokinase (CPK), and that about 95% of patients with ICI-associated myocarditis have elevations in at least three biomarkers. Among noncardiac biomarkers, CPK correlates with the development of myocarditis and all-cause mortality, and of the non-troponin biomarker values observed within the first 30 days of hospitalization for myocarditis, CPK peaks the fastest, with a median time of peak attainment of 2 days prior to the diagnosis of myocarditis [15], which may serve as a predictive indicator of ICI-associated myocarditis. Noncardiac biomarkers that are increased, especially CPK, should be of greater concern for the assessment of ICI-associated myocarditis. Elevated cardiac biomarkers, which often precede the onset of clinical symptoms, are positively correlated with the severity of the disease, with cTn having the highest specificity, with a positivity rate of approximately 90% [16], and the higher the cTn and NT-proBNP, the greater the risk of death [17]. At symptom presentation, an echocardiogram may reveal decreased left or right ventricular ejection fraction (with global or regional abnormalities). Cardiac MRI can demonstrate evidence of myocarditis but is less sensitive than endomyocardial biopsy [11].

According to the ICI-associated myocarditis severity classification [18], the 3 patients in this paper were diagnosed with case 1 (grade G1), case 2 (grade G3, severe), and case 3 (grade G4, life-threatening). The NCCN guidelines suggest suspending ICI therapy upon detection of cardiotoxic reactions [19]. High-dose hormone shock therapy is preferred, but 24-h inefficacy and the need for alternative approaches should be considered. Combining other immunosuppressive drugs might also be necessary. Early and adequate glucocorticoids can improve myocarditis prognosis. If high-dose glucocorticoid shock therapy is contraindicated (e.g., upper gastrointestinal bleeding, severe infections, or poorly controlled diabetes mellitus), methylprednisolone sodium succinate 1–2 mg/kg/d and gamma globulin 0.4 g/kg/d may be attempted, along with direct intensive immunosuppressive therapy.

Case 2 had a poor prognosis due to several risk factors. Being on the 1st or 2nd treatment cycle is a risk factor, as 82.1% of national ICI-associated myocarditis cases occur during this period [20]. Additionally, the patient’s first immunotherapy, history of coronary artery disease, and abnormal electrocardiograms and segmental ventricular wall dyskinesia on cardiac ultrasound prior to treatment all contributed to a higher risk of cardiotoxicity. Furthermore, at the time of diagnosis, the patient’s tumor was large and invaded the fundus of the stomach, posing a constant risk of bleeding, making high-dose hormone shock therapy less favorable due to its gastrointestinal bleeding side effect.

Choice of treatment plan: After 3 days of hormone therapy, atrioventricular block still existed, fulfilling the definition of hormone-resistant myocarditis [21]. This necessitated consideration of an intensive or second-line immunosuppression program. The treatment failed to adjust the program in a timely manner. Five days after hormone therapy, immunoglobulin 10 g/d was added. Study [22] suggests that intravenous immunoglobulin is effective against ICI-related myocarditis. The Chinese consensus recommends a total intravenous immunoglobulin dose of 2 g/kg, with 20–40 g/d for the first 2 days, followed by a switch to 10–20 g/d for 5–7 days before discontinuation [23, 24]. The patient’s initial immunoglobulin dose was lower than the consensus recommended dose.

This article reports three consecutive cases of immune-associated myocarditis caused by camrelizumab within 1 month. A review of the camrelizumab drug insert mentioned a total of three cases (0.1%) of immune-associated myocarditis among 2,011 patients treated with the product, including two grade 1 and one grade 5 case. Several studies have shown the incidence of ICIs-associated myocarditis to be approximately 1% [13, 15] and that of PD-1 inhibitors to be approximately 0.5% [13]. However, due to nonspecific clinical presentation and lack of routine cardiac biomarker testing, the actual incidence may be underestimated [17]. The real-world incidence of ICI-associated myocarditis requires further research and attention. This article suggests baseline patient assessment before ICI treatment, cardiac monitoring for at-risk patients, readily adjusting the treatment regimen based on condition during treatment, and intensive follow-up and observation after immunotherapy. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000540891).

This study was conducted in accordance with the Declaration of Helsinki. Ethical approval is not required for this study in accordance with local or national guidelines. Written informed consent was obtained from the patients for the publication of this case report and accompanying images.

All authors declare no conflict of interest.

This study was supported by National Key Research and Development Program of Ministry of Science and Technology (2020YFC2008902).

W.J.: writing – original draft and formal analysis. Q.W.: literature review. Z.T.: data collection. W.Z.: case tracking and writing – review and editing. All authors contributed to the article and approved the submitted version.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.