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Ibrutinib-Associated Cardiovascular Events in a Patient Wearing an Implanted Loop Recorder

Daniel Rivera1, Koichi Takahashi1, Jean-Bernard Durand2 and Alessandra Ferrajoli1.

1 Department of Leukemia, The University of Texas MD Anderson Cancer Center.
2 Department of Cardiology, The University of Texas MD Anderson Cancer Center.

Correspondence to: Alessandra Ferrajoli, BS, MD Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 0428. Houston, TX 77030. E-mail: aferrajo@mdanderson.org

Published: July 1, 2021
Received: May 3, 2021
Accepted: June 6, 2021
Mediterr J Hematol Infect Dis 2021, 13(1): e2021044 DOI 10.4084/MJHID.2021.044

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(
https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Ibrutinib is a well-tolerated and effective therapy used for the treatment of chronic lymphocytic leukemia (CLL). However, its use has been associated with cardiovascular events such as atrial fibrillation (Afib), hypertension, and ventricular arrhythmias. Cardiac arrhythmias represent a significant cause of morbidity and mortality. Implanted loop recorders have been integrated into our clinical practice and have been considered a useful tool in guiding the management of patients with cardiac arrhythmias. We report a case that describes our experience on a patient diagnosed with CLL treated with ibrutinib.



Introduction. Learning objectives

•    The importance of Ibrutinib-related cardiovascular events.
•    Differential diagnosis of patients with a newly diagnosed tachyarrhythmia.
•    The role of an implanted loop recorder for the management of ibrutinib-associated arrhythmias.

History of presentation

The patient is a 67 y.o. man, who in February 2017 presented to the emergency center with a chief complaint of dizziness, lightheadedness, and palpitations. He was found to be hypotensive, and his physical exam was remarkable for tachycardia with an irregularly irregular heart rhythm.

Past Medical History

The patient had a history of hyperlipidemia treated with atorvastatin and well-controlled essential hypertension treated with losartan/hydrochlorothiazide. In 2015 he was diagnosed with CLL with chromosome 11 deleted and IGHV mutated. In October 2016, the patient required treatment because of progressive disease and started therapy on a clinical trial with ibrutinib at the dose of 420 mg daily.
 

Differential diagnosis

Laboratory evaluation did not show electrolyte imbalances or thyroid dysfunction. An echocardiogram did not detect valvular or structural abnormalities and showed an LVEF of 61% with no regional wall motion abnormalities or evidence of myocardial disorders. The patient was admitted with the diagnosis of Afib with a rapid ventricular rate (RVR) and a CHADSVASc of 2.

Investigations and Management

The patient was initially treated with amiodarone without success; electrical cardioversion was performed, achieving normal sinus rhythm (NSR). The patient was discharged on amiodarone, 400 mg daily, apixaban 5 mg BID, and the ibrutinib dose was reduced to 140 mg daily. However, fifteen days after the event, due to the concern of the interaction between ibrutinib and amiodarone, which could reduce Ibrutinib clearance and, consequently, increase the risk of bleeding due to its interaction with apixaban, these two drugs were discontinued.
 Ibrutinib was increased to its total dose of 420 mg daily, and the patient was started on metoprolol 12.5 mg daily and aspirin 81 mg daily. At this time, the cardiology team implanted a subcutaneous insertable loop recorder (Reveal) to optimize the monitoring of future arrhythmias. The next phase of his treatment on clinical trial consisted of venetoclax at the dose of 400 mg daily.
Over the next 2 months, the loop recorder detected 2 episodes of Afib, which were asymptomatic and, on one occasion, followed by a non-sustained monomorphic ventricular tachycardia (NSVT) with no hemodynamic sequela. (Figure1 A and B). The patient at this time was asymptomatic with a CHADSVASc of 2 and HAS-BLED of 1. Due to the presence of recurrent arrhythmias, a Pharmacological nuclear EKG stress test was done and showed normal myocardial perfusion with no evidence of stress-induced ischemia and normal left ventricular systolic function with a left ventricular ejection fraction of 66%. His treatment was optimized with a change of metoprolol 12.5 mg daily to metoprolol XL 50 mg daily.


Figure 1A Figure 1A. Electrocardiogram showing non-sustained monomorphic ventricular tachycardia (NSVT).

Figure 1B Figure 1B. Reveal LINQ monitor interrogation: Percentage of time in Atrial tachycardia/ Atrial Fibrillation: 4.3%. Findings: One Ventricular tachycardia episode was noted with rates of 207-222 bpm. Two Afib episodes.

Between May 2017 and February 2018, the implantable loop recorded continued to detect Afib with a burden that remained <6%, but no further episodes of VTs (Table 1). The patient continued to experience borderline hypertension (Table 1).

Table 1 Table 1. The burden of Atrial fibrillation, Blood pressure readings, and management.

In February 2018, the patient developed an erythematous rash which was attributed to ibrutinib. CLL re-staging was found to have achieved complete remission with undetectable measurable residual disease on bone marrow test. Ibrutinib was, therefore, discontinued in February 2018 and venetoclax monotherapy was continued for one additional year until January 2019 when all treatments were discontinued.

 

Discussion

Ibrutinib is a first-generation BTK inhibitor that has been effective for the treatment of CLL. BTK inhibition reduces B-cell proliferation, adhesion, and migration.[1,2] treatment with ibrutinib has been associated with cardiovascular toxicities. The proposed mechanisms of the cardiovascular effect are not exactly known; however, it has been thought they are related to off-target effects on kinases different than BTK. Inhibition of cardiac PI3K-Akt signaling, which is a critical regulator of cardiac protection under stress conditions,[3] the binding of ibrutinib to ErbB2/HER2, ErbB4/HER4, and BMX receptors in cardiomyocytes, and inhibition of C-terminal Src kinase have been reported to be involved.[4]
In the case reported here, shortly after starting ibrutinib, the patient began experiencing cardiovascular events such as an increase in blood pressure, recurrent episodes of Afibr, and one episode of VT, which were attributed to ibrutinib therapy.
We observed that our patient had a median systolic BP of 127 mmHg and a diastolic BP of 81 mmHg while receiving treatment with ibrutinib. The development of hypertension has been reported in up to 68% of the patients undergoing treatment with ibrutinib, and worsening HTN is common in patients with pre-existing HTN. The risk for HTN continues for the entire duration of treatment with ibrutinib and can increase the risk of major adverse cardiovascular events such as Afib, stroke, or myocardial infarction.[5]
Our patient experienced one symptomatic Afib episode four months after initiating therapy with ibrutinib, requiring electrical cardioversion. Antiarrhythmic treatment with amiodarone and anticoagulation with apixaban was initially implemented but soon deemed not feasible due to interactions with ibrutinib and increased risk for bleeding. This highlights the complexity in managing these patients with risks for drug interactions with strong or moderate CYP3A4 inhibitors/inducers. Additionally, the concomitant administration of vitamin K antagonists is prohibited in patients receiving ibrutinib, and insufficient data are available on the risk of bleeding in patients receiving DOAC and ibrutinib considering that the coadministration of DOAC and ibrutinib could increase ibrutinib exposure via CYP3A4-mediated interaction.
Consequently, our patient continued metoprolol for rate control. His loop recorder showed a median percentage of time in Afib of 2.2% over 12 months. The patient remained on ibrutinib since he remained asymptomatic with successful medical management. Pooled analysis of 4 randomized trials showed an incidence of ibrutinib related-atrial fibrillation of 3.3 per 100 person-year.[6] However, a higher incidence has been reported in studies, with a longer follow-up being up to 16% of the patients.[7] The common etiologies for ventricular arrhythmias include untreated or unrecognized ischemic heart disease; wherein ischemia can serve as a substrate for ventricular tachycardia. Ventricular arrhythmias have been associated with ibrutinib therapy. Avirup et al. reported a median time-to-event of 16 months with an incidence rate of 617 per 100,000 person-year in the general population and patients without baseline CAD, and heart failure; similar to our patient, the incidence rate was lower at 596 per 100,000.[8] Similarly, the REVEAL AF study performed in the general population in 446 patients, reporting a detection rate at 18 months of 29%, this proved to be of value in detecting undiagnosed AF in patients with risk factors for Afib and stroke.[9]
In this case, Ibrutinib was not discontinued as this patient was asymptomatic with no hemodynamic compromise. Early discontinuation of Ibrutinib can impact the ability to control CLL and affect long-term survival. The risks and benefits of discontinuing ibrutinib must be discussed extensively with the oncology team, cardio-oncology specialists, and patients.[10,11]

Follow-up

No further episodes of Afib were observed after discontinuation of ibrutinib. Since then, the patient continues to be without treatment for his CLL, which remains in remission, with good quality of life and no cardiovascular events to date.

Conclusions

The management of ibrutinib-related cardiovascular toxicities remains a challenge in daily practice, and their importance is going to increase with the growing number of older patients being treated with this agent. The presence of an implanted loop recorder helps monitor patients, following the impact of treatment modifications, and trigger additional testing to identify contributing factors or alternative etiologies to the observed arrhythmias.

References  

  1. Burger, JA, et al., Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia, 2020. 34(3): p. 787-798. https://doi.org/10.1038/s41375-019-0602-x
  2. Munir, T., et al., Final analysis from RESONATE: Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol, 2019. 94(12): p. 1353-1363. https://doi.org/10.1002/ajh.25638
  3. McMullen, J.R., et al., Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. Blood, 2014. 124(25): p. 3829-30. https://doi.org/10.1182/blood-2014-10-604272
  4. Xiao, L., et al., Ibrutinib-Mediated Atrial Fibrillation Attributable to Inhibition of C-Terminal Src Kinase. Circulation, 2020. 142(25): p. 2443-2455. https://doi.org/10.1161/CIRCULATIONAHA.120.049210
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  7. Thompson, P.A., et al., Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood, 2016. 127(3): p. 303-9. https://doi.org/10.1182/blood-2015-09-667675
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  9. Reiffel, J.A., et al., Incidence of Previously Undiagnosed Atrial Fibrillation Using Insertable Cardiac Monitors in a High-Risk Population: The REVEAL AF Study. JAMA Cardiol, 2017. 2(10): p. 1120-1127. https://doi.org/10.1001/jamacardio.2017.3180
  10. Maddocks, K.J., et al., Etiology of Ibrutinib Therapy Discontinuation and Outcomes in Patients With Chronic Lymphocytic Leukemia. JAMA Oncol, 2015. 1(1): p. 80-7. https://doi.org/10.1001/jamaoncol.2014.218
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