A 36-year-old man with severe Crohn disease complicated by urethral strictures and enterocutaneous and enterovesicular fistulas presented for several weeks of poor appetite, weight loss, failure to thrive, and newly worsening altered mentation. Further history revealed he chronically did not urinate through his urethra, but rather "leaked" through multiple enterocutaneous fistulas in his abdomen and perineum. Medications included ustekinumab (anti-IL12/IL23 monoclonal antibody) for Crohn disease, methadone, and hydrocodone. He had had multiple surgeries because of fistulas related to his Crohn disease, which included subtotal colectomy with ileostomy creation, proctectomy, and ischiorectal flap creation. He drank 10-15 ounces of liquor per week, smoked 10 cigarettes daily, and smoked marijuana weekly.

Zanubrutinib is an orally administered second-generation covalent inhibitor of Bruton tyrosine kinase that was recently approved by the US Food and Drug Administration for the treatment of chronic lymphocytic leukemia and small lymphocytic leukemia. It has been associated with significant major and minor bleeding events, including intracranial and GI hemorrhage and hematuria, with or without concurrent antiplatelet or anticoagulation therapy. We report a case of a 65-year-old man with relapsing chronic lymphocytic leukemia. He presented to us with repeated episodes of worsening dyspnea secondary to hemorrhagic pleural effusion 2 months after the initiation of zanubrutinib with concomitant apixaban use. On discontinuation of zanubrutinib after the second episode, he remained asymptomatic on further follow-up examination. Previously only described with the first-generation Bruton tyrosine kinase inhibitor, our case focuses attention on a rare adverse event and a first reported incidence, to our knowledge, of recurrent hemorrhagic pleural effusion associated with zanubrutinib in a patient with relapsing chronic lymphocytic leukemia.