Nivolumab-induced myocarditis complicated by complete atrioventricular block in a patient with metastatic non-small cell lung cancer

Abstract

We report a case of a 74-year-old man who developed myocarditis complicated by atrioventricular (AV) block following two doses of nivolumab for the treatment of non-small cell lung cancer. A diagnosis of drug-induced acute myocarditis with complete AV block was considered on the basis of elevated troponin, new onset left ventricular (LV) systolic dysfunction, absence of acute myocardial infarction and some findings suggestive of myocarditis on cardiac magnetic resonance. The patient was commenced on glucocorticoids, perindopril and carvedilol. AV block and LV dysfunction persisted despite 2 weeks of treatment. He ultimately became hypotensive which prompted an implantation of a cardiac resynchronisation therapy pacemaker. Follow-up echocardiogram at 6 weeks showed resolution of LV systolic dysfunction. However, he continued to have AV block.

Background

Immune check point inhibitors such as nivolumab have shown promising outcomes in the treatment of several types of malignancies. Contrary to our case, most published case reports of nivolumab-induced myocarditis had resulted in death. We present this case to highlight the clinical importance of early recognition of this relatively rare but potentially fatal complication due to an essential medication that is of increasing use.

Case presentation

A 74-year-old Caucasian man presented with a 1-week history of increasing exertional dyspnoea, orthopnoea and lethargy. This was associated with left-sided chest discomfort and palpitations. He denied wheeze, haemoptysis, syncope, peripheral oedema or any infective symptoms. These symptoms began 3 days after his second dose of intravenous nivolumab infusion, given 2 weeks apart using standard dosing protocol of 3 mg/kg.

His background medical history was significant for metastatic non-small cell lung cancer (NSCLC) diagnosed 2 years prior, moderate chronic pulmonary airways disease, both related to a 50 pack-year cigarette smoking history. He also had stable depression. He had stopped smoking since the diagnosis of NSCLC. At the time of diagnosis of NSCLC, he was found to have a poorly differentiated right upper lobe adenocarcinoma, measuring up to 50 mm with lymphovascular invasion. He was treated with a right lobectomy and adjuvant chemotherapy using cisplatin and vinorelbine but only tolerated three cycles due to severe nausea and vomiting. Interval imaging using CT 6 months later revealed recurrence of a right apical mass and a new metastatic left adrenal lesion. These lesions were treated with radical stereotactic ablative radiotherapy. He was subsequently offered nivolumab for metastatic NSCLC.

His regular medications were budesonide/formoterol inhaler 200/6 mg two times per day and sertraline 50 mg daily.

On clinical examination, he was stable. His vitals revealed respiratory rate of 22 breaths/min, oxygen saturation of 97% on room air, blood pressure (BP) of 110/70 mm Hg, a regular pulse with a rate of 60 beats/min. He was afebrile, temperature of 36.7°C. Cardiorespiratory examination was unremarkable. However, his ECG in figure 1 showed complete atrioventricular (AV) block with a stable ventricular escape of 60 beats/min; QRS duration was 140 ms. There were no previous ECGs for comparison. He was admitted to the cardiology ward and placed on continuous cardiac monitoring.

Figure 1.

ECG showing complete atrioventricular block.

Investigations

Laboratory evaluation revealed elevated cardiac and inflammatory markers. Complete blood count revealed a normocytic normochromic anaemia (likely from chronic illness related to lung cancer). His electrolytes and liver function tests were unremarkable (table 1).

Table 1.

Laboratory results

	Reference interval	Admission	Day 4	Day 16 discharge	4-month follow-up
Haemoglobin (g/L)	135–175	107	108	114	95
White cell count (×109/L)	4.00–11.00	13.92	21.77	14.19	6.89
Platelet count (×109/L)	150–450	488	444	214	491
Neutrophils (×109/L)	1.80–7.50	13.2	14	11.8	4.6
Lymphocytes (×109/L)	1.50–3.50	0.5	0.9	1.3	1.4
Monocytes (×109/L)	0.2–0.80	0.16	1.04	0.68	0.64
Eosinophils(×109/L)	0.02–0.50	0	0	0.06	0.19
C reactive protein (mg/L)	0.0–8.0	33.4	7.5	7.0	–
Troponin T (ng/L)	0–29	1410	1904	1418	179
Creatine kinase(U/L)	0–250	1075	682	201	43
NT-proBNP (ng/L)	<125	11 598	–	–	–
Sodium (mmol/L)	135–145	137	140	137	138
Potassium (mmol/L)	3.5–5.2	4.7	4.5	4.1	4.6
Urea (mmol/L)	2.7–8.0	13.1	15.6	11.7	7.4
Creatinine (μmol/L)	60–110	115	134	124	140
LDH (U/L)	110–230	544			238

Bold values are the values are in the abnormal range. LDH, Lactate dehydrogenase; NT-proBNP, N-terminal (NT)-pro hormone b-type natriuretic peptide.

Chest X-ray showed background emphysaema, persistent right apical mass, stable small right pleural effusion, stable cardiomediastinal contours and no pulmonary congestion. Transthoracic echocardiogram findings showed non-dilated left ventricle with moderate to severe global left ventricular (LV) systolic dysfunction (Simpson’s biplane left ventricular ejection fraction (LVEF) 31%, reference range 52%–62%). Coronary angiogram excluded any significant coronary artery disease. Cardiac magnetic resonance (CMR) confirmed severe global LV systolic dysfunction with T2-weighted imaging showing increased signals in the basal inferior regions consistent with myocardial oedema seen in figure 2. Unfortunately T1 mapping was not performed. There was absence of delayed hyper-enhancement with gadolinium.

Figure 2.

Cardiac magnetic resonance (T2 weighted) showing mild increase in signal in the basal inferior segments (white arrow).

A diagnosis of drug-induced acute myocarditis with complete AV block was considered on the basis of elevated troponin, new onset LV systolic dysfunction, absence of acute myocardial infarction and some findings suggestive of myocarditis on CMR. There was no evidence of thoracic or cardiac metastasis.

Treatment

Nivolumab was permanently discontinued. This was classified as a grade 4 reaction according to the Common Terminology Criteria for Adverse Events V4.0.

Treatment was commenced with 3 days of intravenous methylprednisolone at 1 g daily for 3 days followed by prednisolone 1 mg/kg daily orally. His inflammatory and cardiac biomarkers gradually improved over 2 weeks: C reactive protein (33.4–7 mg/L) and troponin T (1901–1291 ng/L). Treatment was commenced with the aim of reducing myocardial inflammation and reversing his conduction defects. Regarding new LV systolic dysfunction, he was also commenced on carvedilol 3.125 mg daily and perindopril 2.5 mg with a plan to up titrate to guideline recommended doses as tolerated. However, at 2 weeks, despite biochemical and clinical improvement, there was absence of resolution of AV block and LV systolic dysfunction. Rather, he developed episodic bradycardic and hypotensive episodes with a ventricular escape rate of 45 beats/min and BP of 95/50 mm Hg. Carvedilol was ceased and a pacemaker was implanted. In view of his LV systolic dysfunction, a cardiac resynchronisation therapy pacemaker (CRT-P) was implanted. Carvedilol was restarted after the implantation of the CRT-P. He was discharged home 5 days later in a stable condition on maintenance prednisolone 1 mg/kg/daily orally and both carvedilol and perindopril.

Outcome and follow-up

Follow-up echocardiogram at 6 weeks showed resolution of LV systolic dysfunction with an LVEF of 62%. However, he continued to have AV block.

Discussion

Nivolumab is an immune checkpoint inhibitor, a novel monoclonal antibody that targets programmed death receptor 1 (PD-1). It is a fully human monoclonal IgG. It inhibits the PD-1 receptor from binding to its ligands (PD-L1 and PD-L2) on tumour cells, reactivating cytotoxic T lymphocytes and anti-tumour immunity.¹

Nivolumab has been shown to improve survival in following cancers: melanoma; NSCLC; renal cell carcinoma; classical Hodgkin’s lymphoma; head and neck squamous cell carcinoma and urothelial carcinoma.^2–7 According to the Therapeutic Goods Administration, Australian Department of Health, nivolumab is currently approved (as of 6 August 2018) to treat these malignancies.⁸

Severe immune reactions are uncommon (<1%) and may involve any organ system resulting in pneumonitis, colitis, hepatitis, renal dysfunction, endocrinopathies, severe skin reactions, myasthenic syndrome and myotoxicity.⁹

The clinical manifestations of myocarditis are highly variable as it depends on its aetiology, extent of inflammation and degree of myocardial involvement. It can range from subclinical disease to fatigue, chest pain, heart failure, cardiogenic shock, arrhythmia and sudden death.¹⁰ Endomyocardial biopsy (EMB) is the gold standard for the diagnosis of myocarditis with known established histological criteria. However EMB is rarely performed due to the invasive nature of the procedure and the potential significant complications. Therefore commonly a combination of clinical, biochemical and imaging findings assist in establishing the diagnosis of myocarditis. CMR has had an increasing role in the diagnosis of myocarditis.¹¹ Three CMR techniques have been applied in myocarditis: (1) late gadolinium enhancement sequences for detection of myocardial necrosis and/or fibrosis; (2) T2-weighted images for assessment of myocardial oedema and (3) T1-weighted sequences before and after contrast injection for detection of myocardial hyperaemia. The ‘Lake Louise criteria’ for CMR diagnosis of myocarditis state that CMR findings are consistent with the diagnosis of myocarditis if 2 of 3 of the above-mentioned sequences are positive.¹¹ Our patient met only 1 of the required 3 criteria for CMR diagnosis as T1 mapping was not performed (it is not routinely performed at our centre).

The likely pathophysiology of AV block with nivolumab is thought to be a consequence of myocarditis resulting in inflammation of the cardiac conduction system, rather than a direct effect of the medication itself. To our knowledge, there is no well-documented cases of nivolumab directly causing AV block in the absence of myocarditis.

Myocarditis secondary to nivolumab was rarely described in initial clinical trials. In a review of 68 trials with a total number of 10 531 patients, there were only 6 reported cases of myocarditis.¹² There are, however, increasing numbers of case reports of this severe clinical complication emerging in the last couple of years. The first such reported case of nivolumab associated autoimmune myocarditis was in 2016, in which a 69-year-old woman with NSCLC developed myocarditis and new right bundle branch block.¹³ Since then similar cases have been published which are summarised in table 2.

Table 2.

Literature review of case reports of nivolumab-induced autoimmune myocarditis 2016–2018

Publication	Therapy	Clinical summary	Time of clinical onset	Outcome
Gibson et al13	Nivolumab—after second dose	69F. NSCLC. Myocarditis and RBBB	21 days post dose 1 (7 days post dose 2)	Death
Johnson et al14	Nivolumab/ipilimumab—after first dose	65F. Melanoma. Myocarditis and complete heart block	12 days post dose 1	Refractory ventricular tachycardia and death
Johnson et al14	Nivolumab/ipilimumab—after first dose	63M. Melanoma. Myocarditis and complete heart block	15 days post dose 1	Cardiac arrest and death
Mehta et al15	Nivolumab/ipilimumab—after second dose	68F. Melanoma. Myocarditis.	14 days post dose 1 (arm pain which resolved) – then 1 day post dose 2 confirmed myocarditis (time between doses unspecified)	Survival and recovery of LV function
Behling et al16	Nivolumab—after second dose	63M. Melanoma. Myocarditis and complete heart block	24 days post dose 1 (3 days post dose 2)	Death
Matson et al17	Nivolumab—after second dose	55M. Lung adenocarcinoma. Myocarditis and heart failure	24 days post dose 1 (3 days post dose 2)	Death
Velez et al18	Nivolumab/ipilimumab—after first dose	69F. Merkel cell carcinoma. Myocarditis and complete heart block	7 days post dose 1	Death
Frigeri et al19	Nivolumab – after seven doses	76F. Lung adenocarcinoma. Myocarditis and cardiogenic shock	84 days post dose 1 (following dose 7 – number of days post dose 7 unspecified)	Survival
		Median time of clinical onset and IQR	18 days post dose 1 (IQR: 11 days) 3 days post dose 2 (IQR: 3 days)

IQR, interquartile range; LV, left ventricular; NSCLC, non-small cell lung cancer; RBBB, right bundle batch block.

We note that most cases of immune-related myocarditis occurred after one to two doses of nivolumab infusions,^13–18 mostly lead to death,13 14 16 18 and most were associated with significant cardiac arrhythmias, particularly complete heart block.13 14 16 18 Prompt treatment using corticosteroids, intravenous immunoglobulin (IVIg), plasmapheresis and heart failure therapy resulted in partial LV systolic function recovery and death was averted in one case.¹⁹

Similarly, our patient presented after his second dose (17 days post first dose and 3 days post second dose) of nivolumab infusion with myocarditis complicated by complete AV block. With prompt treatment with immunosuppressive and heart failure therapy, LV systolic dysfunction should be transient. However, it is not known whether AV block will recover. Our patient had refractory AV block despite biochemical recovery while on corticosteroid therapy for 2 weeks. We therefore decided on a permanent cardiac pacing option (grade I recommendation) and chose to implant a CRT-P instead of conventional pacemaker as we were uncertain about recovery of his ventricular dysfunction given high burden of ventricular pacing (grade IIa recommendation).²⁰ We continued carvedilol and perindopril for heart failure with reduced ejection fraction with ongoing follow-up for up titrating to target doses and consideration of other therapies downstream. At 6-week follow-up, LV systolic dysfunction had resolved with an LVEF of 62%. However, AV block persisted.

In conclusion, myocarditis is a serious but rare side effect of nivolumab which is potentially fatal. Nivolumab-induced myocarditis tends to manifest after first two doses of nivolumab infusions (median time of onset was 18 days and 3 days for the first and second doses, respectively). It appears that this adverse event is idiosyncratic and it is likely not dose dependent. Early recognition is pivotal as prompt treatment with corticosteroids (and in some cases with additional IVIg and plasmapheresis) and heart failure therapy could increase the chances of survival. We suggest screening for myocarditis with basic investigations such as ECG, cardiac and inflammatory markers despite the rarity of this condition due to its potentially fatal complications. We propose screening from day 10 after first dose and at day two after second dose CMR could improve the diagnostic yield in suspected cases. More importantly we advocate awareness of this rare side effect to prevent adverse outcomes. A multidisciplinary team approach involving early cardiology input is required to manage the cardiac complications particularly cardiac arrhythmias (mostly complete heart block) and some instances of LV systolic dysfunction.

Learning points.

• Myocarditis is a serious but rare side effect of nivolumab which is potentially fatal.

• Nivolumab-induced myocarditis tends to manifest after first two doses of nivolumab infusions.

• We suggest screening for myocarditis with basic investigations such as ECG, cardiac and inflammatory markers despite the rarity of this condition due to its potentially fatal complications.

• A multidisciplinary team approach involving early cardiology input is required to manage the cardiac complications particularly cardiac arrhythmias (mostly complete heart block) and some instances of left ventricular systolic dysfunction.