Hypertension, Cardiovascular and Renal Complications Observed in Patients with Chronic Lymphocytic Leukemia Receiving Long-Term Therapy with Ibrutinib
Authors: Jones Jade , George Binsah Susan , Peterson Christine B , Ha Thao-Mi Tran , Burger Jan A. , Jain Nitin , Keating Michael J. , Wierda William G. , Durand Jean-Bernard , Ferrajoli Alessandra 
Published: November 2020

Long-term therapy with ibrutinib is commonly used to treat patients with chronic lymphocytic leukemia (CLL). Hypertension (HTN) has been reported as a side effect of ibrutinib in 21- 78% of patients treated, but this was after short exposure (29-30 months). Limited information is available regarding the development of cardiovascular and renal complications in these patients. In this study, we explored the effect of long-term ibrutinib exposure on blood pressure (BP) and on the development of cardiovascular and renal complications.
Three hundred and one patients with CLL were included in this analysis. Patients were participants enrolled on ibrutinib-based clinical trials from 2010 to 2017. Collected information included patient demographics, comorbidities, tobacco use, and antihypertensive therapy. BP was evaluated at baseline, at 1 month, then every 3 months for one year followed by every 2 years for a total of 5 years. Development of HTN was characterized as a systolic BP (SBP) of ≥ 130 mmHg and/or diastolic BP (DBP) ≥ 80 mmHg on two separate visits with no prior diagnosis of HTN or use of antihypertensive therapy. We also recorded any change in systolic or diastolic BP ≥10 mmHg. Univariate logistic regression and linear regression analysis was performed to assess the relationship of HTN risk factors and new or worsened HTN.
Patients' characteristics are described in the table 1 below. Median follow-up was 3 years (range 3 months-5 years). Pre-existing HTN was present in 68% of patients, and 47% were on antihypertensive therapy prior to ibrutinib. New HTN developed in 71% of patients without prior diagnosis of HTN. Worsening HTN developed in 56% of patients who had HTN at baseline. However, only 37% of them were started on antihypertensive therapy or received additional antihypertensive therapy. Of the patients who experienced an increase in BP, 29% experienced isolated systolic HTN. Median SBP was 131 mmHg at baseline, 132 mmHg at 1 month, 137 mmHg at 3 months, 137 mmHg at 6 months, 139 mmHg at 12 months, 140.5 mmHg at 3 years, and 139.5 mmHg at 5 years (mean increase in SBP: 8.15, 95% CI: 5.9 - 10.4). In patients whose SBP was &lt; 130 mmHg at baseline the median SBP was 118 mmHg at baseline, 122.5 mmHg at 1 month, 131 mmHg at 3 months, 130 mmHg at 6 months, 134 mmHg at 12 months, 133.5 mmHg at 3 years and 138 mmHg at 5 years (mean increase in SBP: 17.3, p=0.001). Seventy-nine percent of patients experienced an increase in SBP ≥10 mmHg. The median time to onset of new or worsened HTN (50% cumulative incidence) was 12 months. New HTN on ibrutinib was not associated with tobacco use, obesity, chronic kidney disease, or obstructive sleep apnea (p &gt; 0.05).
Development of cardiovascular and renal complications associated with HTN were also studied. New or worsening atrial fibrillation occurred in 17.3% of patients, new or worsening congestive heart failure in 3.0% of patients, new or clinically significant worse coronary artery disease was documented in 8.0% of patients, ischemic stroke occurred in 3.3% of patients and intracerebral hemorrhages occurred in 2.7% of patients. New or worsening chronic kidney disease was observed in 14.3% of patients.
Based on our findings, an increase in BP is common in patients with CLL being treated with long-term ibrutinib therapy. We observed that HTN in these patients is persistent, progressive and independent of other common risk factors for HTN. A proportion of patients developed cardiovascular complications during treatment and worsening renal function. Only 37% of patients in our study received new or additional antihypertensive medications, which may account for the persistent BP elevation and suggests a suboptimal HTN management in these patients.

Disclosures
Burger: Pharmacyclics, an AbbVie company: Consultancy, Research Funding, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Speakers Bureau; Gilead Sciences: Consultancy, Research Funding; Beigene: Research Funding, Speakers Bureau; AstraZeneca: Consultancy; TG Therapeutics: Research Funding, Speakers Bureau. Jain:BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aprea Therapeutics: Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.