Bing-Neel Syndrome in Waldenström Macroglobulinemia: Updates on Clinical Management and BTK Inhibitor Efficacy

Bing-Neel syndrome (BNS) is a rare complication of Waldenström macroglobulinemia (WM) caused by the direct infiltration of the central nervous system (CNS) by lymphoplasmacytic cells. Since clinical manifestations are heterogeneous and overlap with IgM-related neuropathies, BNS is often under-recognized and diagnosed late. Due to its extreme rarity, there are no prospective studies on BNS. In 2025, a consensus panel from the 12th international workshop on WM updated the guidelines for BNS, recognizing zanubrutinib as a standard therapy, clarifying imaging and cerebrospinal fluid (CSF) assessments during the follow-up, and introducing revised response categories. Although the incidence of BNS is approximately 1% of WM, overall survival is inferior to WM and early deaths were reported in historical series. Diagnostic confirmation requires a high index of suspicion and a multimodal approach combining MRI of the brain and spine with gadolinium, CSF cytology and flow cytometry, molecular testing, such as MYD88 L265P, and occasionally tissue biopsy. Differentiation from IgM-mediated neuropathies is critical because management strategies markedly differ. Historically, high-dose methotrexate- or cytarabine-based chemotherapy, intrathecal therapy, and radiotherapy have been used; however, responses varied and toxicity was considerable. In contrast, CNS-penetrant Bruton tyrosine kinase (BTK) inhibitors have reshaped therapeutic strategies. Retrospective data support durable responses with ibrutinib, tirabrutinib, and zanubrutinib, while early findings suggest that non-covalent BTK inhibitors expand options for relapsed or refractory cases. We herein synthesize current evidence on epidemiology, pathophysiology, and the diagnostic work-up. We also outline therapeutic recommendations integrating the genotype, disease pattern, and patient fitness, and conclude with unmet needs and future directions.