Ibrutinib-induced sick sinus syndrome requiring permanent pacemaker

SESSION TITLE: Cardiovascular Disease Case Report Posters 5 SESSION TYPE: Case Reports PRESENTED ON: 10/09/2023 02:10 pm - 02:55 pm INTRODUCTION: Ibrutinib (Imbruvica) is a potent irreversible inhibitor of the B-cell receptor pathway. By binding to Bruton's tyrosine kinase, it leads to the cessation of cell differentiation and growth of malignant B-lymphocytes in Chronic lymphocytic leukemia (CLL). The shift of the treatment paradigm from non-specific chemotherapy regimens to targeted kinase inhibitors for CLL was achieved after the FDA approval of Ibrutinib in 2014. It is also used in the treatment of small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), waldenstrom's macroglobulinemia and chronic graft versus host disease. Several studies have associated Ibrutinib use with pneumonia, atrial fibrillation, ventricular arrhythmias, prolonged QTc, syncope and pulmonary hypertension. We report a case of ibrutinib-induced sick sinus syndrome requiring a permanent pacemaker in a CLL patient. CASE PRESENTATION: A 66-year-old caucasian male with a past medical history of CLL presented to the hospital with fatigue and dizziness for 3 days. He was started on Ibrutinib 10 days ago in view of very high risk disease (17-P deletion). He denied any syncopal episodes, chest pain, or palpitations. Lab work was unremarkable except for leukocytosis with lymphocyte predominance due to his underlying CLL. His baseline 12-lead electrocardiogram shows normal sinus rhythm. Physical examination was normal. Transthoracic echocardiography showed normal heart architecture with a left ventricular ejection fraction of 60-65%. Ibrutinib was restarted along with other home medications. During the initial 48 hrs of hospitalisation, he experienced multiple episodes of bradycardia (lowest 35 bpm) , PVCs, sinus pauses (upto 7 seconds), along with episodes of high-grade Mobitz type 2 and transient complete heart blocks. Ibrutinib was further discontinued.Although he was initially evaluated for a permanent pacemaker, later it was deferred as he remained asymptomatic off Ibrutinib therapy without telemetry changes thereafter. He was discharged with an outpatient holter monitor. On 2-week follow up, event monitor review showed 36 pauses with the longest pause being 6 seconds along with dizzy spells, and his heart rate fluctuating between 40 - 133 bpm with evidence of sick sinus syndrome. Thus, a dual-chamber permanent pacemaker was placed, and he remained asymptomatic thereafter. DISCUSSION: To our knowledge, this is the second case report of Ibrutinib-induced sick sinus syndrome requiring a pacemaker. Although increased cardiac toxicities are seen in patients on Ibrutinib, atrial fibrillation is the most reported. Sinus pauses and arrest are among the rarest complications associated with Ibrutinib usage. Irreversible inhibition of tyrosine kinase by Ibrutinib explains why the cardiac manifestations retain even after drug withdrawal. The RESONATE trial for CLL reported a 10-fold increase in the incidence of atrial fibrillation in patients treated with Ibrutinib compared to Ofatumumab. Life-threatening ventricular arrhythmias and sudden cardiac deaths have been reported in multiple cases by Lampson et al. CONCLUSIONS: Due to irreversible and potentially life-threatening side effects of Ibrutinib, clinicians must be vigilant in its usage. Our case highlights the need for further studies to provide insight into the cardiac toxicities of the drug. REFERENCE #1: 1. Stephens DM, Byrd JC. How I manage ibrutinib intolerance and complications in patients with chronic lymphocytic leukemia. Blood. 2019 Mar 21;133(12):1298-1307. doi: 10.1182/blood-2018-11-846808. Epub 2019 Jan 14. PMID: 30642919; PMCID: PMC6428663. REFERENCE #2: 2. Byrd JC, Brown JR, O'Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213-223. doi:10.1056/NEJMoa1400376 REFERENCE #3: 3. Lampson BL, Yu L, Glynn RJ, Barrientos JC, Jacobsen ED, Banerji V, Jones JA, Walewska R, Savage KJ, Michaud GF, Moslehi JJ, Brown JR. Ventricular arrhythmias and sudden death in patients taking ibrutinib. Blood. 2017 May 4;129(18):2581-2584. doi: 10.1182/blood-2016-10-742437. Epub 2017 Feb 21. PMID: 28223277; PMCID: PMC7219062. DISCLOSURES: No relevant relationships by Himaja Dutt Chigurupati No relevant relationships by Ahsan Khan No relevant relationships by Sivaram Neppala No relevant relationships by YASHWITHA SAI PULAKURTHI No relevant relationships by Hamid Shaaban No relevant relationships by Addi Suleiman