Successful Zanubrutinib Monotherapy in a Rare CNS Presentation of Relapsed CLL.

Background: Central nervous system (CNS) involvement is an infrequent complication of chronic lymphocytic leukemia (CLL), occurring in less than 1% of cases. We report a case of a 63-year-old male with a history of CLL previously treated with ibrutinib but discontinued early due to intolerance. As a result, the patient was then treated with obinutuzumab plus venetoclax, achieving undetectable minimal residual disease (MRD) but relapsed after 2 years with CNS involvement. Case Presentation: The patient initially presented to the emergency department with confusion and altered mental status. Magnetic resonance imaging (MRI) of the brain revealed abnormal subcortical hyperintensities and leptomeningeal enhancement concerning leukemic infiltration. Lumbar puncture confirmed malignant CD5+ CLL cells in the cerebrospinal fluid (CSF), and a bone marrow biopsy revealed 50%-60% CLL involvement. Zanubrutinib 320 mg daily was initiated. The patient exhibited marked cognitive improvement within full resolution after four weeks of therapy. Follow-up MRI after 8 weeks showed full resolution of CNS, lesions with repeat LP demonstrating CSF cleared of CLL cells. He remains in complete remission with continued daily zanubrutinib 6 months follow-up; no significant adverse effects were observed. Conclusion: This case highlights the rare occurrence of CNS involvement in CLL and is the first to demonstrate successful CNS disease eradication with zanubrutinib monotherapy.