Authors: Sally Badaan, Adi Abbass, Svetlana Tov, Gil Bar-Sela, Naiel Bisharat
Categories: Review, Adverse effects, Cardiac biomarkers, Cardiac troponin, Cardiac magnetic resonance imaging, Immune checkpoint inhibitor, Management, Myocarditis, Myositis, Myasthenia gravis.
Source: Cardio-oncology
Authors: Sally Badaan, Adi Abbass, Svetlana Tov, Gil Bar-Sela, Naiel Bisharat
Immune checkpoint inhibitors (ICIs) have significantly advanced cancer therapy. However, these therapies can disrupt immune self-tolerance, leading to immune-related adverse events, among which immune checkpoint inhibitor-related myocarditis (ICIrM) is associated with the highest mortality rates. Clinical presentation of ICIrM varies widely, ranging from asymptomatic cardiac biomarker elevation to fulminant heart failure. As such, uniform treatment guidelines may not be appropriate, and a personalized approach is essential. There is no universal consensus on routine screening; however, baseline ECG and echocardiography are recommended by most cardio-oncology guidelines. Serial cardiac biomarker monitoring may aid in early detection and intervention. Both cardiac troponin T and cardiac troponin I are sensitive for the diagnosis of ICIrM and prognosis of increased risk of major adverse cardiovascular events. Two diagnostic frameworks for ICIrM help clinicians in establishing diagnosis. Echocardiographic global longitudinal strain measurement provides a more sensitive risk assessment than traditional measures like ejection fraction. Cardiac MRI plays a critical role, offering high diagnostic accuracy. Endomyocardial biopsy confirms ICIrM and provides both diagnostic and prognostic information based on the presence or absence of myocyte necrosis. For confirmed ICIrM, corticosteroids remain the cornerstone of therapy, with high-dose regimens shown to reduce major adverse cardiovascular events. In steroid-refractory or severe cases, adjunctive immunomodulators such as mycophenolate mofetil, janus kinase inhibitors, and notably abatacept are utilized, although evidence is largely case-based. Abatacept, a CTLA-4 fusion protein, is the only drug under investigation in a randomized trial as a targeted therapy for ICIrM. In conclusion, ICIrM represents a diagnostic and therapeutic challenge due to its rarity, heterogeneous presentation, and the limitations of current tools. By describing the management of three illustrative real-life cases, this article aims to provide a framework for individualized management of ICIrM in adults, integrating current guidelines, literature, and clinical experience. Continued research and prospective trials are critical to refine diagnostic algorithms and improve patient outcomes.
The advent of immune checkpoint inhibitors (ICIs) has revolutionized cancer therapy, with rapidly expanding indications for their use. These monoclonal antibodies boost T cell-mediated antitumor activity by blocking inhibitory immune pathways, including the programmed cell death protein 1 (PD-1) and its ligand (PD-L1), as well as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) [1, 2]. However, despite significant advances in cancer immunotherapy, these agents can disrupt T-cell self-tolerance, resulting in immune-related adverse events (irAEs)-autoimmune-like toxicities that may involve nearly any organ system [3]. The most common irAEs affect the skin, endocrine organs, liver, and gastrointestinal tract. Although cardiac toxicity is rare, it is associated with the highest mortality rate among irAEs [3, 4]. The exact mechanisms underlying the pathophysiology of immune checkpoint inhibitor-related myocarditis (ICIrM) are still unclear. Current knowledge suggests three potential mechanisms; an autoimmune response induced by the breakdown of inhibitory immune pathways resulting in T cell targeting myocardial tissue, cross-reactivity of tumor antigens that resemble cardiac or muscle antigens, and elevated blood levels of interleukin 17 (IL-17) triggered by ICI therapy [5]. The incidence of ICIrM is estimated at 0.35% to 1% [4, 6, 7], although higher rates have been reported [8]. Expanding use of ICIs, variations in diagnostic criteria, clinician vigilance, and surveillance protocols are likely to account for these discrepancies [9]. The spectrum of ICI induced cardiotoxicity includes ICIrM, pericarditis, vasculitis, acute coronary syndrome, conduction disturbances (e.g., complete atrioventricular block), atrial and ventricular arrhythmias, Takotsubo syndrome, and heart failure [10]. Myocarditis is the most frequently reported cardiac irAE, and combination ICI therapy (e.g., anti-CTLA-4 with anti-PD-1) is considered the most established risk factor for its occurrence [7]. Clinical manifestations of ICIrM are heterogeneous, ranging from asymptomatic cardiac biomarker elevation to fulminant heart failure. While asymptomatic cases may not require cessation of ICI therapy, patients with symptomatic myocarditis will often need to discontinue these potentially life-saving agents. As such, uniform treatment guidelines may not be appropriate, and a personalized approach based on clinical, laboratory, imaging, and pathological findings is essential. This article aims to provide a framework for individualized management of ICIrM in adults, integrating current guidelines, literature, and clinical experience.
The following real-life cases were all treated at our medical center, these cases exemplify the complexity and dilemmas of treating patients with ICIrM.
A 75-year-old woman diagnosed with melanoma of the scalp received her first treatment as part of a clinical trial involving bempegaldesleukin (NKTR-214) in combination with nivolumab (December 2021). A baseline transthoracic echocardiogram (TTE) demonstrated normal left ventricular systolic function (LVSF) with a normal average global longitudinal strain (GLS). Baseline cardiac biomarkers were not obtained. Approximately two weeks after initiating treatment, she began experiencing fatigue but denied muscle pain or chest discomfort. Cardiac biomarker testing revealed a significantly elevated high-sensitivity cardiac troponin T (hs-cTnT) of 500 ng/L (normal < 14), an elevated creatine phosphokinase (CPK) of 600 U/L (normal < 200), and a normal brain natriuretic peptide (BNP) level. Electrocardiogram (ECG) findings were unremarkable. A repeat echocardiogram showed no changes, with preserved GLS values. ICI therapy was discontinued. One week later, she reported no improvement in symptoms. Laboratory tests showed a decrease in CPK to 217 U/L, but hs-cTnT levels continued to rise, reaching 617 ng/L. At this point, prednisone was initiated at a dose of 1 mg/kg. Cardiac magnetic resonance imaging (CMR), performed nearly two weeks after symptoms onset, showed no signs of myocarditis. Her condition improved slowly with corticosteroid therapy, and a gradual tapering of prednisone was initiated over 10 weeks. Troponin levels remained elevated for five months, but CPK levels normalized within 4 weeks of ICI discontinuation. The patient declined to resume ICI treatment.
An 85-year-old man with a history of ischemic heart disease and hypothyroidism was diagnosed in June 2024 with metastatic melanoma involving a right inguinal lymph node. In July 2024, he received his first dose of neoadjuvant pembrolizumab prior to excisional removal of the affected lymph node. No baseline cardiac enzyme testing was performed prior to initiation of ICI therapy. A pre-treatment echocardiogram demonstrated normal LVSF. Prior to the second scheduled pembrolizumab dose, the patient developed generalized weakness, difficulty walking, bilateral ptosis, headaches, and shortness of breath. He denied chest pain. Blood tests revealed elevated CPK up to 4,330 U/L and a hs-cTnT level of 269 ng/L. He was hospitalized with a presumptive diagnosis of overlap syndrome—manifesting as a combination of myositis, myasthenia gravis-like symptoms, and myocarditis. Initial management included discontinuation of ICI therapy and initiation of intravenous methylprednisolone at 1.5 mg/kg/day along with pyridostigmine. Laboratory workup revealed elevated aspartate transferase (AST) of 650 U/L (N < 35), alanine transaminase (ALT) of 337 U/L (N < 45), and lactate dehydrogenase (LDH) of 896 U/L (N < 248). ECG monitoring did not reveal any abnormalities, and TTE showed preserved LVSF with a normal GLS values of 19%. Acetylcholine receptor antibody testing was negative. Electromyography (EMG) excluded neuropathy and classical myositis but revealed myopathic changes. After three days of corticosteroid therapy, there was no clinical improvement in ptosis or muscle weakness. While CPK, AST, ALT, and LDH levels began to trend downward, hs-cTnT levels continued to rise, peaking at 2,304 ng/L, while BNP levels were within normal limits. At this point, the methylprednisolone dose was increased to 1,000 mg/day, and intravenous immune globulin (IVIg) was administered over five days. Coronary angiography ruled out significant coronary artery disease and CMR, performed approximately 10 days after symptoms onset, did not show suggestive signs of myocarditis. Four weeks following ICI discontinuation, the patient continued to experience bilateral ptosis and weakness. He remained on prednisone at 0.5 mg/kg and pyridostigmine. At that time, hs-cTnT levels remained markedly elevated (~ 1,000 ng/L), although CPK, AST, ALT, and LDH had normalized. Approximately two months after the first (and only) pembrolizumab dose, the patient underwent surgical excision of the involved lymph node. He reported no clinical improvement and required continued treatment with prednisone (0.3–0.5 mg/kg) and monthly IVIg. Due to local disease recurrence, he received radiotherapy to the right groin. Three months after lymph node excision, the patient experienced significant local recurrence requiring extensive right inguinal dissection. Two months later, a positron emission tomography–computed tomography (PET/CT) scan revealed widespread metastatic disease involving the skeleton, lungs, and liver.
A 70-year-old male patient, with type 2 diabetes mellitus, hypertension, and ischemic heart disease was diagnosed with locally advanced cutaneous squamous cell carcinoma on both hands, for which he was treated with cemiplimab. Of note, baseline serum cardiac biomarker assays were not obtained prior to the initial immunotherapy administration. Approximately two weeks following the index treatment, the patient reported the onset of asthenia and myalgias. Subsequent laboratory tests revealed a markedly elevated CPK (2353 U/L) and elevated hs-cTnT concentration of 550 ng/L, while BNP level was within normal limits. TTE showed preserved LVSF, the presence of grade II diastolic dysfunction, and an abnormal GLS values [~ 13%]. Intravenous methylprednisolone at a dose of 2 mg/kg was initiated and continued for five days, following which hs-cTnT levels continued to exhibit an upward trajectory, while CPK concentrations reached a peak and subsequently decreased. A follow-up TTE did not reveal any change from previous exam. CMR was deemed non-diagnostic due to poor imaging quality caused by limited patient cooperation. Continuous electrocardiographic monitoring did not reveal any arrhythmias or conduction disturbances. Concurrently, the patient complained of dyspnea and bilateral lower extremity edema. Blood tests showed elevated hs-cTnT reaching 1250 ng/L. To pursue a definitive characterization, the potential for endomyocardial biopsy was discussed with the patient; however, the patient declined. Consequently, corticosteroid therapy was escalated to intravenous methylprednisolone at a dosage of 1000 mg per day for five days, followed by oral prednisone at a dosage of 1.5 mg/kg, without apparent clinical or biochemical improvement. At this stage mycophenolate mofetil was added. While serum CPK concentrations normalized within a two-week interval, hs-cTnT levels did not decrease and continued to rise reaching 1850 ng/L. Under the presumptive diagnosis of refractory myocarditis, and in the absence of a sustained clinical benefit, the addition of abatacept therapy was deemed necessary. Unfortunately, few days following abatacept administration, the patient developed a bloodstream infection complicated by multi-organ failure, ultimately leading to his death.
Making a diagnosis of ICIrM requires a multi-modal approach involving a combination of clinical manifestations, cardiac biomarkers, imaging, and sometimes endomyocardial biopsy (EMB). To date, several professional societies have published consensus statements on the diagnosis of ICIrM, while some have proposed specific diagnostic criteria [11], others have offered more general guidance without outlining defined criteria [12–14]. Establishing a diagnosis of myocarditis carries significant implications for patients, both in terms of potential complications—such as heart failure, life-threatening arrhythmias, and even death—and the broader consequence of discontinuing a potentially life-saving therapy. As such, diagnosing myocarditis places a considerable burden on the treating physicians, who are driven by a clear imperative not to miss such a critical diagnosis. Furthermore, this determination requires careful consideration of the severity of the condition, in order to guide appropriate treatment selection. The diagnosis of ICIrM will be discussed below after addressing clinical presentation, cardiac biomarkers, imaging, and EMB. Clinical manifestations range from asymptomatic troponin elevation to life-threatening disease. Symptoms may include fatigue, myalgias, chest pain, shortness of breath, orthopnoea, lower-extremity oedema, palpitations, light-headedness/dizziness, syncope, muscle weakness, and cardiogenic shock. The American Society of Clinical Oncology (ASCO) classifies ICIrM into four grades of severity (Table 1) [15]. It is notable that ICIrM may present concurrently with myositis (e.g., myalgia, muscle weakness) and myasthenia gravis-like symptoms (e.g., ptosis, diplopia, dysphagia), likely due to shared antigens between cardiac and skeletal muscle tissues [7]. The time to onset of myocarditis following initiation of ICI therapy is variable, ranging from few days and up to 1 year. However, the vast majority of cases present early, with a median onset of one month after initiation of therapy [4, 16–18].
Table 1Grades of severity of immune checkpoint inhibitor related myocarditisGrade 1Asymptomatic with elevated cardiac biomarkers or ECG abnormalitiesGrade 2Mild symptoms with abnormal cardiac biomarkers or ECG findingsGrade 3Moderate disease, defined by a reduced left ventricular ejection fraction (< 50%), regional wall motion abnormalities, or cardiac MRI findings consistent with myocarditisGrade 4Severe, life-threatening disease including cardiogenic shock, overt heart failure, or complete atrioventricular block.
Although elevations of cardiac troponin I (cTnI) and cardiac troponin T (cTnT) are both considered sensitive for the diagnosis of ICIrM and prognosis of increased risk of major adverse cardiovascular events (MACE) [19–21], some authors favor the use of cTnI due to concerns that cTnT elevations in patients with immune-related myositis may occur without cardiac involvement [20, 22–26]. Nevertheless, serial monitoring of both cTnT and cTnI in a cohort of 60 patients hospitalized with ICIrM showed that cTnT has superior diagnostic performance compared to cTnI, though exhibiting a more prolonged and sustained elevations compared to a rapid rise and decline of cTnI [20]. Additionally, a large observational study of adults who received at least one dose of ICIs and underwent systematic serial testing for muscle enzymes (AST, ALT, LDH, and CPK) during ICI therapy showed that a total of 95% of patients with ICIrM had elevations in at least 3 biomarkers compared with 5% of patients without myocarditis. Among the noncardiac biomarkers, only CPK was associated with the development of myocarditis and all-cause mortality [21]. Therefore, in terms of diagnosis and prognostication, cTnI, cTnT, and CPK, are all important biomarkers for the diagnosis and prognosis of ICIrM. Natriuretic peptides, are valuable in assessing cardiac function and can help identify heart failure or significant cardiac stress. Monitoring BNP levels can help track the response to corticosteroid treatment and guide further management [27, 28]. However, unlike cTn, elevations in natriuretic peptides are not good predictors for MACE. But similar to troponin, these biomarkers are also nonspecific for ICIrM, and the clinical setting along with other modalities should be used to confirm the diagnosis [28]. Data on time to cTn normalization after ICIrM are limited, but can be prolonged and up to several months [29–32].
Electrocardiogram (ECG) studies are a fundamental component of the diagnostic workup for ICIrM. While current guidelines do not support the routine use of serial ECGs in all patients undergoing ICI therapy, they do recommend obtaining a baseline ECG prior to initiation of treatment [11]. ECG plays a critical role in detecting early signs of myocarditis, such as sinus tachycardia and prolonged QTc intervals—both identified as predictors of severe myocarditis [33]. Other common ECG abnormalities in severe ICIrM include new-onset arrhythmias, ST-T segment changes, and fragmented QRS complexes [34]. Additionally, a prolonged QRS duration on ECG is associated with an increased risk of MACE in patients with ICIrM, each 10 ms increase in QRS duration was associated with a 1.3-fold increase in the odds of MACE, underscoring the prognostic value of this parameter [35].
Echocardiography is a key diagnostic modality in the evaluation of ICIrM. It may reveal reduced left or right ventricular ejection fraction and regional wall motion abnormalities suggestive of myocardial involvement [14]. However, a preserved LVSF is not sufficient for ruling out myocarditis and is not necessarily indicative of a favorable prognosis [4, 36]. In contrast, GLS measurement has emerged as a more sensitive and earlier marker of myocardial injury; its reduction has been associated with increased risk of MACE [37]. These findings support the routine integration of GLS measurement into echocardiographic evaluations for enhanced risk stratification. In addition to baseline imaging at presentation, serial echocardiographic assessments are valuable for monitoring disease progression and therapeutic response.
CMR plays a central role in the diagnosis and management of ICIrM. Its advantage lies in the ability to combine detailed tissue characterization with functional assessment. The most relevant CMR markers in ICIrM are late gadolinium enhancement (LGE), T1 and T2 mapping, and extracellular volume fraction (ECV) quantification. Elevated native T1 values are of particular importance, as they have been shown to independently predict major adverse cardiac events [38]. T2 mapping, indicative of myocardial edema, is also frequently abnormal in affected patients [39]. Incorporating both T1 and T2 mapping into the modified Lake Louise Criteria has significantly enhanced diagnostic accuracy for myocarditis [38]. However, within the context of ICIrM, the diagnostic performance of LGE, T1, and T2 remains limited in the detection of early or mild disease, and current evidence describing their specific behavior in this setting is inconclusive [40, 41]. Notably, postponing CMR for at least 4 days following symptom onset has been associated with improved diagnostic accuracy [40]. Moreover, LGE is not entirely it may appear in non-inflammatory cardiac conditions, lacks sensitivity for early myocardial involvement, and fails to detect changes that occur without fibrosis [36]. Importantly, prior myocardial injury has been associated with reduced sensitivity of both LGE and the Lake Louise Criteria in diagnosing ICIrM [41]. Finally, although CMR provides unique diagnostic advantages, its use is restricted in certain clinical settings. The need for prolonged acquisition times and patient cooperation during breath-hold sequences can limit its feasibility in critically ill patients.
Current clinical guidelines do not specify criteria for the use of PET/CT in diagnosing ICIrM. Its use is mainly in specific clinical scenarios where other diagnostic modalities are inconclusive or when assessing for systemic involvement. A study evaluating the diagnostic utility of ^18^F-fluorodeoxyglucose (FDG) PET/CT in ICIrM found that its value in this setting may be limited [42], while others reported more promising results using ^68^Ga-DOTATOC (^68^Gallium- Edotreotide) PET/CT [43].
Endomyocardial biopsy (EMB) is considered the gold standard for diagnosing myocarditis, including myocarditis induced by ICIs. The primary use of EMB is in cases where the diagnosis of myocarditis cannot be confirmed due to the absence of definitive findings in non-invasive tests. EMB findings from patients on ICI therapy were used to describe a grading system for ICIrM correlating with clinical outcomes [44]. The study showed that patients with higher grades of inflammation (inflammatory infiltrate with myocyte necrosis) had worse outcomes compared with those exhibiting inflammatory infiltrate without myocyte necrosis, emphasizing the diagnostic and prognostic value of EMB. An additional, equally important aspect of this grading is that patients who exhibited an inflammatory infiltrate without myocyte necrosis were able to continue ICI therapy without requiring immunosuppressive treatment [44]. There are several limitations associated with EMB. First, it is not readily available in all medical centers. Second, the inflammatory process is often focal rather than diffuse, and to optimize diagnostic yield, it is necessary to obtain at least five separate biopsies from each patient to minimize the risk of a missed diagnosis. In line with that, a recent systematic review suggested that left ventricular EMB, compared to right ventricular EMB, provides a higher diagnostic yield in diagnosing myocarditis [45]. Additionally, this is an invasive procedure, which many patients are reluctant to undergo due to the potential risk of complications and the fact that their medical condition may not permit such an invasive intervention.
Diagnosing ICIrM remains a significant clinical challenge. Currently, two primary diagnostic frameworks have been proposed. The first, by Bonaca et al. introduced in 2019, classifies ICIrM as ‘definite,’ ‘probable,’ or ‘possible’ based on clinical and diagnostic findings [46] (Fig. 1). The second, introduced in 2022 by the European Society of Cardiology (ESC) in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS), provides a unified diagnostic approach, issuing a single diagnosis of ICIrM when specific criteria are met [11] (Table 2). Aside from EMB, both sets of criteria incorporate a combination of clinical presentation, elevated cardiac biomarkers, and imaging abnormalities detected by TTE and CMR, though the emphasis on each component differs between the two frameworks [47, 48]. A comparison between the two diagnostic frameworks revealed that the ESC/EHA/ESTRO/IC-OS criteria are more stringent than those proposed by Bonaca et al., for diagnosing ICIrM, while offering comparable prognostic value [49].
Fig. 1 Proposed diagnostic criteria for ICIrM introduced in 2019 [46] cTn; cardiac troponin, CMR; Cardiac magnetic resonance imaging, ECG; electrocardiogram, ICIrM; immune checkpoint inhibitor related myocarditis, TTE; transthoracic echocardiogram, WMA; wall motion abnormality, 18 F-FDG PET: 18 F-fluorodeoxyglucose positron emission tomography
Table 2Proposed diagnostic criteria introduced in 2022 by the ESC, EHA, ESTRO, and the IC-OS (11)ESC European society of cardiology, EHA European Hematology Association, ESTRO European Society for Therapeutic Radiology, IC-OS International Cardio-Oncology Society
Two diagnostic frameworks for ICIrM help clinicians in establishing diagnosis.Both cTnT and cTnI are sensitive for the diagnosis of ICIrM and prognosis of increased risk of MACE.Monitoring BNP levels can help track the response to corticosteroid treatment but unlike cTn, elevations in natriuretic peptides are not good predictors for MACE.Elevated CPK in patients with irAEs is associated with myocarditis and all-cause mortality.Echocardiographic GLS measurement provides a more sensitive risk assessment than traditional measures like ejection fraction.CMR is a key tool in diagnosing ICIrM; while T1/T2 mapping and LGE improve accuracy, their sensitivity is reduced in early or mild disease.EMB confirms ICIrM and provides both diagnostic and prognostic information based on the presence or absence of myocyte necrosis.
Given the high risk of severe cardiovascular complications such as heart failure, arrhythmias, and cardiogenic shock, all patients with ICIrM should be treated. The severity of myocarditis can vary, and treatment should be tailored accordingly. Additionally, once ICIrM is suspected or diagnosed, ICI therapy must be stopped till further work up is completed. The mainstay of therapy is high-dose corticosteroids which is clearly associated with lower risk of MACE. Patients presenting with severe myocarditis, characterized by rapid progression to cardiogenic shock or refractory arrhythmias, require immediate and aggressive treatment. This includes high-dose corticosteroids (pulse dose intravenous methylprednisolone at 1,000 mg daily for 3–5 days) followed by lower doses (usually 1–2 mg/kg) for 3–4 days, then prednisone at 1 mg/kg and tapering over 4–20 weeks. This approach is supported by clinical practice guidelines by nearly all international societies of oncology and immunotherapy, which found that severe cases required aggressive management, including high dose corticosteroids, additional immunosuppressive therapies, and potentially mechanical circulatory support [4, 15, 27, 48, 50–55]. The only exception to that, are the ASCO guidelines that advise using lower doses of corticosteroids (e.g., oral or IV 1–2 mg/kg of prednisone) and increase to higher doses if there is no immediate response [14]. For patients with mild-moderate myocarditis (severity grade < 3), some advice to consider regular-dose corticosteroids (1–2 mg/kg) [14, 56]. This however is not supported by the ESC and Society of Immunotherapy of Cancer (SITC) guidelines that do not distinguish between severity grades of ICIrM and steroid dosing. For patients with subclinical asymptomatic elevations in cTn (grade 1), lower-dose steroids are recommended [36, 55] (Fig. 2).
Fig. 2Treatment algorithm of immune checkpoint related myocarditis. ICI; immune checkpoint inhibitors, ICIrM; immune checkpoint inhibitor related myocarditis, LVSF; left ventricular systolic function, BNP; brain natriuretic peptide * See text for detailed discussion
To date, no standardized definitions for assessing therapeutic response exist. Current clinical practice typically defines response based on a combination of factors, including the absence of life-threatening arrhythmias, stable hemodynamic parameters, improved LVSF, and a downward trend in cTn levels. Conversely, the lack of clinical improvement, and either stagnation or rebound of cTn levels after a decline are indicative of a lack of response [55].
Treat all suspected/confirmed cases; hold ICI therapy during evaluation.High-dose corticosteroids is recommended, with pulse IV methylprednisolone for severe cases, followed by taper.No standard definition exists for defining response; monitor clinical stability, LV function, arrhythmias, and troponin decline.
Current practice guidelines recommend the use of non-steroidal immunomodulators in patients who are unresponsive to corticosteroids. However, in cases of severe, life-threatening myocarditis (e.g., heart failure with severely reduced LVSF, ventricular arrhythmias, cardiogenic shock), earlier administration of non-steroidal immunomodulators either as adjunct therapy with corticosteroids or within 24 h is endorsed by the ESC [48] and other clinical practice guidelines [36]. In this context, current evidence is insufficient to support the recommendation of a specific non-steroidal immunomodulator, and a multidisciplinary approach is advised. Some authors have explicitly advocated for the use of abatacept in such clinical circumstances [36].
To date, several non-steroidal immunomodulators have been utilized as adjunct therapies to corticosteroids in patients with ICIrM, either alone or in combination [57]. These include IVIg [58] and plasmapheresis [59], both of which are commonly employed in autoimmune disorders. Drugs targeting T-cell mediated immunity including anti-thymocyte globulin (ATG) [60, 61], mycophenolate mofetil [62], infliximab [29] [caution is advised against the use of infliximab for steroid-refractory myocarditis and heart failure [63, 64] and alemtuzumab (anti-CD52) which binds specifically to CD52, a cell surface antigen highly expressed on T and B lymphocytes, leading to the depletion of circulating CD52-positive cells [65]. Tocilizumab (an interleukin-6 receptor antagonist) prevents IL-6 signaling to inflammatory mediators that recruit B and T cells [66–68]. Additionally, Janus kinase inhibitors, such as ruxolitinib and tofacitinib, inhibit cytokine-activated T cell maturation and the signaling of IL-6 and IL-15 [69–71]. Notably, abatacept, due to its mechanistic specificity, represents perhaps the most targeted immunomodulatory therapy for ICIrM. Abatacept is a CTLA-4 immunoglobulin fusion protein that binds CD80/CD86, leading to T-cell anergy by specifically reversing pathways activated by ICIs [70, 72, 73]. Current guidelines for adjunctive therapies in ICIrM are not uniform across international societies. While the National Comprehensive Cancer Network (NCCN) recommends abatacept for steroid-refractory myocarditis [74], the European Society of Medical Oncology (ESMO) advises its use as a third-line option [75], following second-line therapies such as mycophenolate or tocilizumab, and the ASCO suggests administering abatacept only in life-threatening cases after the use of mycophenolate, infliximab, or ATG [14].
Assessing the comparative efficacy of the different non-steroidal immunomodulators is challenging, as the available evidence is primarily based on case reports or case series. Moreover, in several instances, patients received multiple treatments during hospitalization, making it difficult to determine which specific intervention contributed to the final outcome [59, 62, 70, 71, 76]. Due to its mechanistic specificity, abatacept is the only immunomodulatory drug that is currently enrolled in a randomized trial to test in efficacy in patients with ICIrM (ATRIUM: AbatacepT for ImmUne Checkpoint Inhibitor Associated Myocarditis) (NCT05335928).
Non-steroidal immunomodulators are recommended for steroid-refractory cases. Earlier administration is advised in severe, life-threatening myocarditis.Abatacept is the most targeted therapy mechanistically and is the only agent currently being studied in a randomized clinical trial.
The patient suffered from fatigue without myalgia or chest pain and without electrocardiographic or echocardiographic signs of myocarditis. Her CPK levels normalized within 4 weeks of ICI discontinuation, but elevated cTnT levels persisted for 5 months and decreased very slowly. The patient was treated with prednisone that was tapered slowly (over 10 weeks). In this case there were no suggestive signs of myocarditis, but elevated cTnT necessitated workup to rule out myocarditis and ICI discontinuation. Currently, there is no universally accepted threshold for cardiac troponin elevation that indicates ICIrM. Nonetheless, some expert consensus suggests that an increase exceeding five times the upper limit of normal may serve as a cut-off to prompt further diagnostic evaluation [36].
The patient presented with predominant neuromuscular features that appeared within 3 weeks after the first exposure to ICI therapy. Apart from markedly elevated cTn we did not identify any other suggestive signs of myocarditis. Elevations in cTn levels in patients treated with ICI do not necessarily lead to myocarditis diagnosis as evidenced by a recent study that examined the dynamics of cTnT in patients treated with ICI [77]. The study found that significant elevations in hs-cTnT were often asymptomatic and did not always lead to a myocarditis diagnosis. Due to persistent neurological symptoms the patient continued on chronic steroid therapy (0.3 mg/kg) together with monthly administration of IVIg. Abnormal cTn levels persisted for 6 months opposed to muscle enzymes that normalized within 4–6 weeks. Current practice guidelines suggest to use upfront plasmapheresis for 5 sessions concomitantly with steroids for patients presenting with overlap ICIrM and myositis/myasthenia gravis like syndromes [36], and use antibody mediated therapies such as IVIg or rituximab for those that are left with predominant neuromuscular symptoms [36, 74].
This case highlights two critical aspects associated with ICIrM: the challenges of establishing diagnosis and the management of refractory cases. In the present case, the patient was diagnosed with ICIrM, based on elevated hs-cTnT and the presence of two minor peripheral limb edema and another irAE (myositis). Definitive confirmation of the diagnosis was not possible, as the patient declined endomyocardial biopsy. The patient was considered steroid-refractory, given the lack of clinical or biochemical improvement despite receiving high-dose pulse methylprednisolone therapy. Despite preserved LVSF on multiple echocardiographic assessments, GLS measurements were consistently abnormal, averaging 13%. Although baseline GLS data prior to the initiation of ICI therapy were not available, the combination of poor clinical response to corticosteroid therapy and persistently reduced GLS values suggested an ongoing myocardial inflammation. This finding supported the decision to escalate immunosuppressive treatment. Unfortunately, the patient developed a severe bloodstream infection and succumbed to septic complications, precluding assessment of abatacept’s therapeutic efficacy.
ICIrM remains a rare but potentially fatal complication of cancer immunotherapy, requiring a multidisciplinary approach for timely diagnosis and management. Given the heterogeneous presentation and lack of standardized diagnostic criteria, individualized care based on clinical, biomarker, and imaging data is essential. These cases underscore the limitations of current diagnostic tools, the difficulty in interpreting elevated troponin levels, the importance of considering overlap syndromes, and the challenges in treating refractory cases. The cases also underscore the variable utility of ECG and TTE, the lack of consensus on routine troponin screening, and the need for individualized treatment plans based on the severity of the condition and the patient’s clinical context. Ongoing trials, such as ATRIUM, are expected to inform future treatment algorithms and improve outcomes in this challenging patient population.