Real-World Incidence and Management of Ibrutinib-Induced Hypertension in Patients with Chronic Lymphocytic Leukemia

Abstract

Background: Clinical trials demonstrated that ibrutinib improves progression-free and overall survival in patients with chronic lymphocytic leukemia (CLL). After widespread use of ibrutinib in clinical practice, the incidence of ibrutinib-induced hypertension (HTN) has been more frequent than reported in the clinical trials, with an incidence between 35% and 72%. No guidelines exist for the management of ibrutinib-induced HTN. Methods: A single-center, retrospective cohort study was conducted in patients with CLL initiated on ibrutinib from April 2014 to May 2020. We identified patients at least 18 years old, prescribed ibrutinib for CLL at UNC Medical Center and affiliated centers, alive and not transitioned to hospice or discontinued from ibrutinib within two months of initiation. Patients were excluded if they had blood pressure (BP) measurements documented at less than 3 visits within 24 weeks of initiating ibrutinib. Co-primary study outcomes were overall incidence and severity of HTN within 24 weeks of ibrutinib initiation. Secondary study outcomes include change in systolic BP (SBP) and diastolic BP (DBP), and the probability of increasing the antihypertensive intensity (e.g., new agent or increased dose) adjusted for mean SBP. Incidence of HTN, including new onset (defined by ACC/AHA 2017 Guideline for High Blood Pressure in Adults) or worsening HTN (defined by change in version 5 of Common Terminology Criteria for Adverse Events [CTCAE v5.0] grade), was assessed by descriptive statistics. A linear mixed effects regression model, with random intercepts for patients, estimated mean SBP and DBP measurements at weeks 0, 4, 8, 12, 16, 20, and 24. A logistic mixed effects model was used to estimate the probability of antihypertensive therapy intensification, adjusting for SBP. Results: Among 37 patients (mean age 67.3 ± 10.6 years, 87% Caucasian, 65% male), mean baseline SBP and DBP were 134.0 ± 17.9 mmHg and 70.5 ± 9.87 mmHg, respectively, and 73% were on at least one antihypertensive agent prior to ibrutinib initiation. The prevalence of HTN at baseline was 54% (Stage 2, 38%). Over 24 weeks, the incidence of new onset HTN was 69% (Stage 2, 33%) and worsening HTN was 68% (Stage 2, 92%). At 24 weeks, 29% of BPs were defined as Grade 3 per CTCAE v5.0. Over 24 weeks, mean SBP increased 9.7 mmHg (95% CI 2.20, 16.50) and mean DBP increased 5.9-mmHg (95% CI 1.03, 9.13). On average, patients who had a SBP measurement less than 165 mmHg had a less than 5% chance of antihypertensive intensification. The chance of intensification for patients with a SBP measurement of 165-210 mmHg increased up to 15%. Conclusions: Following initiation of ibrutinib in CLL patients, the incidence of new onset and worsening HTN was higher than previously described. Over 24 weeks, a clinically meaningful increase in BP occurred. Regardless of BP severity, antihypertensive intensification was minimal.