B80-6-33 Zanubrutinib-induced Pneumonitis: A Rare But Serious Adverse Event in Btk Inhibitor Therapy

Introduction Bruton tyrosine kinase inhibitors (BTKi) are used for B-cell malignancies. Pneumonia occurs in 13-15% of recipients [1]. Pneumonitis is a rare complication [2] and has only been reported for Zanubrutinib in conjunction with obinutuzumab [3]. Case Presentation Based on initial workup including computed tomography (CT) scan which showed ground glass infiltrates, he was treated for pneumonia and volume overload with antibiotics and diuretics. Unfortunately his respiratory status worsened. Investigations showed progressive bilateral patchy ground-glass opacities on CT, a Respiratory Syncytial Virus positive swab (RSV), negative interstitial lung disease panels, acute kidney injury, and a normal right atrial pressure. Given his failure to respond to antibiotics and diuretics along with lack of additional workup findings, Zanubrutinib pneumonitis was suspected. He received intravenous methylprednisolone for 48 hours followed by daily prednisone, leading to rapid clinical improvement. He was discharged on tapering prednisone and Pneumocystis jiroveci prophylaxis. Zanubrutinib was discontinued indefinitely. Given the robust steroid response, Zanubrutinib pneumonitis was favored as a diagnosis over RSV. Discussion Zanubrutinib, approved for B-cell malignancies, inhibits BTK, a key enzyme in B-cell receptor signaling [2]. This inhibition compromises humoral and cellular immunity, increasing susceptibility to respiratory infections [4]. However while pneumonia is well-documented, BTKi-induced pneumonitis is a rare but life-threatening complication that should be considered, and we report the first case of association with Zanubrutinib specifically [1,4,5]. BTKi-associated pneumonitis is believed to arise from immune dysregulation or direct pulmonary toxicity [2]. Diagnosis is challenging due to nonspecific symptoms and frequently overlapping infectious pneumonia [4]. Radiologically, BTKi pneumonitis most commonly presents with ground-glass opacities [2]. A thorough infectious workup including blood and sputum cultures, viral testing, and often bronchoalveolar lavage, is recommended to exclude infection [2,6]. Delays in diagnosis are common, especially in immunocompromised patients, due to overlapping features [2]. No validated tool differentiates pneumonitis from infection in this setting [2].Pneumonitis management is guided by severity. For moderate-to-severe presentations, immediate BTKi discontinuation and corticosteroid therapy are recommended [2]. Severe cases may require permanent BTKis discontinuation and additional immunosuppressive therapy[2]. Most cases resolve with prompt intervention [2]. Conclusion BTKi-induced pneumonitis is rare but should be considered in patients with new or worsening respiratory symptoms on BTKi therapy. This case highlights the importance of early recognition in order to minimize morbidity, and documents it as a complication to zanubrutinib.