Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (BTK) that was approved as a novel therapy against B-cell malignancies by the US Food and Drug Administration (FDA) in 2013. As a first-in-class agent, ibrutinib inhibits B-cell receptor signaling by covalently binding to the cysteine 481 residue within the adenosine-triphosphate-binding site of BTK, an enzyme that plays an important role in cell proliferation and survival in B-cell malignancies. Ibrutinib has demonstrated excellent efficacy in chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma, mantle cell lymphoma, marginal zone lymphoma, and Waldenström's macroglobulinemia.¹

Although ibrutinib is generally considered to be well-tolerated,² atrial fibrillation (AF) has emerged as an important issue in the cancer population treated with this drug.³ In fact, in a retrospective cohort study of patients with CLL, development of AF was the most common cause of ibrutinib discontinuation.⁴ In a meta-analysis of 4 randomized clinical trials of patients with CLL, small lymphocytic lymphoma, and mantle cell lymphoma treated with ibrutinib or non-ibrutinib therapy, the pooled incidence rate of AF in those treated with ibrutinib was 3.3 per 100 person years. The pooled incidence rate of AF among patients who received the non-ibrutinib therapy was 0.84 per 100 person years.⁵ There have also been reports of sudden cardiac death and ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, shortly after starting therapy with ibrutinib, with a median time to event of 65 days from ibrutinib initiation.⁶ Furthermore, the incidence of hypertension is also increased in patients with lymphoproliferative disorders treated with ibrutinib.⁷ Survival in patients with CLL correlates with the reason for ibrutinib discontinuation, and patients who discontinue due to intolerance or toxicity have a median survival of 33 months.⁸

The molecular mechanisms of ibrutinib-associated AF have not been elucidated. BTK appears to be expressed in human cardiac tissue, and BTK expression is increased in atrial tissue isolated from patients with AF undergoing cardiac surgery compared with those in sinus rhythm.⁹ Electrophysiological studies in in vivo mouse models have demonstrated an arrhythmogenic effect of ibrutinib.¹⁰ In rat ventricular myocytes, ibrutinib treatment is associated with inhibition of the phosphoinositide 3-kinase/Akt signaling pathway that is regulated by BTK, although the role of this pathway in the pathogenesis of ibrutinib-associated AF is not well-understood.⁹

Several risk factors have been identified for the development of AF in patients with B-cell lymphoproliferative disorders, including age over 65 years, previous history of AF, and ibrutinib therapy.¹¹ In comparison to other chemotherapeutic and chemo-immunotherapeutic agents used for B-cell malignancies, the risk of AF and atrial flutter in those treated with ibrutinib is increased by almost ninefold (relative risk [RR] 8.81; p = .0003).¹² In patients with CLL treated with ibrutinib, male gender, older age, valvular heart disease, and hypertension at the time of CLL diagnosis have been identified as independent risk factors for de novo AF.¹³ In a retrospective study of 562 patients with lymphoproliferative disorders treated with ibrutinib, new or worsening hypertension was associated with increased major cardiovascular events, especially arrhythmia (hazard ratio [HR] 3.18; 95% confidence interval [CI]; 1.37-7.37). In this study, the incidence of hypertension appeared to be increased in patients receiving ibrutinib, regardless of AF development. During a median follow-up of 30 months, nearly 80 percent of patients developed new or worsening hypertension, one-third of whom had high-grade hypertension (grade 3 or 4). The initiation of new anti-hypertensive therapy was associated with a decreased risk of subsequent major cardiovascular events (HR 0.40; 95% CI, 0.24-0.66).⁷

The highest incidence of AF has been observed during the first 6 months of ibrutinib treatment.^11,14 In a pooled analysis of 4 randomized clinical trials including a total of 756 patients treated with ibrutinib, the cumulative incidence of AF was 11.2% after 36 months of follow-up from drug initiation. The severity of AF was grade 1 or 2 and did not necessitate hospitalization in the majority of patients. More than half of patients who developed AF on ibrutinib experienced only 1 episode of AF during a median follow-up of 3 years. The mean duration of these episodes was 12.6 days (standard deviation = 29.5). In half of these patients, ibrutinib was continued without dose reduction or interruption of the drug.¹¹ According to the ibrutinib FDA label, ibrutinib interruption is recommended for any non-hematologic toxicity that is grade 3 or greater. Once the symptoms of toxicity have resolved to grade 1 or baseline, ibrutinib may be reinitiated at the starting dose.¹⁵ Dose reduction or permanent discontinuation of ibrutinib may be necessary for severe or refractory arrhythmias.

In addition to the increased risk of AF associated with ibrutinib therapy, the RR of all-grade bleeding has also been reported as higher than alternative treatments used for CLL, small lymphocytic lymphoma, or mantle cell lymphoma (RR 2.93; p = .03).¹² In a systematic review evaluating the incidence of bleeding with ibrutinib, the pooled annual incidence of any bleeding and major bleeding was 20.8 per 100 patient years and 2.76 per 100 patient years, respectively.¹⁶ Platelet adhesion and aggregation defects have been described in in vivo and in vitro studies evaluating the effects of ibrutinib on platelet function.^17,18 However, the role of other clinical risk factors associated with bleeding, such as prior anticoagulant/antiplatelet therapy or malignancy-related thrombocytopenia, need to be further studied in this context.

There are no clinical guidelines for ibrutinib-associated AF management; however, Ganatra et al. have proposed an algorithm based on the hemodynamic stability of the patient and need for anticoagulation (Figure 1).¹⁹ The bleeding diathesis associated with ibrutinib and possible drug-drug interactions are important considerations when instituting rate/rhythm control strategies and anticoagulation for thromboembolism prevention. Ibrutinib inhibits the P-glycoprotein (P-gp) transporter and is primarily metabolized by hepatic cytochrome P450 3A4 (CYP3A4). Amiodarone and the calcium channel blockers diltiazem and verapamil are antiarrhythmic drugs with CYP3A4 inhibitory activity that can result in increased serum concentrations of ibrutinib.²⁰ Digoxin is a P-gp substrate that should be taken at least 6 hours before or after taking ibrutinib to avoid toxic digoxin levels in the plasma.¹⁹ Furthermore, the class IA antiarrhythmic quinidine and the beta-blockers carvedilol and nadolol also interact with ibrutinib, increasing the serum concentrations of the former. Class IB and IC antiarrhythmics are the least likely to cause drug-drug interactions with ibrutinib.²¹

Figure 1: Proposed Algorithm for Ibrutinib-Associated AF Management

Patients on ibrutinib therapy tend to have higher predictive scores for ischemic stroke due to an older age of diagnosis and multiple co-morbidities.¹¹ In a retrospective cohort study of patients with a new diagnosis of cancer and pre-existing AF, the risk of stroke increased 1.4-fold per point increase in the CHADS₂ score (p < 0.001) and 1.2-fold per point increase in CHA₂DS₂-VASc score (p < 0.001). Interestingly, in the multivariable analysis of this population with cancer, only the CHADS₂ score but not the CHA₂DS₂-VASc score was associated with increased risk of stroke.²² In those patients already receiving warfarin before starting ibrutinib therapy who have international normalized ratio levels in the therapeutic range, warfarin can be continued with adequate monitoring. Ibrutinib can theoretically interact with direct oral anticoagulants such as dabigatran, apixaban, or rivaroxaban through P-gp-mediated interactions; however, these interactions have not been shown to be clinically significant.²³ The risk-benefit ratio of anticoagulation for stroke prophylaxis should be evaluated on a case-by-case basis given the increased risk of bleeding associated with ibrutinib use.

Left atrial abnormality on electrocardiogram has been suggested as a simple clinical tool to predict AF in patients treated with ibrutinib, although this may be non-specific.²⁴ Electrocardiographic monitoring every 1-2 months during the first 6 months of treatment may be reasonable given the high incidence of AF during this period.²⁵ Blood pressure monitoring should also be taken into account given the increased incidence of hypertension associated with ibrutinib. More detailed investigation will be necessary to better understand the mechanisms of ibrutinib-associated AF, to evaluate the associated stroke risk, and to develop clinical guidelines for the management of AF in this patient population.

References

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2. Burger JA, Keating MJ, Wierda WG, et al. Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study. Lancet Oncol 2014;15:1090-9.
3. Tang CPS, McMullen J, Tam C. Cardiac side effects of bruton tyrosine kinase (BTK) inhibitors. Leuk Lymphoma 2018;59:15-64.
4. Mato AR, Nabhan C, Barr PM, et al. Outcomes of CLL patients treated with sequential kinase inhibitor therapy: a real world experience. Blood 2016;128:2199-205.
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10. Tuomi JM, Xenocostas A, Jones DL. Increased Susceptibility for Atrial and Ventricular Cardiac Arrhythmias in Mice Treated With a Single High Dose of Ibrutinib. Can J Cardiol 2018;34:337-41.
11. Brown JR, Moslehi J, O'Brien S, et al. Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials. Haematologica 2017;102:1796-805.
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Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Cardiac Surgery, Cardio-Oncology, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Prevention, Valvular Heart Disease, Anticoagulation Management and Atrial Fibrillation, Implantable Devices, EP Basic Science, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Cardiac Surgery and Arrhythmias, Cardiac Surgery and VHD, Lipid Metabolism, Novel Agents, Statins, Interventions and Structural Heart Disease, Interventions and Vascular Medicine, Hypertension

Keywords: Cardiotoxicity, Adenosine Triphosphate, Algorithms, Anti-Arrhythmia Agents, Amiodarone, Antihypertensive Agents, Anticoagulants, Arrhythmias, Cardiac, ATP Binding Cassette Transporter 1, Atrial Fibrillation, Atrial Flutter, Blood Pressure, Binding Sites, Brain Ischemia, Calcium Channel Blockers, Cardiac Surgical Procedures, Cell Proliferation, Confidence Intervals, Cohort Studies, Cysteine, Disease Susceptibility, Digoxin, Diltiazem, Drug Interactions, Electrocardiography, Cytochrome P-450 CYP3A, Death, Sudden, Cardiac, Factor IX, Follow-Up Studies, Heart Valve Diseases, Hemorrhage, Hemodynamics, Hospitalization, Immunotherapy, Hypertension, Incidence, Leukemia, Lymphocytic, Chronic, B-Cell, International Normalized Ratio, Lymphoma, B-Cell, Lymphoma, Mantle-Cell, Nadolol, Neoplasms, Phosphatidylinositol 3-Kinases, Platelet Aggregation Inhibitors, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Pyrazoles, Pyridones, Pyrimidines, Quinidine, Receptors, Antigen, B-Cell, Retrospective Studies, Risk Assessment, Risk Factors, Signal Transduction, Stroke, Tachycardia, Ventricular, Thrombocytopenia, Thromboembolism, United States Food and Drug Administration, Ventricular Fibrillation, Verapamil, Waldenstrom Macroglobulinemia, Warfarin

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