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

Bing-Neel syndrome (BNS), a rare complication of Waldenström macroglobulinemia (WM), is caused by the direct infiltration of lymphoplasmacytic cells into the central nervous system (CNS). Since clinical manifestations are heterogeneous and may overlap with IgM-related neuropathies, BNS is often under-recognized and diagnosed late. The incidence of BNS has been reported to be approximately 1% of patients with WM. Because of 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 follow-up, and introducing revised response categories. Although the incidence of BNS is approximately 1% of WM, it decreases overall survival compared to WM alone, 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. Importantly, MYD88 L265P is also observed in most cases of diffuse large B-cell lymphoma of the CNS and is therefore not disease-specific. 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. Herein, we synthesize current evidence on epidemiology, pathophysiology, and diagnostic work-up. We also outline therapeutic recommendations integrating the genotype, disease pattern, and patient fitness and conclude with unmet needs and future directions.