Azacitidine-associated cardiotoxicity: A systematic review of case reports, observational studies, and clinical trials Free

Background: Azacitidine, a hypomethylating agent, is widely used in the treatment of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), especially in older adults or those unfit for intensive chemotherapy. Although hematologic and gastrointestinal toxicities are well documented, rare cardiotoxic events,- including pericarditis, pericardial effusion, and myocarditis - have been sporadically reported in case reports, observational studies, clinical trials. These events are potentially serious but underrecognized, often mimicking infection, disease progression, or fluid overload. We conducted a systematic review to describe risk factors, focusing on potential risk factors including cumulative dose, timing of onset, and concurrent therapies.

Methods: We conducted a systematic search of PubMed, Embase, and Scopus through July 2025 for case reports, case series, and clinical studies describing azacitidine-associated cardiotoxicity, specifically myocarditis, pericarditis, and pericardial effusion with or without tamponade. Following removal of duplicates and screening for relevance, 12 articles published between 2014 and 2025 met inclusion criteria. From each study, we extracted available quantitative and qualitative data, including patient age, sex, comorbidities, underlying malignancy, concomitant therapies, cumulative azacitidine dose, timing of the cardiac event, and type of cardiotoxicity reported.

Results: A total of 9 patients from 7 case reports met criteria for azacitidine-associated cardiotoxicity. Additionally, 4 observational studies and 1 randomized controlled trial (RCT) reported 8 relevant adverse cardiac events. Reported manifestations included pericarditis (n=7), pericardial effusion (n=4), pleuropericardial effusion (n=2), myopericarditis (n=1), cardiac tamponade (n=1), and combined cardiac tamponade with pleural effusion (n=1). Underlying diagnoses included acute myeloid leukemia (AML) in 7 patients and myelodysplastic syndrome (MDS) in another 7. Concomitant therapies were reported in 5 studies, including case reports and observational studies: venetoclax (n=7), enasidenib (n=1), pembrolizumab (n=1) and cytarabine (n=1), with 4 patients receiving azacitidine monotherapy. The cumulative azacitidine dose was reported in 7 patients, with a median of 1,050 mg/m². Timing of the cardiotoxic event was reported in 6 cases: 3 occurred during cycle 1, and one each during cycles 2, 5, and 8. Day of symptom onset was available in 8 patients, with a median onset on day 9. Demographic and clinical details were available from case reports only. Among these, the median age was 62 years; 6 patients (66.7%) were male and 3 (33.3%) female. Comorbidities were described in 2 cases and included hypertension, hyperlipidemia, and type 2 diabetes; one patient also had coronary artery disease. One patient had an elevated BNP of 708 pg/mL at the time of pleuropericardial effusion, despite no prior history of heart failure. Renal function data were not reported in any of the included studies.

Conclusions: Azacitidine-associated cardiotoxicity is a rare but potentially serious complication, most often manifesting as pericarditis or pericardial effusion, with some cases progressing to tamponade. Events typically occurred early in treatment—frequently during the first two cycles—and within the first two weeks of therapy. All reported cases involved patients with AML or MDS, and nearly half were receiving combination therapy, particularly with venetoclax. Although demographic and laboratory data were incompletely reported, the consistent timing and recurrence across case types highlight the need for increased clinical vigilance. Further prospective studies are needed to better define risk factors, causality, and optimal monitoring strategies during azacitidine therapy.