Hypertension in Patients Treated With Ibrutinib for Chronic Lymphocytic Leukemia

This cohort study describes patterns of development, management strategies, and long-term vascular consequences of hypertension associated with ibrutinib in the non–clinical trial setting.


Introduction
Hypertension is a commonly noted adverse event for patients with chronic lymphocytic leukemia who are treated with ibrutinib in the clinical trial setting (incidence, 18%; grade Ն3 hypertension, 6%). 1 In clinical practice settings, patterns of development of and management strategies for hypertension are less well understood. Thus, we aimed to describe patterns of development, management strategies, and long-term vascular consequences of hypertension associated with ibrutinib in the non-clinical trial setting.

Methods
This multicenter cohort study took place at the Memorial Sloan Cancer Center in New York, New York; the Lombardi Cancer Center, Georgetown University Hospital, in Washington, DC; and the Abramson Cancer Center, University of Pennsylvania, in Philadelphia. It included patients treated with 420 mg of ibrutinib daily for at least 6 months outside of clinical trials; patients requiring dose reductions were excluded. Baseline cardiovascular comorbidities and medication regimens, sequential blood pressure (BP) measurements before and after ibrutinib exposure, adjustments to cardiovascular medication regimens, and development of cardiovascular complications were collected. Institutional review boards at all institutions approved the study, and informed consent was not required because of minimal risk to participants. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
The t test was used to compare medians. Univariate analysis was performed to assess associations of baseline features with the development of hypertension. Other statistics were descriptive. Statistical significance was set at P < .05, and all tests were 2-tailed. Statistical analysis was performed using Stata statistical software version 10.1 (StataCorp).

Results
We identified 247 patients at 3 institutions treated with ibrutinib. Before initiation of ibrutinib,

Discussion
Ibrutinib-associated hypertension is a common adverse event affecting those with and without preexisting hypertension. [1][2][3][4] We found that median time to peak BP was 6 months, suggesting the need for ongoing and close monitoring of BP in patients treated with ibrutinib for several months after drug initiation. The observed rate of incident hypertension and grade 3 or higher systolic hypertension was higher than that observed in clinical trials, 3 perhaps reflecting the inclusion of a more comorbid population with potentially less stringent monitoring or different management strategies used in practice vs clinical trial settings. The discrepancy between the proportion of patients experiencing new or worsening hypertension and those with a change in their antihypertensive regimens suggested a potential opportunity for care optimization as well as patient and clinician education. This study is limited by its retrospective design. This study, combined with available clinical trial data on hypertension incidence, may be influenced by natural variation in BP, emphasizing the importance of measuring the variability of BP before and after ibrutinib exposure.
Because ibrutinib is given continuously and hypertension prevalence is cumulative, ongoing study of long-term vascular consequences of ibrutinib-associated hypertension is needed. reported receiving grants and personal fees from Pharmacyclics, Johnson and Johnson, AbbVie, Loxo Oncology, Sunesis Pharmaceuticals, Genetech, and Adaptive Biotechnologies; receiving grants and personal fees from and serving on the data and safety monitoring board of TG Therapeutics; serving on the data and safety monitoring board of Celgene; and receiving grants from Regeneron Pharmaceuticals outside the submitted work. No other disclosures were reported.