Treatment of corticosteroid refractory immune checkpoint inhibitor myocarditis with Infliximab: a case series

Glucocorticoids remain the cornerstone of treatment for ICI myocarditis. Most patients experienced clinical improvement and biomarker normalization with steroid monotherapy. However, there remain several gaps in our understanding of the optimal medical therapy. There is no consensus on the initial dosing of steroids, the type of steroid, addition of alternative immunosuppressive agents when necessary, or outpatient steroid tapering protocols.

Mahmood et al. observed that MACE occurred less frequently in patients who received high-dose (> 2 mg/kg of prednisone or equivalent) steroids compared with those receiving low-dose steroids (< 1 mg/kg of prednisone or equivalent) [7]. In addition, Zhang et al. showed that initiating corticosteroids earlier and at higher doses was associated with lower risk of MACE [15]. The ASCO guidelines recommend 1 mg/kg of prednisone or equivalent either by mouth or intravenously [13]. Our clinical practice has been to administer 1 gram of intravenous solumedrol daily for three days, followed by a 1–2 mg/kg steroid taper of oral prednisone. The ASCO clinical practice guidelines for irAEs recommend a glucocorticoid taper over 4–6 weeks while trials for viral myocarditis have examined steroid treatment durations of at least 3 months and in some cases up to a year [12]. For ICI-mediated myocarditis, most case reports and case series track response to steroids by monitoring troponin levels. If the troponin levels increase, our practice has been to increase the steroid dose and extend the taper. This situation arose in one patient in our cohort who had a significant clinical deterioration when the troponin levels began to rise despite steroid therapy. However, we acknowledge that there is a lack of research into a standardized steroid protocol in these patients. Additionally, whether the ICI should be permanently discontinued or whether restarting ICI therapy is safe remains controversial. Our institution has not restarted anyone on ICI therapy after the development of grade 4 myocarditis. In addition to immunosuppressive therapy, patients should also receive appropriate cardiac support including inotropes, mechanical circulatory support, and management of arrhythmias including temporary pacemakers and external defibrillators when indicated. Our approach has been to treat ICI myocarditis aggressively as a potentially reversible complication of therapy even in patients with advanced incurable cancer. Decisions regarding levels of mechanical circulatory support offered to patients with active malignancy but a reversible cause of cardiac decompensation are controversial and need to be discussed with heart failure, cardiothoracic surgery and oncology. The intensity of therapy offered to individual patients should always be consistent with their stated goals of care.

There have been case reports or small case series describing the use of several immunomodulating agents for ICI-induced myocarditis with varying degrees of efficacy. These therapies include intravenous immunoglobulin, [16, 17] mycophenolate, [17] anti-thymocyte globulin, [18] plasmapheresis, [17] infliximab, [17] alemtuzumab, [19]] and abatacept [20]. In our cohort, we have demonstrated that infliximab, a chimeric IgG1 monoclonal antibody that blocks tumor necrosis factor-alpha, appears to be an effective and safe agent for steroid-refractory ICI myocarditis. Although there is a black box warning regarding the potential for infliximab to worsen heart failure based on observations by Kwon et al. of the development of heart failure in patients with rheumatoid arthritis treated with infliximab, [21] we have demonstrated in a small sample that infliximab safely improved decompensated heart failure and cardiogenic shock due to ICI myocarditis. In our limited experience, a single dose of infliximab 5 mg/kg has been effective and safe. While we have not re-dosed infliximab at our institution, there have been case series describing additional 5 mg/kg doses or a single dose of 10 mg/kg [22, 23]. There are limited data outside oncology suggesting that 5 mg/kg may be safer in treating patients with heart failure not due to ICIs [24].

In the setting of therapeutic immunosuppression with both infliximab and prolonged high dose steroids, patients are at increased risk for opportunistic infections and need to be monitored closely. Two of the four patients in our series eventually died of septic shock, so it is formally possible that these events were due to the effects of combined immune suppression with infliximab and glucocorticoids. Anti-TNF agents such as infliximab have been associated with an increased risk of mycobacterial infections, invasive fungal infections, viral infections as well as bacterial pathogens [25‐27]. Prior to starting therapy, patients should be screened for HIV and Hepatitis B and C, a history of invasive fungal infections and should undergo assessment for active or latent tuberculosis. Concern for any of these infections warrants consultation with Infectious Diseases. Of note, immediate therapy for ICI myocarditis may be necessary and should not be withheld even with infectious screening tests pending, particularly if the patient is in cardiogenic shock or having sustained life-threatening arrythmias refractory to other therapies.

To prevent infections, we recommend patients receive prophylaxis for Pneumocystis jirovecii pneumonia until the steroid taper dose is below 20 mg of prednisone or equivalent, ideally with trimethoprim-sulfamethoxazole. There are insufficient data at this time to recommend prophylaxis against invasive fungal infections [27, 28]. Patients should also be up to date on all appropriate vaccinations, noting that administration may be deferred in the acute setting given significant immunosuppression and lower likelihood of vaccine response.

While we have only used infliximab in steroid-refractory cases, further study should consider earlier initiation of infliximab or other additional immunosuppressive agents together with initial high-dose steroids in patients with grade 3 or 4 myocarditis. Early initiation of a second immunosuppressive agent such as infliximab may reduce the total duration of steroid exposure. Given the potential effect of corticosteroids on T-cell function, prolonged use in patients with advanced cancer may decrease the efficacy of ICIs and is generally avoided whenever possible [29, 30]. Additionally, initial dosing of steroids should be studied further; data from heart transplant cellular rejection, which has similarities to T-cell driven ICI myocarditis, has shown equivalent outcomes with 500 mg and 1000 mg of intravenous solumedrol [31, 32]. While many questions remain unanswered and additional prospective studies are needed to address the best ways to manage ICI-related cardiovascular adverse events, we believe it is prudent to have a multidisciplinary team to help manage these high-risk patients. The Fig. 2 is a suggested algorithm for the treatment of ICI myocarditis developed by a multi-disciplinary team involving medical oncology, heart failure, cardiothoracic surgery, cardio-oncology, and pharmacists. We recognize that this protocol will surely change as more research is done within this field, but we hope this serves as a guide until then as there is currently a paucity of data and treatment recommendations for ICI myocarditis.

There are several limitations to the current study. This is a single center study, which limits its generalizability. This study is also limited by its retrospective nature, which increases the possibility of comorbidity misclassification. The lack of control subjects makes it difficult for comparative evaluation to determine if the standard therapy also produced the same outcomes, although it may be difficult to power studies in this population for clinically important outcomes. Given the small sample size, our study has insufficient power to detect small changes in the effectiveness and safety associated with infliximab. A larger sample size is needed to confirm our findings.