Managing Hypertension in Patients Treated with Ibrutinib for Chronic Lymphocytic Leukemia

Blood pressure should be monitored closely and on an ongoing basis for several months after initiating ibrutinib treatment in patients with chronic lymphocytic leukemia (CLL), according to our retrospective study published this month in JAMA Network Open.

Hypertension is a common adverse event among CLL patients treated with ibrutinib in clinical trials. We studied the patterns of development, management strategies, and long-term vascular consequences of hypertension associated with ibrutinib in CLL patients in the non-clinical trial setting. ⁽¹⁾

Our results showed that blood pressure was significantly elevated for the entire cohort of 247 CLL patients treated with ibrutinib, including those with and without pre-existing hypertension.

Median range peak blood pressure increased significantly from baseline as follows: systolic rose to 153 (105–215) mm Hg from 127 (90–182) mm Hg, and diastolic rose to 80 (53–121) mm Hg from 71 (48–95) mm Hg (p < 0.001). Notably, the median time to peak blood pressure was six months (0 to 35 months). ⁽¹⁾

CLL and Ibrutinib

CLL is the most common type of leukemia in adults, with an estimated 20,720 Americans diagnosed and 3,930 dying from the disease in 2019. Almost all people diagnosed with CLL, about 90 percent, are over the age of 50 years.

The targeted therapy ibrutinib is an oral, small-molecule inhibitor of Bruton’s tyrosine kinase (BTK). It binds to and inhibits the BTK activity, thereby inhibiting the growth of malignant B cells that overexpress BTK. In March 2016, the U.S. Food and Drug Administration expanded the approval of ibrutinib to include treating patients with CLL in the first-line setting. The approval was based on the drug’s superiority in progression-free survival, overall survival, response rate, and improved hematologic markers compared to the chemotherapy chlorambucil in the RESONATE-2 clinical trial. ⁽²⁾

Hypertension has been identified as a common adverse event for CLL patients treated with ibrutinib in clinical trials, with an incidence of 18 percent and with six percent of study participants developing grade 3 or higher hypertension as defined by the Common Terminology Criteria for Adverse Events. ⁽³⁾

Study Design

In collaboration with our colleagues, we conducted the study at three cancer centers: Memorial Sloan Kettering Cancer Center (MSK), the Lombardi Cancer Center at Georgetown University Hospital in Washington, D.C., and the Abramson Cancer Center at the University of Pennsylvania, in Philadelphia. We identified 247 patients with CLL who were treated with 420 mg of ibrutinib daily for at least six months and who had not participated in clinical trials. ⁽¹⁾

Before starting ibrutinib, baseline cardiovascular comorbidities included hypertension (43.3 percent of patients), hyperlipidemia (35.2 percent), diabetes (16.2 percent), coronary artery disease (9.7 percent), heart failure (2.0 percent), valvular heart disease (2.8 percent), atrial fibrillation (4.5 percent), other arrhythmia (6.5 percent), stroke (2.8 percent), and smoking history (42.1 percent). ⁽¹⁾

Study Findings

At baseline, before ibrutinib initiation, median systolic blood pressure was 127 (90–182) mm Hg, and median diastolic blood pressure was 71 (48–95) mm Hg. ⁽¹⁾

In the first year after ibrutinib initiation, median range peak blood pressure increased significantly as follows: systolic rose to 153 (105–215) mm Hg and diastolic rose to 80 (53–121) mm Hg (p < 0.001) compared to baseline. ⁽¹⁾The median time to peak blood pressure was six months, with a range of 0 to 35 months.

A total of 86 patients (34.8 percent) of 247 patients had incident hypertension (blood pressure ≥ 140/90 mm Hg), and 82 patients (33.2 percent) developed grade 3 or higher systolic hypertension. ⁽¹⁾These observed rates of hypertension were higher than has been reported in clinical trials. ⁽⁴⁾

Among 140 patients without hypertension at baseline, new systolic hypertension developed in 92 patients (65.7 percent), and new diastolic hypertension developed in 25 patients (17.9 percent).

Among 107 patients with hypertension at baseline, 72 (67.3 percent) had a well-controlled baseline blood pressure of less than 140/90 mm Hg. During treatment with ibrutinib, grade 3 or higher systolic hypertension developed in 53 patients (49.5 percent) and grade 3 or higher diastolic hypertension developed in 5 patients (4.7 percent). ⁽¹⁾

Over the entire cohort, pre-existing cardiovascular comorbidities, smoking history, and diabetes were not associated with the development of hypertension in the univariate analysis. Fifty-one patients (20.6 percent) had a change in their cardiovascular medications while taking ibrutinib. Almost one-third had an increased dose for an existing prescription, and 80 percent started at least one new antihypertensive medication. New atrial fibrillation was observed in 16 patients (4 percent), and coronary artery disease was diagnosed in 4 patients (1.6 percent). ⁽¹⁾

Advancing CLL Research and Patient Outcomes

Our findings suggest that there is an opportunity to optimize care for all patients with CLL who are treated with ibrutinib. Whether they have pre-existing hypertension or not, we should monitor blood pressure closely for several months after ibrutinib initiation and on an ongoing basis.

Since ibrutinib is administered continuously and hypertension is cumulative, an ongoing study of the long-term vascular outcomes of hypertension associated with ibrutinib is needed.

At MSK, we are dedicated to advancing research to find new ways to help patients maximize outcomes and minimize adverse events following cancer treatment. We are currently conducting 18 clinical trials for patients with CLL including novel combinations of targeted and chemotherapies, as well as a phase I/II study of CAR T-cell therapy for patients with persistent or recurrent CLL.

Dr. Roeker reported having a spouse with a minority ownership interest in AbbVie and Abbott Laboratories; receiving a travel grant from AbbVie; and receiving a grant from the American Society of Hematology outside the submitted work.

Dr. Mato 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.