Ibrutinib is an irreversible inhibitor of Bruton tyrosine kinase (BTK), which is an integral component of the B-cell receptor (BCR) and cytokine (CYK) pathways. Ibrutinib is approved by the US Food and Drug Administration for use in multiple B-cell related conditions including mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia (WM), marginal zone lymphoma (MZL), and chronic graft versus host disease (cGVHD).1 Ibrutinib use has been associated with multiple adverse events (AEs), of which cardiovascular (CV) toxicity represents one of the most commonly studied.
The exact pathophysiology to explain the CV risks associated with ibrutinib have not yet been fully elucidated, although several mechanisms have been proposed. Ibrutinib has been shown to inhibit the phosphoinositide 3-kinase (PI3K)/Akt pathway, which could lead to increased vascular tissue fibrosis and cellular remodeling.2 Additional mechanisms include VEGF downregulation, decreased nitric oxide, and promotion of endothelial cell dysfunction.
According to the prescribing information (PI) for the medication, potential CV toxicities include cardiac arrhythmias such as ventricular tachyarrhythmias (grade 3 or higher in 0.2% of patients) and atrial fibrillation (grade 3 or higher in 4% of patients). Hypertension (HTN) of any grade was reported in 12% of patients in clinical trials with grade 3 or higher events occurring in 5% of patients, with a median time to onset of approximately 6 months.
Despite these reported numbers in the PI, multiple postmarketing studies have pointed to higher percentages of CV-associated AEs.
To further clarify the “real-world” CV risk associated with ibrutinib, a group of authors led by Dickerson and colleagues recently published a study evaluating the incidence of new or worsened HTN along with the relationship of HTN with developing incident major adverse cardiovascular events (MACE) including arrhythmias, acute myocardial infarction (AMI), cerebrovascular accident (CVA), heart failure, and CV death.3
The authors retrospectively evaluated 562 adult patients with lymphoid malignancies treated with ibrutinib at a single center at Ohio State University between 2009 and 2016. New HTN was defined as a systolic blood pressure (SBP) of 130 mmHg or higher on 2 separate visits within 3 months. Worsened HTN was diagnosed by an increase in the grade of HTN according to the Common Terminology Criteria for Adverse Events (CTCAE) or an increase in the patient’s anti-HTN medications. Baseline HTN was defined as SBP of 130 mmHg or higher on 2 visits within 3 months prior to starting ibrutinib or a reported history of HTN with current use of at least 1 anti-HTN medication.
Most patients were diagnosed with CLL (73.8%) and were administered ibrutinib for relapsed disease. And, 62% of patients had a diagnosis of HTN at the time ibrutinib was started, of which 63% were receiving at least 1 anti-HTN medication.