Fulminant Myocarditis Presenting With Refractory Ventricular Fibrillation During BRAF/MEK Inhibitor Therapy

Abstract

Background

Myocarditis is a rare but potentially fatal complication of BRAF/MEK inhibitor therapy. Early detection through vigilant monitoring is crucial.

Case Summary

A 35-year-old woman with stage IIIB melanoma treated with adjuvant trametinib and dabrafenib suffered a cardiac arrest due to refractory ventricular fibrillation. Coronary angiography excluded culprit lesions. Despite intensive management and extracorporeal life support, the patient exhibited irreversible multiorgan failure and died. A postmortem examination revealed massive biventricular and septal lymphohistiocytic myocarditis.

Discussion

BRAF/MEK inhibitors have been demonstrated to enhance survival outcomes in melanoma. However, there exists a potential for cardiotoxic events, including myocarditis, which can be severe albeit infrequent. To date, only isolated cases of fatal myocarditis have been reported. This case highlights the importance of systematic cardiac surveillance, even in asymptomatic patients.

Take-Home Messages

Fulminant myocarditis is a rare but life-threatening adverse event of BRAF/MEK inhibitor therapy. Multimodal cardiac evaluation is strongly recommended.

Graphical Abstract

Visual Summary.

Case Timeline

ECG = electrocardiogram; ECMELLA = extracorporeal membrane oxygenation therapy with Impella devices; GLS = global longitudinal strain; MCS = mechanical circulatory support; MODY = maturity-onset diabetes of the young; OHCA = out-of-hospital cardiac arrest; VF = ventricular fibrillation.

Acute myocarditis is an inflammatory disease of the myocardium with a broad spectrum of etiologies and clinical manifestations, ranging from asymptomatic forms to life-threatening conditions such as fulminant myocarditis. Cases of acute myocarditis after treatment with combination trametinib/dabrafenib in oncological patients have been previously reported, including a case of sudden cardiac death. We report a case of fulminant myocarditis presenting with refractory ventricular fibrillation needing extracorporeal life support in a young patient in therapy with BRAF/MEK inhibitors for a stage IIIB melanoma. We then reviewed the current literature on cardiac adverse effects due to trametinib/dabrafenib and the guidelines regarding diagnosis and prevention of cancer therapy–related cardiotoxicity. This dramatic case highlights the importance of careful clinical and multimodal instrumental monitoring in oncologic patients receiving chemotherapies.

History of Presentation

A 35-year-old woman was admitted to the catheterization laboratory of Cattinara Hospital, Trieste, Italy, on June 13, 2024, for witnessed out-of-hospital cardiac arrest at her workplace. Immediate cardiopulmonary resuscitation was initiated; the initial cardiac rhythm was ventricular fibrillation nonresponsive to direct-current shocks. Considering that no flow interval was <1 minute and the end-tidal carbon dioxide level was 22 mm Hg during cardiac pulmonary resuscitation in refractory ventricular fibrillation, the extracorporeal life support protocol was activated, and the patient was emergently centralized to the catheterization laboratory. During transportation, a total of 6 mg of adrenaline and 750 mg of amiodarone were administered. No temporary return of spontaneous circulation was reported.

Past Medical History

Reviewing her medical history, the patient had maturity-onset diabetes of the young, complicated by mild diabetic retinopathy and under oral therapy (metformin, gliclazide, and empagliflozin) as well as dyslipidemia, had been diagnosed with virus-negative chronic active hepatitis with diffuse steatosis when she was 12, and had polycystic ovary syndrome treated with hormonal contraception. There was no documented family history of cardiovascular disease or sudden cardiac death.

In October 2023, the patient was diagnosed with left gluteal melanoma stage IIIB (pT3aN1, Breslow thickness: 2.4 mm, mitotic index: 2/mm²), treated with resection in October 2023 and enlargement with excision of the lymph node sentinel in December 2023. Having confirmed BRAF V600E mutation, adjuvant therapy with dabrafenib 300 mg/d and trametinib 2 mg/d was initiated in March 2024, with an expected duration of 1 year. Electrocardiogram and echocardiogram at baseline and 1 month into therapy were normal. The QTc interval (according to Bazett's formula) was 396 ms at baseline and 388 ms after 1 month of therapy. The left ventricular ejection fraction was 73% before treatment initiation and 65% after 1 month. Cardiac biomarkers and creatine phosphokinase were not assessed.

The trametinib/dabrafenib was discontinued on May 16 because of hyperpyrexia with nausea and vomiting, hypotension with loss of consciousness, and transaminase elevation (up to 3 times normal value) and was restarted after 2 weeks (May 30) at a reduced dosage (dabrafenib 100 mg twice a day, trametinib 1.5 mg/d). The patient was reported to have discontinued treatment on June 2 because of recurrence of nausea and vomiting without fever. Treatment was resumed on June 6 with a reduced dosage (dabrafenib 75 mg twice a day and trametinib 1 mg/d) after premedication with paracetamol 1 g and metoclopramide 10 mg twice a day.

Differential Diagnosis

When considering the patient's presentation, several potential diagnoses were examined. At first, fulminant myocarditis could explain the sudden cardiac arrest without remote cardiac events. Given the patient's history of diabetes, acute coronary syndrome should be ruled out. Additionally, a primary electrical heart disease or an arrhythmogenic cardiomyopathy were contemplated, though previous electrocardiogram and the absence of family history made these diagnoses less likely.

Investigations

The echocardiogram performed during cardiac pulmonary resuscitation revealed absent contractility and previously unreported left ventricular hypertrophy (interventricular septum thickness: 15 mm). The remaining cardiac structures were within normal limits, exhibiting no severe valvular defects, aortic dilation, or significant pericardial effusion.

The emergency coronary angiography indicated the presence of multivessel coronary disease. However, the procedure was unable to identify a specific culprit lesion for the patient's clinical presentation (Figure 1). Laboratory investigations revealed a markedly elevated troponin I level of 11,970 ng/L (normal: <16 ng/L), whereas blood count and ions were normal. A whole-body computed tomography scan excluded the presence of intracranial bleeding and aortic dissection. Instead, it revealed the presence of bilateral lower lobe consolidations with ground-glass opacities and bilateral hilar lymphadenopathy.

Figure 1.

Emergency Coronary Angiogram

(A) RAO 3° CRA 27° projection showing mid-distal LAD 70% stenosis (arrow) with diffuse distal LAD disease, first diagonal branch 90% stenosis (arrow), occluded second diagonal branch (low-caliber vessel, arrow), and second posterolateral branch of circumflex artery 80% stenosis (arrow). (B) LAO 7° CRA 27° projection showing nonsevere stenosis of the right coronary artery. AO = left anterior oblique; CRA = cranial; LAD = left anterior descending artery; RAO = lright anterior oblique.

Management

Femorofemoral venoarterial extracorporeal membrane oxygenation (VA-ECMO) was implanted (total low-flow time: 75 minutes) along with an Impella 2.5 device (Abiomed) for left ventricular unloading, obtaining return of spontaneous circulation with slow idioventricular rhythm. Owing to the suspicion of cancer therapy–related acute myocarditis, boluses of methylprednisolone were administered.

Outcome and Follow-Up

After 8 hours of VA-ECMO assistance, dramatic progressive multiorgan dysfunction, persistent gastrointestinal bleeding, persistent bilateral mydriasis, and systemic hypotension refractory to increasing ECMO flow and massive doses of vasoactive drugs, hemodynamic support was progressively scaled down and discontinued. The patient was declared dead shortly after the withdrawal of mechanical support.

Autopsy revealed the presence of massive biventricular and septal lymphohistiocytic myocarditis as defined by Dallas criteria, accompanied by extensive regions of active scarring. The inflammatory population consisted primarily of T helper cells (CD4⁺) and histiocytes, with occasional suppressor T (CD8⁺) lymphocytes (Figure 2). No signs of cardiomyocyte injury from myocardial ischemia were identified. A modest pleural and pericardial effusion was observed. Hepatomegaly with hepatic steatosis and precirrhotic aspect, alongside giant cells and a non-necrotizing microgranulomatous trend, was also described.

Figure 2.

Histopathology

(A to D) Hematoxylin-eosin staining showing significant infiltration of lymphocytes and histiocytes, suggestive of an inflammatory myocardial process, accompanied by extensive regions of active scarring. (E and F) Hematoxylin-eosin staining showing the presence of inflammatory processes in regions beyond the myocardial tissue, including the epicarditis and multifocal pericoronaritis, respectively. (G and H) Immunohistochemical analysis indicated that the inflammatory population consisted predominantly of T helper cells (CD4+) and histiocytes, with occasional suppressor T (CD8+) lymphocytes.

Discussion

We report a fatal case of fulminant myocarditis in a young woman treated with trametinib/dabrafenib after a diagnosis of stage IIIB melanoma. Combination trametinib/dabrafenib acts on the mitogen-activated protein kinase (MAPK) pathway, suppressing cell proliferation, and it was found to have a favorable effect on overall survival and progression-free survival rates in the treatment of unresectable advanced/metastatic melanoma with BRAF V600 mutation.¹ This treatment was approved for advanced melanoma in the United States in 2014 and in the European Union in 2015. According to the latest melanoma guidelines by the European Society for Medical Oncology, treatment with BRAF/MEK inhibitors is recommended for stage III/IV melanoma (Class 1, Level of Evidence: A).² Subsequently, the European Medicines Agency and the U.S. Food and Drug Administration also approved combination trametinib/dabrafenib for patients with stage IV non–small-cell lung cancer harboring the BRAF V600E mutation.³

Cardiotoxicity has been described as a possible side effect of trametinib/dabrafenib therapy. Hypertension has been commonly observed (>10%), hence the 2020 European Society of Cardiology guidelines on cardio-oncology recommends (Class 1, Level of Evidence: C) blood pressure monitoring at each clinical visit and weekly outpatient monitoring during the first 3 months of treatment and monthly thereafter. Atrial fibrillation and hyperglycemia are also frequently reported.⁴

Several studies have described a risk of left ventricular ejection fraction deterioration during treatment with BRAF/MEK inhibitors⁵; in fact, considering that MEK is not an oncogene and that it, along with its substrate ERK, belongs to a group of prosurvival protein kinases mediating cardioprotection, inhibition of its pathway could lead to cardiomyopathy development.⁶ According to the European Society of Cardiology guidelines, echocardiography is recommended (Class 1, Level of Evidence: C) at baseline and should be considered (Class 2a, Level of Evidence: C) every 4 months for the first year with BRAF/MEK in patients at high or very high cardiovascular risk, whereas it may be considered (Class 2b, Level of Evidence: C) in patients at low to moderate risk.⁴ There has been 1 previously reported case of fatal myocarditis after treatment with combination trametinib/dabrafenib, with histopathology suggestive of chronic granulomatous myocarditis with mononuclear inflammatory infiltration and epithelioid cells in granulomatous configuration.⁷

Although our patient did not show cardiac impairment at baseline and 1-month echocardiogram, inflammatory cardiomyopathy may occur progressively, notwithstanding preserved ejection fraction and normal kinetics at baseline, or may be fulminant without prodromal symptoms. The characteristics of the myocardial inflammatory infiltrate and the leopard-spot appearance of scars at the autopsy, given the nonculprit evidence at coronary angiography, ruled out acute coronary syndrome as the “primum movens.” It is reasonable to conclude that myocarditis was the most probable cause responsible for refractory ventricular arrhythmia and irreversible cardiogenic shock. Moreover, QTc prolongation and risk of torsades de pointes development have been described in patients treated with trametinib/dabrafenib therapy.⁸ Although QTc was normal in our patient after starting treatment, concomitant drugs (metoclopramide) and electrolyte disturbances in an inflamed myocardium could have led to ventricular fibrillation.

Regarding hepatic involvement, although elevation of serum alanine transaminase was observed in 35% to 42% of patients treated with trametinib/dabrafenib, with levels exceeding 5 times the upper limit of normal in 4% of cases, there were no instances of clinically apparent acute liver injury or hepatic failure reported in prelicensure studies.^9,10 Furthermore, since its approval and more widespread use, there have been no published reports of acute hepatotoxicity, nor have there been any specific recommendations.

Conclusions

Fulminant myocarditis should be acknowledged as a rare adverse effect of combination trametinib/dabrafenib, a BRAF/MEK inhibitor. It is important to monitor and prevent cancer therapy–related cardiotoxicity, even when initial findings are normal. We propose conducting serial tests, including electrocardiogram, echocardiography, and cardiac markers (specifically, N-terminal pro–B-type natriuretic peptide and high-sensitivity troponin I) if signs and symptoms of possible cardiac origin arise. Although myocarditis appears to be a rare complication, it is important to be cautious and engage in proactive monitoring, given the potential for significant severity associated with this condition.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Take-Home Messages

• •Fulminant myocarditis is a rare but potentially life-threatening adverse effect of BRAF/MEK inhibitor therapy.
• •A multimodal and proactive cardiac assessment should be performed routinely, even in asymptomatic patients.
• •Serial follow-up is crucial to detect early signs of cardiotoxicity and ensure timely management.