Rare CNS manifestation of high-risk CLL with excellent response to triplet targeted therapy

Central nervous system (CNS) involvement in chronic lymphocytic leukemia (CLL) is rare and presents major diagnostic and therapeutic challenges. We report the case of a man in his late 40s with small lymphocytic leukemia, initially managed conservatively, who presented after four years with progressive left facial numbness, diplopia, and left oculomotor nerve palsy without B symptoms or raised intracranial pressure. He had high-risk disease biology with TP53 mutation and unmutated IGHV status. Positron emission tomography-computed tomography showed mildly FDG-avid systemic lymphadenopathy but intensely avid thickened spinal nerve roots, while magnetic resonance imaging demonstrated enhancement of the bilateral oculomotor nerves, left optic nerve, and extradural tissue at the cervical level. Cerebrospinal fluid analysis showed elevated protein and 34% abnormal B-lymphoid cells with a CLL phenotype. Biopsy of the involved nerve/root tissue confirmed direct CNS and nerve-root infiltration by CLL rather than Richter transformation. The patient was treated with acalabrutinib, venetoclax, obinutuzumab, and intrathecal chemotherapy. He showed rapid neurological improvement, with early symptom resolution, progressive cerebrospinal fluid clearance, and near-complete radiologic response, followed by complete metabolic response on follow-up PET-CT. This case highlights that CNS involvement may occur even in treatment-naïve or early-stage CLL and may not correlate with systemic disease burden. It also supports the clinical activity of novel triplet CNS-penetrant targeted agents, in achieving durable remission in rare CNS manifestations of high-risk CLL.