Pericarditis and Cardiac Tamponade in Patients Treated with First and Second Generation Bruton Tyrosine Kinase Inhibitors: An Underappreciated Risk

Introduction The introduction of Bruton's tyrosine kinase (BTK) inhibitors significantly improved the management of chronic lymphocytic leukemia (CLL). However, BTK carry the risk of cardiotoxicity, which is not only limited to atrial fibrillation. Case Reports. We report three cases of patients on BTK inhibitors who developed acute pericarditis and cardiac tamponade. We report the first patient who developed this complication on treatment with zanubrutinib. This patient's treatment was changed to zanubrutinib due to atrial fibrillation. Shortly after cardioversion, he developed cardiac tamponade and shock. He underwent pericardiocentesis, received treatment for acute pericarditis with steroids and colchicine, and made a full recovery. We also report two further cases, both involving patients treated with ibrutinib. These patients also developed acute pericarditis and cardiac tamponade and required pericardiocentesis. All three patients discontinued BTK therapy following the events. Conclusions These three cases highlight the rare but potentially life-threatening risk of cardiac tamponade which can occur even with newer generations of BTK inhibitors. Haemato-oncologists should remain vigilant in patients who report dyspnea or who show sinus tachycardia on routine electrocardiography. Even in the absence of classical clinical signs of tamponade, patients require urgent evaluation with echocardiography and potentially emergency pericardiocentesis.


Introduction
Ibrutinib, an oral once-daily inhibitor of Bruton's tyrosine kinase (BTK), has signifcantly improved progression-free survival (PFS) and overall survival (OS) in patients with chronic lymphocytic leukemia (CLL) [1].Its suitability spans a broad patient demographic, encompassing the elderly and those with high-risk disease profles.Te specifcity of ibrutinib's action on BTK is limited, resulting in of-target efects in various tissues.Cardiac complications such as atrial fbrillation and hypertension occur frequently [2].Furthermore, ibrutinib has an "aspirin-like" infuence on collagen-induced platelet aggregation and adhesion to von Willebrand factor, which enhances the bleeding risk [3].Tere have been instances of cardiac tamponade associated with ibrutinib, especially when used concurrently with antiplatelet therapy [4].Pericardial efusions in cancer patients can have a multifactorial etiology (Figure 1), attributable to direct neoplastic invasion of the pericardium, hemorrhage, the efects of chemotherapy or radiotherapy, or concurrent infections [5].Pericarditis and pericardial efusions are infrequently observed in patients treated with ibrutinib [6,7].Without prompt and appropriate management, pericarditis can progress to cardiac tamponade [8].Tis report presents three cases of pericarditis and cardiac tamponade necessitating hospitalization and decompressive interventions in patients undergoing BTK inhibitor therapy.

Case 1
Tis patient, a 75-year-old male, was diagnosed with chronic lymphocytic leukemia (CLL) fve years ago and initially treated with ibrutinib.However, in October 2023, he developed atrial fbrillation.He was anticoagulated and switched to the second-generation TKI zanubrutinib.On December 5th, 2023, he underwent successful DC cardioversion.However, within a week postcardioversion, he experienced increasing shortness of breath and eventually collapsed at home.On admission to the local hospital, he presented in shock with blood pressure of 60/40 mm Hg.A "triple rule out" computed tomography (CT) scan was performed to exclude pulmonary embolus, aortic dissection, and acute coronary event.Te scan was negative for all three but revealed a large pericardial efusion.Subsequent echocardiography confrmed a 6 cm efusion with evidence of tamponade physiology with right ventricular diastolic collapse and exaggerated changes in mitral and tricuspid infow velocities with respiration.He underwent emergency pericardiocentesis with the removal of two liters of serosanguinous fuid with no evidence of malignant cells or infection on fuid analysis.Following drainage, his hemodynamic status improved, and his drain could be removed.Subsequent magnetic resonance imaging (MRI) showed pericardial thickening with evidence of acute pericardial infammation suggestive of acute pericarditis (Figure 2).Te remainder of his cardiac structures and function were within normal limits.Anticoagulation and zanubrutinib were discontinued, and he received a treatment course of steroids and colchicine.Eight weeks later, he remained of BTK inhibitor therapy, and his blood counts continued to be stable.However, he remained breathless.A repeat MRI scan showed resolution of the acute pericarditis, but an ECG confrmed he had reverted to atrial fbrillation with a heart rate of 110 beats per minute.He successfully restarted anticoagulation and is scheduled for repeat DC cardioversion.We are expecting his CLL will eventually progress, in which case we would start venetoclax and obinutuzumab.

Case 2
An 80-year-old female diagnosed with Waldenström's macroglobulinemia had been under ibrutinib therapy for three years.She had achieved durable disease control with an IgM M-band of <0.5 g/L.She presented with acute breathlessness on minimal exertion and a left swollen and painful leg.Ultrasound Doppler of the leg and a computed tomography pulmonary angiogram (CTPA) were negative for deep vein thrombosis and pulmonary embolism but revealed a large pericardial efusion.An echocardiogram confrmed a moderate circumferential pericardial efusion (Figure 3).Laboratory blood tests showed a CRP of 170 mg/ L and impaired renal function with a urea level of 16.5 mmol/L.She underwent pericardiocentesis where 450 ml of hemorrhagic fuid were drained.Microscopic examination revealed predominantly acute and chronic infammatory cells, without malignant cells.Flow cytometry confrmed a majority of small, polyclonal B-cells, while Tcells constituted 32% of the total cell, with a CD4/CD8 ratio of 3.59 and natural killer (NK) accounting for 4%.Te total protein content was 42 g/L.Both Gram and Ziehl-Neelsen staining failed to demonstrate any organisms.Despite drainage and diuretic treatment, the patient's clinical condition did not improve.Consequently, prednisolone and colchicine were initiated, which resulted in a swift response with a marked decrease in C-reactive protein and a clinical recovery.In view of the cardiac complication, ibrutinib was withdrawn, and she was followed with watchful waiting.Subsequent echocardiograms and a PET-CT scan conducted two months later showed no recurrence of pericarditis.Her IgM levels remained stable for a further six months before rising again.Unfortunately, throughout that period, her overall  health had signifcantly declined; thus, when her IgM levels began rising again, the patient and her family opted for palliative care.

Case 3
An 87-year-old male, receiving long-term treatment for chronic lymphocytic leukemia (CLL) with ibrutinib developed atrial fbrillation, which was managed with bisoprolol and apixaban alongside ibrutinib.Two weeks before his current presentation, he was admitted to a diferent hospital due to breathlessness with minimal exertion and pleuritic chest pain.Elevated C-reactive protein (CRP) levels were noted.A chest CT-scan revealed consolidation of the lung and large bilateral pleural efusions.Te efusions were drained, and although no organism was confrmed, he received antibiotic treatment with piperacillin/tazobactam and amikacin.
A week later, he was transferred to our institution.On admission to our hospital, he exhibited a raised jugular venous pressure (JVP) and ankle edema.Although cardiac examination and 12-lead electrocardiograms were normal, echocardiography revealed a mild to moderate circumferential pericardial efusion and reaccumulation of pleural efusions (Figure 4(a)).Te pleural efusions were drained, and a second course of antibiotics was administered.Te pleural fuid was bloodstained, containing acute and chronic infammatory cells, with fow cytometry revealing 8% of small cells with a CLL phenotype but no organisms were detected in culture.Respiratory viral PCR testing was incidentally positive for rhinovirus.
His condition initially improved clinically with broadspectrum antibiotics (piperacillin/tazobactam, amikacin, clarithromycin, and meropenem) but the pericardial efusion persisted.After a week of observation, the efusion had enlarged (Figure 4(b)) and was now hemodynamically compromising.In addition, episodes of rapid atrial fbrillation occurred.Consequently, ibrutinib therapy was discontinued.He underwent a pericardial window procedure during which hemorrhagic fuid was removed.Pericardial biopsies showed no evidence of malignancy.
Postprocedure recovery was uneventful, and he could be discharged from hospital.Ibrutinib was withheld for four months, during which his total white cell count increased to 322.Subsequently, treatment with venetoclax and rituximab was initiated.

Discussion
To our knowledge, this is the frst case report of cardiac tamponade for a patient on zanubrutinib.Patients with cardiac tamponade typically present with hypotension, tachycardia, and jugular venous distension.Detailed clinical examination may reveal mufed heart sounds and Pulsus paradoxus.Pulsus paradoxus is a misnomer, as it is not strictly paradox but rather exaggerates physiological efects of inspiration [9].In classic tamponade, patients will exhibit a decrease in stroke volume and blood pressure (>10 mmHg) during inspiration, which results in the "paradox" of audible heart sounds but concurrent loss of a palpable radial pulse.Importantly, patients with cardiac tamponade have reduced renal perfusion and can present with renal failure.Tough cardiac tamponade is a clinical diagnosis, echocardiography is important to evaluate the hemodynamic signifcance of the efusion.
Te occurrence of pericarditis and pericardial efusions with ibrutinib has previously been recognized; however, most of the current literature is limited to case reports [4,7,10,11].A larger meta-analysis of cardiovascular events reported a small risk of pericardial efusions (0.5%) and pericarditis (0.4%) [12].Tus, the risk of pericardial toxicity appears to be generally low compared to atrial fbrillation; however, it carries a potential risk of life-threatening cardiac tamponade.Te problem with pericardial complications in ibrutinib may potentially be wider than generally appreciated.Pharmacovigilance data (VigiBase) contain 81 cases of pericardial efusions, 24 of pericarditis, 16 cardiac tamponades, and 14 pericardial hemorrhages [13].Tis could be due to the large number of patients treated with ibrutinib in the hematology practice.Hemorrhagic pericardial efusion combined with pleural efusions has been described by Johnson et al. [10] and is a characteristic of acute pericarditis with pleuropulmonary involvement [8].
Te suggested mechanism for BTK to increase the risk of pericardial efusions is inhibition of platelet-derived growth factor receptor β (PDGFR-β) and Src family tyrosine kinases, which regulate endothelial permeability and interstitial tissue pressure [14].In addition to serosal infammation, ibrutinib's "aspirin-like" efect on platelets can aggravate bleeding [4], with major hemorrhage reported in up to 7% of the patients on ibrutinib [1].Te aspirin-like efect of ibrutinib is related to impairment of GPVIdependent platelet aggregation.Interestingly, this inhibition appears to be limited to thrombus formation around plaques, whilst sparing physiological haemostasias [15].Tere is variability in the sensitivity to ibrutinib oftarget efects, depending on an individual's drug efux pump efcacy [16].Te efect is to some extent dose dependent and drugs that block efux pumps can further increase sensitivity such as calcium channel blockers (e.g., verapamil), which should be avoided when treating atrial fbrillation concomitantly with ibrutinib therapy.
In addition, anticoagulation, which is prescribed for prevention of embolic strokes in atrial fbrillation, can contribute to hemorrhage.However, it is extremely rare for patients on DOACs alone to develop spontaneous cardiac tamponade [17].Also, DC cardioversion is associated with only a small risk of tamponade (1%) [18].Together, this suggests that other factors, such as the BTK efects described before potentially in combination with the aspirin-like efect, are required for signifcant pericardial efusions to develop.
A baseline cardiovascular assessment including evaluation for palpitation, dyspnea, exertional chest pain, edema, unexplained syncope, or arrythmias, together with measurement of pulse and blood pressure, as well as an electrocardiogram and an echocardiogram for patients over 50 is usually obtained before initiating BTK inhibitor treatment [19].Typically, repeat ECGs are then obtained at periodic 4 Case Reports in Hematology clinic visits to screen for new onset atrial fbrillation ECGs.However, the sensitivity of the ECG is low to detect pericardial efusions.In a study by Wang et al. in 216 patients with malignant pericardial efusions, sinus tachycardia was the most common sign (42.1%), whereas more specifc signs such as low QRS-voltage or electrical alternans were detected in a minority of patients (17.6% and 21.3%, respectively) [20].It would be more efective to periodically screen for cardiac symptoms.Te most common clinical symptom of tamponade is breathlessness (63%).To confrm tamponade, clinical signs are unreliable.For example, Pulsus paradoxus was an insensitive sign only present in 10%.Te classical Beck's Triad (hypotension, increased JVP, and quiet/distant heart sounds) detected only a third of the cases.Echocardiography, in contrast, has a sensitivity of 96% and specifcity of 98% to detect pericardial fuid, even when performed as a bedside study [21].Te management of acute pericarditis includes highdose NSAIDs.However, their use in patients concomitantly on ibrutinib can theoretically aggravate the antiplatelet effect.On the balance of risks, we would, therefore, treat with colchicine and steroids instead of NSAIDs.Temporarily discontinuing ibrutinib should be considered where feasible.Following improvement, steroids should be tapered swiftly, while colchicine may be extended for several weeks to ensure full symptom resolution.For those intolerant to ibrutinib, switching to second-generation BTK inhibitors with reduced cardiac cross-reactivity can be considered.Acalabrutinib has demonstrated a lower incidence of adverse cardiac efects compared to ibrutinib [22] and also exhibits less platelet inhibition [16].Similarly, zanubrutinib in the ASPEN study showed reduced cardiac toxicity [23]; however, as our case report demonstrates, a small risk remains.For high-risk patients who developed cardiac tamponade while on BTK therapy, we would recommend switching to a venetoclaxbased regimen.Venetoclax is a BCL2-inhibitor with no direct cardiotoxic efects which has demonstrated high effcacy when combined with obinutuzumab for CLL [24] or as a monotherapy for Waldenström's [25].

Conclusion
We present the frst case report of a patient who develops cardiac tamponade on zanubrutinib.We present two further cases of cardiac tamponade for patients on ibrutinib.BTK can directly and indirectly cause pericarditis and dosedependent platelet inhibition, which exposes patients to bleeding events.While uncommon, clinicians must be vigilant of the risk of cardiac tamponade, which can develop rapidly and presents a life-threatening complication.

Figure 3 :
Figure3: A moderate pericardial efusion with measurements of 1.25 cm adjacent to the right ventricular (RV) free wall, 1.44 cm adjacent to the lateral wall, and 1.24 cm encircling the right atrium (RA).In addition, the left ventricle (LV) displayed diminution, exhibiting midcavity obliteration and generating a late systolic peak gradient of 41 mmHg at rest.Calcifcation was observed in the mitral and aortic valves, each showing mild stenosis causing some degree of hemodynamic compromise.

Figure 4 :
Figure 4: (a) Pericardial efusion measuring 1.5 cm posterior and 1 cm anteriorly not causing hemodynamic consequences.(b) One week later: the pericardial efusion has increased in size and is now causing hemodynamic compromise (case 3).