Hypertension as a Cardiovascular Toxicity of Bruton’s Tyrosine Kinase Inhibitors for Chronic Lymphocytic Leukemia

Abstract

In 2014, ibrutinib, a covalent Bruton’s tyrosine kinase inhibitor (BTKi), became available as a treatment for chronic lymphocytic leukemia (CLL) in Canada. It was welcomed with enthusiasm given its oral administration, lower rate of neutropenia and infections, and efficacy in heavily pretreated and high-risk del17p subtypes, at a time when only chemotherapy and monoclonal antibodies were available. Soon adverse events (AE) due to off-target effects emerged; particularly concerning were cardiac arrhythmias, bleeding, and hypertension (HTN). Second-generation BTKis were designed to target BTK more directly, and fortunately, clinical trials reported a lower rate of cardiac AEs. Less attention has been given to HTN despite it being an important modifiable risk factor for subsequent cardiac AEs. This is particularly relevant for CLL, given that the predominantly elderly patient population with CLL tend to survive as long as age-matched peers. This review focuses on HTN as an adverse effect of BTKis, and recommending a management approach.

Many contemporary CLL studies with BTKi define HTN as an AE using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0, and typically consider severe HTN to be grade 3-5 (Table 1). HTN is generally defined as a disorder characterized by a pathological increase in blood pressure (BP), which is defined as a repeated elevation in the BP exceeding 140 over 90 mm Hg. It is clinically relevant even at a grade 2 level from a global perspective for most patients.