Azacitidine-induced myopericarditis in acute myeloid leukemia

Abstract

Hypomethylating agents are commonly used in the treatment of myelodysplastic syndromes and are known to cause bone marrow suppression; however, cardiac complications are rare. We describe a patient who was diagnosed with acute myeloid leukemia and developed myopericarditis after receiving chemotherapy with azacitidine. Our case highlights the importance of a thorough history, including medication review, in patients with suspected myopericarditis. It also raises awareness about the potential cardiac side effects of azacitidine.

Hypomethylating agents such as azacitidine (AZA) and decitabine are widely used in the treatment of myelodysplastic syndrome, especially in elderly patients who often can’t tolerate aggressive treatment such as allogenic stem cell transplant.¹ A recent randomized trial revealed that the most common cardiac adverse event reported with AZA was atrial fibrillation, with an event rate of about 5% in the AZA/venetoclax arm and 1% in the AZA/placebo arm. However, in prior clinical trials on AZA, the most common adverse events were myelosuppression related, and cardiac complications were rarely reported.^2,3 In a recent meta-analysis of six trials, the most common side effects of venetoclax were congestive heart failure (0.3%) and myocardial infarction (0.3%).⁴ Here we discuss a patient who was diagnosed with acute myeloid leukemia (AML) and developed myopericarditis after receiving chemotherapy with AZA.

CASE DESCRIPTION

A 76-year-old man with known diabetes mellitus type 2, hypertension, and hyperlipidemia was recently diagnosed with AML and received induction chemotherapy with intrathecal cytarabine, 7 days of intravenous AZA 75 mg/m², and a 3-day dose ramp-up of oral venetoclax (100 mg on day 1, 200 mg on day 2, and 400 mg on day 3 and beyond). One week later, he was admitted with a chief complaint of fever without chills or night sweats. He denied headache, chest pain, shortness of breath, cough, abdominal pain, and changes in urination. On admission, his temperature was 38.5°C; heart rate, 96 beats/min; blood pressure, 156/94 mm Hg; and respiratory rate, 18 breaths/min. His physical examination was unremarkable. The initial blood workup is presented in Table 1. Chest x-ray, urinalysis, respiratory pathogen screen, and a COVID-19 polymerase chain reaction test were negative. Blood cultures were drawn and intravenous cefepime was started for neutropenic fever.

Table 1.

Initial blood workup

Test	Laboratory value	Reference range
White blood cell count (k/µL)	0.6	4–12
Absolute neutrophilic count (k/µL)	0.25	1.5–8.0
Hemoglobin (g/dL)	7.1	12–16
Platelet count (k/µL)	43,000	140–440
Lactic acid (mmol/L)	1.2	0.4–2.0
Procalcitonin (ng/mL)	0.103	<0.05
Erythrocyte sedimentation rate (mm/h)	18	0–15
C-reactive protein (mg/L)	34	<9

On day 1, the patient experienced intermittent chest tightness. An electrocardiogram (ECG) showed diffuse ST elevations and no reciprocal changes, suggestive of pericarditis (Figure 1a), and his troponin level was elevated at 0.722 ng/L and continued to climb, peaking at 23.92 ng/L. Echocardiography revealed an ejection fraction of 45% with inferolateral wall motion abnormalities. Coronary angiography showed nonobstructive disease and no culprit lesion. Given the patient’s clinical presentation coinciding with recent initiation of AZA for AML, diffuse ST elevation on ECG, elevated troponin, and nonobstructive disease on coronary angiography, we diagnosed myopericarditis.

Figure 1.

Electrocardiograms (a) on day 1, showing normal sinus rhythm with diffuse ST elevations and no reciprocal changes, and (b) prior to discharge, showing normal sinus rhythm with improved ST segment changes.

Antibiotics were discontinued once blood cultures appeared negative. The patient was started on colchicine 0.3 mg twice daily (for 3 months) and aspirin 650 mg 3 times daily (for 2 weeks) with resolution of chest pain. Prior to discharge, the ST-segment changes on the ECG improved (Figure 1b) and blood counts stabilized. AZA was also switched to an alternative chemotherapy while oral venetoclax was continued with no further recurrence of myopericarditis during follow-up visits.

DISCUSSION

Myopericarditis is defined as inflammation of the pericardium and heart muscle, which can be acute, subacute, or chronic and can involve focal or diffuse areas of myocardium.⁵ Myopericarditis is uncommon and has a wide spectrum of presentations ranging from simple fever or chest pain to fatal cardiogenic shock or arrhythmias.⁵ The etiology of myopericarditis can be infectious (viral/bacterial) and noninfectious, including systemic diseases, toxins, and drugs.

Hypomethylating agents (AZA and decitabine) have been implicated as cardiotoxic in several case reports.^6–9 However, trials evaluating AZA and decitabine for the treatment of myelodysplastic syndrome reported no myopericarditis.^10–12 In a case series by Newman et al, three patients had new-onset pericarditis with repeated administration of AZA, which may suggest that cardiotoxicity could be secondary to a hypersensitivity or immune reaction to hypomethylating agents.⁶ This view was supported by the quick resolution of symptoms with corticosteroids in the three patients in their series.⁶ In another case by Bibault et al, acute myocarditis secondary to AZA was reported in a 50-year-old patient who presented with intense chest pain.⁷ The patient had ST elevations on ECG and an elevated troponin level up to 13.1 ng/mL with normal echocardiography and coronary angiography. After 1 week, the troponin level normalized and the chest pain resolved. With a final diagnosis of viral myocarditis, the patient was rechallenged with AZA. A similar scenario occurred on day 4, and cardiac magnetic resonance imaging demonstrated signs of myocarditis.⁷

Our patient’s presentation and findings were similar to those described in Bibault’s case report of AZA-induced myocarditis.⁷ Thus, we did not perform cardiac magnetic resonance imaging to confirm myopericarditis, given the high likelihood based on clinical presentation, elevated troponin, and ECG findings in the setting of nonobstructive disease on coronary angiography. The grade of certainty of causality between myopericarditis and AZA was high in our case, as we ruled out other common causes of myopericarditis, particularly viral infections such as COVID-19 and other respiratory pathogens. Additionally, the patient was not on any other medications implicated in myopericarditis prior to admission. Although venetoclax has been associated with cardiovascular adverse events,⁴ the patient continued taking venetoclax on discharge after discontinuing AZA without experiencing any further episodes of myopericarditis during follow-up, suggesting AZA as the underlying cause of myopericarditis.