Link between ibrutinib-related hypertension, heart problems necessitates close monitoring
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Ibrutinib — a Bruton tyrosine kinase inhibitor that inhibits B cell-receptor signaling — has demonstrated long-term efficacy as treatment for many mature B-cell malignancies, including chronic lymphocytic leukemia and mantle cell lymphoma.
Ibrutinib (Imbruvica; Janssen, Pharmacyclics) requires continuous dosing and is taken until disease relapse or progression.
Although most patients tolerate therapy well, cardiovascular complications — such as hypertension and atrial fibrillation — have emerged as significant treatment-associated adverse events. Atrial fibrillation is a common cause of ibrutinib discontinuation, and hypertension is a key risk factor for this condition.
Mechanism, incidence of atrial fibrillation
Many small-molecule medications often are associated with off-target effects due to inhibition of other pathways.
Ibrutinib has off-target inhibitory effects on TEC tyrosine kinase. BTK and TEC transcripts are elevated during atrial fibrillation compared with during normal sinus rhythm.
BTK and TEC have active roles in managing cardiac stress via their involvement in regulation of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway. Inhibition of BTK and TEC, which results in downregulation of this pathway, may increase risk for arrhythmia.
Incidence of ibrutinib-associated atrial fibrillation in clinical trials ranges from 6% to 16%.
Leong and colleagues conducted a systematic review and meta-analysis of 20 studies that included patients with CLL, mantle cell lymphoma, Waldenström macroglobulinemia or follicular lymphoma.
Researchers evaluated the frequency of atrial fibrillation among ibrutinib-treated patients, as well as the magnitude of increased atrial fibrillation risk among patients who received ibrutinib vs. alternative medications.
The results, published in 2016 in Blood, showed pooled rates of atrial fibrillation of 3.3 per 100 person-years among ibrutinib-treated patients and 0.84 per 100 person-years among those who received alternative therapies.
Brown and colleagues conducted a pooled analysis of 1,505 patients with CLL or mantle cell lymphoma enrolled in four large randomized controlled trials. Researchers aimed to characterize atrial fibrillation among those who received ibrutinib (n = 756).
Most atrial fibrillation developed de novo. At 16.6 months, incidence appeared four times higher among patients assigned ibrutinib than comparator therapy (6.5% vs. 1.6%).
After 36 months follow-up, analyses adjusted for competing risks for progressive disease and death showed estimated cumulative incidence of atrial fibrillation was 11.2%. Identified risk factors included ibrutinib treatment, age 65 years or older, and prior history of atrial fibrillation.
Most patients developed atrial fibrillation in the first 6 months of therapy. Two-thirds were single episodes, and more than half were grade 1 or grade 2.
Although hypertension was not predictive of atrial fibrillation on multivariate analysis, patients with history of hypertension were more likely than those with no history of hypertension to develop atrial fibrillation (9.5% vs. 4.2%). A separate safety analysis showed hypertension occurred more frequently among patients taking ibrutinib.
Wiczer and colleagues conducted a retrospective study to assess atrial fibrillation incidence among 582 adults treated with ibrutinib for hematologic malignancies.
Results, published in 2017 in Blood Advances, showed cumulative incidence of 5.9% at 6 months, 7.5% at 1 year and 10.3% at 2 years. Estimated incidence was 7.4 events per 100 person-years, suggesting the rate may be higher in real-world settings than clinical trials.
Median time to atrial fibrillation onset was 7.6 months.
Finally, Mato and colleagues performed a real-world analysis on one of the largest cohorts of ibrutinib-treated patients with CLL (n = 616).
Results, published in 2018 in Haematologica, showed toxicity was the most common cause of discontinuation among patients treated in the front-line or relapsed settings.
At median follow-up of 17 months, 41% of patients discontinued ibrutinib treatment (median time to discontinuation, 7 months). Twenty-five percent of patients who received ibrutinib in the front-line setting discontinued treatment due to atrial fibrillation.
Role of hypertension
Hypertension is associated with left atrium remodeling and increased risk for atrial fibrillation.
Caldeira and colleagues conducted a systematic review and meta-analysis of eight randomized controlled trials (n = 2,580) to evaluate the risk for hypertension and atrial fibrillation associated with ibrutinib.
Results, published last year in PLoS One, showed ibrutinib increased risk for hypertension by nearly threefold (RR = 2.82; P < .001).
Dickerson and colleagues evaluated the development of new or worsened hypertension after ibrutinib initiation among 562 consecutive patients with B-cell malignancies treated at The Ohio State University Comprehensive Cancer Center. They also collected information about major adverse cardiac events (MACE) among these patients and evaluated the relationship between new or worsened hypertension and incidence of arrhythmia.
Results, published last year in Blood, showed 440 patients (78.3%) developed new or worsening hypertension after median follow-up of 30 months.
Eighty percent of patients had at least a 10 mm Hg increase in systolic blood pressure, and 10% had a 50 mm Hg increase. Of the 215 patients who did not have hypertension at baseline, 71.6% developed new hypertension, with a cumulative incidence of 50% by 4.2 months.
More than one-third (37.6%) of all patients developed grade 3 or grade 4 hypertension, including 17.7% of those who did not have hypertension at baseline. Nineteen (3.4%) were hospitalized.
Multivariate analysis showed CLL, use of a CYP3A4 inhibitor and baseline systolic blood pressure were associated with hypertension development.
Researchers determined 209 patients (37.2%) required initial antihypertensive prescriptions or increases in the number of antihypertensive medications used. The agents used most to manage hypertension included diuretics (22.4%), angiotensin blocking agents (18%), beta blockers (15.4%) and calcium channel blockers (12.4%); however, no individual antihypertensive class appeared associated with control or prevention of worsening hypertension.
Ninety-three patients (16.5%) — including 84 with new or worsened hypertension — experienced MACE. The most common events included atrial fibrillation (13%), heart failure (3.7%), cerebrovascular accident (2.1%), myocardial infarction (1.4%) and ventricular arrhythmia/sudden death (1.1%).
Multivariate regression analysis showed new or worsened hypertension appeared associated with increased risk for MACE (HR = 2.17; 95% CI, 1.08-4.38) and arrhythmia (HR = 3.18; 95% CI, 1.37-7.37). Initiation of antihypertensive medication appeared associated with reduced risk for MACE (HR = 0.4; 95% CI, 0.24-0.66).
Roeker and colleagues conducted a multicenter cohort study to assess the development, management strategies and vascular consequences of ibrutinib-associated hypertension among patients treated in nonclinical trial settings.
The analysis included 247 patients with CLL. Prior to ibrutinib initiation, baseline cardiovascular comorbidities in the study cohort included hypertension (43.3%), hyperlipidemia (35.2%), diabetes (16.2%), coronary artery disease (9.7%) and atrial fibrillation (4.5%).
Baseline median blood pressure prior to ibrutinib initiation was 153 mm Hg/71 mm Hg.
Median time to peak blood pressure was 6 months (range, 0-35), with median changes from baseline of 19% for systolic blood pressure and 11% for diastolic blood pressure.
Approximately one-third (34.8%) of patients experienced blood pressure elevations to 140 mm Hg/90 mm Hg or higher, with a majority being grade 3 or higher.
Among patients who did not have baseline hypertension, researchers reported a 65.7% rate of systolic hypertension and 17.9% rate of diastolic hypertension. More than 50% of patients with baseline hypertension had worsened hypertension of grade 3 or higher.
Sixteen patients (6.4%) developed new atrial fibrillation. Fifty-one patients required cardiovascular medication changes, with 29.4% requiring increases in existing antihypertensive therapy and 80.4% starting new antihypertensive therapy.
Key considerations
New or worsening hypertension is a significant comorbidity that may lead to development of more significant cardiac events, including atrial fibrillation.
Toxicity — cardiovascular or otherwise — is the largest reason for ibrutinib discontinuation. It is important for all patients starting ibrutinib therapy to provide a detailed medical history that documents known cardiovascular comorbidities or potential disease states that may increase the risk for atrial fibrillation.
Patients benefit from aggressive management of treatment-emergent hypertension. For those with significant cardiovascular comorbidities — such as diabetes, prior history of atrial fibrillation, or valvular heart disease — a cardiology consultation should be considered.
Patients should be encouraged to track their blood pressure at home, and to maintain a record of the readings to discuss with their health care provider at routine visits. Patients also should be counseled on the signs and symptoms of arrhythmia, including palpitations, chest pain, dyspnea and syncope.
More detailed electrocardiographic monitoring (at baseline, then every 1 to 2 months) should be considered during the first 6 months of treatment but should continue throughout treatment, especially if symptoms of arrythmia develop.
Normal blood pressure is now defined as 120 mm Hg/80 mm Hg or below.
Although there is no one preferred agent for hypertension management, it is important to consider drug interactions when selecting agents. Co-administration of ibrutinib — a sensitive CYP3A4 substrate — with a moderate to strong CYP3A4 inhibitor should be avoided due to the resulting increase in ibrutinib concentrations and potential increase in toxicity. Examples include the nondihydropyridine calcium channel blockers verapamil and diltiazem.
Most patients with hypertension, or those who develop atrial fibrillation, will be able to continue ibrutinib treatment. All efforts should be made to maximize hypertension and atrial fibrillation management. Current recommendations for grade 3 or greater nonhematologic toxicity warrant ibrutinib interruption until the adverse reaction has improved to grade 1 or better. At that time, ibrutinib may be restarted at the original starting dose. Reoccurrence, in the setting of maximized therapy for hypertension or atrial fibrillation, should warrant a dose reduction by 140 mg or consideration of risk vs. benefit for continuation of ibrutinib.
The benefit of ibrutinib continuation may not be worth the risk for patients with difficult-to-treat hypertension.
Conclusions
CLL is a disease of the elderly. Real-world evaluations suggest many patients initiated on ibrutinib have significant comorbidities, many of them cardiovascular.
Hypertension — an important risk factor for the development of atrial fibrillation — may occur at a much higher rate in real-world practice settings than reported in clinical trials.
Patients should be monitored for the development of new or worsened hypertension, particularly early in the therapy course.
Intervention with antihypertensive medications for patients with hypertension may prevent MACE, including atrial fibrillation. It does not appear that any class of antihypertensives is preferred for hypertension management among these patients.
Treatment of new-onset hypertension, as well as prevention of worsening hypertension and atrial fibrillation development, makes it easier for patients to remain on ibrutinib without dose modification or interruption.
References:
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