Hypertension Development, Management, and Cardiovascular Events Following Ibrutinib Initiation for Hematologic Malignancies
Authors: Dickerson Tyler , Wiczer Tracy , Waller Allyson , Philippon Jennifer , Haddad Devin , Guha Avirup , Porter Kyle , Rogers Kerry A. , Woyach Jennifer A. , Byrd John C. , Addison Daniel , Awan Farrukh T. 
Published: October 2019

Abstract
Background
Ibrutinib (IB), a nonselective Bruton's tyrosine kinase inhibitor, is associated with significantly improved disease control rates, progression free, and overall survival in several B-cell malignancies. Yet, IB's nonselective actions may result in a number of unintended adverse effects and complications that can lead to drug discontinuation. New or worsening hypertension (HTN) has been reported in 10-29% of those receiving IB within clinical trials. However, recent observational data suggest that this rate may be much higher in clinical practice and resistant to treatment. The management of IB-related HTN has not been previously well described. Furthermore, the relationship between IB-associated HTN and serious cardiovascular (CV) complications is unknown. Therefore, we sought to characterize the incidence, risk factors, management, and CV complications associated with IB-related HTN across long-term follow-up.
Methods
We performed a retrospective, single-center cohort study of all consecutive adult patients treated with IB for a hematologic malignancy from 2009-2016. Patient demographics, blood pressure (BP), antihypertensive therapy, cancer variables, and CV complications were collected throughout the duration of IB therapy. HTN was defined as systolic BP of ≥ 130 mmHg on 2 separate visits within 3 months. Worsened HTN was defined as an increase in HTN grade by Common Terminology Criteria for Adverse Events (CTCAE) or an increase an antihypertensive therapy. The composite of major adverse CV endpoint (MACE), including atrial fibrillation, ventricular arrhythmia, myocardial infarction, cerebrovascular accident, heart failure, and CV death, as stratified by HTN status was assessed. Univariate and multivariate Fine and Gray regression analyses accounting for competing risks of death and IB-discontinuation were preformed to determine the association between baseline covariates and outcomes, and survival analysis techniques were used to estimate the cumulative incidence of events. To assess whether any antihypertensive agent(s) was more effective in preventing IB-related HTN, the use of these agents at baseline was assessed by class, as protective factors against worsened HTN.
Results
Overall, 562 patients treated with IB were identified, a majority of which had CLL (73%) and were male (70%); mean age 64 ± 11 years. Sixty-two percent had preexisting HTN at the time of starting IB with 35% requiring at least one antihypertensive medication. During follow-up, 440 (78%) developed new or worsening HTN (figure 1A), with a mean increase in systolic BP of 5.2 mmHg (± 20.7). In those without baseline HTN, 72% developed new HTN while on IB, with a mean increase in systolic BP of 13.4 mmHg (± 20.1). Among patients with preexisting HTN, 82% saw worsening of their BP (mean increase in systolic BP of 4.1 mmHg (± 21.4)), including increased CTCAE grade in 77% and new antihypertensive medications in 46% of patients. Estrogen/progestin use [HR 3.47, 95% CI (1.25-9.64)] and history of diabetes [HR 1.66, 95% CI (1.03-2.66)] were risk factors for new, but not worsened HTN on multivariable analysis. MACE occurred in 19.1% of patients with new or worsened HTN, compared to 8.2% of patients with no HTN (figure 1B). In a multivariable model containing traditional HTN risk factors, new or worsened HTN was not significantly associated with MACE [HR 1.98, 95% CI (0.74-5.31)]. No specific class of antihypertensive agent was associated with the prevention of worsened HTN.
Conclusion
In this retrospective study, IB-therapy was associated with a substantial increase in the incidence and severity of HTN. Further research into the mechanisms, early detection strategies, optimal management, and clinical impacts of this complication are needed.

Disclosures
No relevant conflicts of interest to declare.