Ibrutinib, an Approved Tyrosine Kinase Inhibitor as a Potential Cause of Recurrent Polymorphic Ventricular Tachycardia

Tomcsányi, János; Nényei, Zoltán; Mátrai, Zoltán; Bózsik, Béla

doi:10.1016/j.jacep.2016.07.004

Cited by 28 publications

(19 citation statements)

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“…In the case of BYL719, hyperglycemia was common in all trials with PI3K inhibitors [6][7][8][9], which is consistent with systemic pharmacological inhibition of PI3K in mice [29]. Also, off-target inhibition of PI3K by ibrutinib is linked to increases in cardiac disorders (2-fold) and atrial fibrillation (3-fold) in comparison to the anti-CD20 monoclonal antibody ofatumumab [12], as well as instances of sudden death and ventricular arrhythmias in patients with no prior cardiac history [13,14]. In mice, high doses of ibrutinib increase the susceptibility to induced atrial and ventricular arrhythmias, and this susceptibility was normalized on withdrawal of the drug [36].…”

Section: Development Of New Cancer Therapies Raises Questions Of Posssupporting

confidence: 58%

“…Ibrutinib increased instances of a cardiac disorder and atrial fibrillation by 2-and 3-fold, respectively, in comparison to the anti-CD20 monoclonal antibody ofatumumab [12]. Besides that, ibrutinib is linked to ventricular arrhythmias and sudden cardiac death in patients [13,14]. A link between PI3K activity and arrhythmias has been observed not only for cancer drugs but also for diabetes, which also lowers PI3K activity [15,16].…”

Section: Introductionmentioning

confidence: 98%

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Inhibition of PI3Kinase-α is pro-arrhythmic and associated with enhanced late Na+ current, contractility, and Ca2+ release in murine hearts

Zhabyeyev

McLean

Chen

et al. 2019

Journal of Molecular and Cellular Cardiology

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Background: Phosphoinositide 3-kinase  (PI3K) is a proto-oncogene with high activity in the heart. BYL719 (BYL) is a PI3K-selective small molecule inhibitor and a prospective drug for advanced solid tumors. We investigated whether acute pharmacological inhibition of PI3K has pro-arrhythmic effects. Methods & Results: In isolated wild-type (WT) cardiomyocytes, pharmacological inhibition of PI3K (BYL719) increased contractility by 28%, Ca 2+ release by 20%, and prolonged action potential (AP) repolarization by 10-15%. These effects of BYL719 were abolished by inhibition of reverse-mode Na + /Ca 2+ exchanger (NCX) (KB-R7943) or by inhibition of late Na + current (INa-L) (ranolazine). BYL719 had no effect on PI3K-deficient cardiomyocytes, suggesting BYL719 effects were PI3K-dependent and mediated via NCX and INa-L. INa-L was suppressed by activation of PI3K, application of exogenous intracellular PIP3, or ranolazine. Investigation of AP and Ca 2+ release in whole heart preparations using epicardial optical mapping showed that inhibition of PI3K similarly led to prolongation of AP and enhancement of Ca 2+ release. In hearts of PI3K-deficient mice, -adrenergic stimulation in the presence of high Ca 2+ concentrations and 12-Hz burst pacing led to delayed afterdepolarizations and ventricular fibrillation. In vivo, administration of BYL719 prolonged QT interval [QTcF (Fridericia) increased by 15%] in WT, but not in PI3K-deficient mice. Conclusions: Pharmacological inhibition of PI3K is arrhythmogenic due to activation of INa-L leading to increased sarcoplasmic reticulum Ca 2+ load and prolonged QT interval. Therefore, monitoring of cardiac electrical activity in patients receiving PI3K inhibitors may provide further insights into the arrhythmogenic potential of PI3K inhibition.

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Section: Development Of New Cancer Therapies Raises Questions Of Posssupporting

confidence: 58%

Section: Introductionmentioning

confidence: 98%

Inhibition of PI3Kinase-α is pro-arrhythmic and associated with enhanced late Na+ current, contractility, and Ca2+ release in murine hearts

Zhabyeyev

McLean

Chen

et al. 2019

Journal of Molecular and Cellular Cardiology

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“…5 However, it is unknown whether this favorable risk-benefit balance will be maintained as ibrutinib treatment is expanded to populations that may be older, have more underlying cardiac disease, or have lower-risk CLL. For example, a case of VT has been reported in a trial examining ibrutinib in asymptomatic early-stage CLL, 18 and 2 recent case reports identified VT in ibrutinibtreated patients with a history of AF 19 and cardiomyopathy. 20 In addition, ibrutinib studies currently have short follow-up, and the riskbenefit ratio may change with extended therapy.…”

mentioning

confidence: 99%

“…2,12,13 Diagnosis of PEL was established if .80% bone marrow nucleated cells consisted of immature erythroid precursors 2,[13][14][15] or if bone marrow core biopsy or aspirate clot was composed of sheets of immature undifferentiated blasts positive for glycophorin A. 9,10,[16][17][18] In patients evaluated from 2013 to 2016, whole-bone marrow DNA was subject to a 28-or 53-gene targeted polymerase chain reaction-based next-generation sequencing platform 19 (available in the data supplement on the Blood Web site).…”

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confidence: 99%

Ventricular arrhythmias and sudden death in patients taking ibrutinib

Lampson

Glynn

et al. 2017

Blood

179

101

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Ibrutinib, approved by the US Food and Drug Administration (FDA), is an inhibitor of Bruton tyrosine kinase (BTK). [1][2][3][4][5] Ibrutinib use is associated with atrial fibrillation (AF), with an incidence of 5% to 6% after 18 months on therapy [4][5][6] and up to 16% with longer follow-up. 2,7Prompted by an episode of unexplained ventricular tachycardia (VT) in a patient taking ibrutinib, we hypothesized that ibrutinib use may be associated with ventricular arrhythmias (VAs). To further investigate, we gathered 4 cases of VAs in ibrutinib-treated patients, mined the FDA Adverse Event Reporting System (FAERS) for additional reports of VAs in patients receiving ibrutinib, and estimated incidence rates of VAs in clinical trials of ibrutinib. Individual patients were enrolled on data collection protocols approved by institutional review boards or collected from publicly available data. We obtained adverse events (AEs) for ibrutinib reported to the FAERS from the fourth quarter of 2013 (ibrutinib was approved by the FDA in November 2013) to the fourth quarter of 2015. Additional details were requested for AE reports with the following preferred search terms: ventricular arrhythmia, ventricular fibrillation (VF), Brugada syndrome, right bundle branch block, cardiac arrest, cardiac death, cardiac fibrillation, cardiorespiratory arrest, conduction disorder, sudden death, sudden cardiac death, ventricular extrasystoles, and ventricular tachycardia. If dates of ibrutinib discontinuation, cardiac events, or death were redacted, we used the date when the patient was last seen alive or when the event was filed. Patients for whom there was not enough information to determine the timing of ibrutinib administration or for whom ibrutinib was discontinued before the event were excluded. Clinical trial data were drawn from published results. Median time on therapy was assumed to be mean time on therapy to calculate total time on therapy for the group of interest. Statistical analysis was performed by using STATA 14 (STATA, College Station, TX).Our index patient was a 60-year-old man who had chronic lymphocytic leukemia (CLL) and no prior cardiac history. He was a vigorous exerciser with resting sinus bradycardia. Two months after beginning ibrutinib, he reported new palpitations. He experienced syncope 86 days after initiating ibrutinib. Frequent premature ventricular contractions (PVCs) and nonsustained VT were identified ( Figure 1A). An exercise stress test was negative for ischemic changes, but polymorphic VT occurred when he transferred from stretcher to treadmill ( Figure 1B). Cardiac catheterization and echocardiogram were normal. Electrophysiologic studies induced PVCs originating from the moderator band but could not ablate the focus; therefore, he was started on antiarrhythmics and a cardioverter-defibrillator was implanted. Ibrutinib was resumed at discharge. Attempted downtitration of his quinidine later resulted in an increase in PVCs. He has since been maintained on ibrutinib, quinidine, and metoprolol for 28 mont...

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“…TKIs have been implicated in polymorphic ventricular tachycardia by enhancing automaticity through increased early and late afterdepolarizations. 4,5 Clinical and trial data illustrate that new arrhythmias occurred in w11% of patients during dasatinib use while QTc prolongation .500 ms was seen in 2% of patients. 1,2 Case report data have shown an association between dasatinib and a high burden of PVCs without VF that responded well to cessation of the drug.…”

Section: Discussionmentioning

confidence: 99%

Recurrent ventricular fibrillation with different tyrosine kinase inhibitors for chronic myeloid leukemia

Prashar

Ilsar

Roncolato

et al. 2020

HeartRhythm Case Reports

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Ibrutinib, an Approved Tyrosine Kinase Inhibitor as a Potential Cause of Recurrent Polymorphic Ventricular Tachycardia

Cited by 28 publications

References 0 publications

Inhibition of PI3Kinase-α is pro-arrhythmic and associated with enhanced late Na+ current, contractility, and Ca2+ release in murine hearts

Inhibition of PI3Kinase-α is pro-arrhythmic and associated with enhanced late Na+ current, contractility, and Ca2+ release in murine hearts

Ventricular arrhythmias and sudden death in patients taking ibrutinib

Recurrent ventricular fibrillation with different tyrosine kinase inhibitors for chronic myeloid leukemia

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