Reported Pericardial Toxicities Associated with Acute Myelogenous Leukemia Treatments: A Pharmacovigilance Analysis of the FDA Adverse Reporting Database.

ABSTRACT

Acute myelogenous leukemia (AML) is one of the most common leukemias experienced in adults and conveys significant morbidity and mortality. While the traditional anthracycline based treatments of AML involves cytarabine, developments in alternatives (liposomal cytarabine, fludarabine, cladribine, azacitidine, decitabine), and targeted agents (midostaurin, gilteritinib, enasidenib, ivosidenib, gemtuzumab ozogamicin, and venetoclax) exist. Multiple cardiovascular adverse events, notably pericardial toxicity, have been observed in small studies; however, to date little is known about the comparative pericardial toxicity among these newer regimens. Due to the paucity of data, we sought to investigate the reported pericardial events and mortality associated with treatments for AML. Utilizing the Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS), we identified all adverse events associated with FDA approved treatments for AML (2002-2022). Pericardial events were defined as pericarditis, pericardial effusion and tamponade. We excluded any individuals with age <18 years old. Logistic regression was utilized to identify factors associated with pericardial events. Out of 94,262 reported adverse events, 675 pericardial toxicities were included (243 pericarditis, 479 tamponade). Pericardial events occurred less often in Cladribine (0.3%, P < 0.001), fludarabine (0.4%, P < 0.001), Venetoclax (0.3%, P < 0.001), enasidenib (0.3%, P value < 0.001), and ivosidenib (0.3%, P < 0.001) compared to Cytarabine (0.9%). Tamponade events occurred significantly less often in cladribine (0.1%, P < 0.001), fludarabine (0.4%, P = 0.001), enasidenib (0.1%, P = 0.006), ivosidenib (0.1%, P = 0.01), and venetoclax (0.1%, P < 0.001) compared to cytarabine 0.7%. After adjusting for age and sex, Cladribine (reporting odds ratio [ROR] 0.35 [95% CI 0.18-0.68], P = 0.008) and Fludarabine (ROR 0.65 [0.45-0.92], P = 0.03), venetoclax (ROR 0.57 [0.41-0.79], P < 0.001) remained significantly associated with lower incidence of reported pericardial events. While cytarabine has been the routinely used and/or drug of choice for induction chemotherapy for AML, alternatives like cladribine may have a greater safety profile regarding pericardial toxicities. Future studies should be directed at further investigating cardiovascular safety profiles of AML induction therapy.