Abstract: Introduction: Bing-Neel syndrome (BNS) is present in 1% of patients diagnosed with Waldenström Macroglobulinemia (WM) and consists of infiltration of the central nervous system by lymphoplasmacytic lymphocytes (LPLs). Overall survival (OS) is highly variable, and treatment is not standardized. There are no studies with zanubrutinib (a new generation Bruton tyrosine kinase inhibitor) in this setting. Objectives: To describe the clinical features of BNS and evaluate the efficacy of zanubrutinib in these patients considering the clinical, biological (cerebrospinal fluid (CSF) infiltration) and radiological findings. As a secondary objectives, we analyzed the toxicity of the drug, duration of exposure and survival outcomes. Methods: retrospective study of eleven patients from ten spanish centers who received zanubrutinib as WM treatment with BNS between 2022-2024. All patients who had received at least one cycle were considered evaluable for efficacy and toxicity. Results: Six patients were male and five female. The median age at WM diagnosis was 72 years (range 47-84). Only one patient had hyperviscosity syndrome at the time of diagnosis, whereas and five showed constitutional symptoms. According to the ISSWM risk scale, 4 had low, 4 had intermediate and 3 had high risk. The MYD88L265p mutation was detected in 10 patients and CXCR4 mutation in one. The median age at BNS diagnosis was 75 years (range 61-85). Sensory deficits and visual abnormalities were the most common symptoms observed. Language disorders, motor deficits and altered mental status were also reported. MRI was normal in six patients, three had diffuse leptomeningeal enhancement and two had localized tumor. CSF flow cytometry was performed in all patients with a median B clonal infiltration of 33% (range 13-80). The median IgM monoclonal component in blood was 0.8 g/dl (range 0.5-3). BNS was the initial presenting feature of WM in six patients, while in five, it was diagnosed during the course of WM with a mean time from WM diagnosis to BNS diagnosis of 8.2 years (range 0.1-22). This latter group had received a median of 2 lines of treatment (range 1-3) prior to BNS diagnosis including chemotherapeutic agents such as high-dose methotrexate or bendamustine combinations, immunotherapy in all cases, ASTC (1), and ibrutinib (1). Nine patients received zanubrutinib as first-line treatment for BNS. Another one as a second line after rituximab, high-dose methotrexate and procarbazine regimen; and the last one after ibrutinib. Zanubrutinib was used at a dose of 160 mg/12h in seven patients and as a single dose of 320mg daily in four. Clinical response, defined as symptomatic neurological improvement, was observed in 8 patients: 2 complete responses (CR) and 6 partial responses. The median time of exposure to zanubrutinib was 7 months (range 1-15). Two patients died within one month of treatment: one due to disease progression and other due to neutropenic septic shock and CMV disease. Regarding toxicity, two patients developed neutropenia (one grade 3, one grade 2) during treatment. No patient required dose adjustment and only one discontinued treatment due to lack of efficacy. At the time of the last follow-up, 7 patients are alive (4 of them with BNS as the initial presenting feature of WM, and in three patients it appeared in the setting of Waldenström´s progression). With a median follow-up of 7 months (range 1-39), OS was 82%. Conclusions: zanubrutinib proves to be an effective and safe therapy in patients with WM with CNS infiltration, achieving 73% overall responses. Therefore, it can be considered a treatment option in Bing-Neel syndrome both in first line and in advanced stages of the disease.

Authorship

Download reference