Ibrutinib for the Treatment of Bing-Neel Syndrome

Background: The oral BTK inhibitor ibrutinib is the only approved therapy for patients with symptomatic Waldenström macroglobulinemia (WM). Bing-Neel syndrome (BNS) is a rare complication of WM that results from infiltration of malignant lymphoplasmacytic cells into the central nervous system (CNS) causing neurological deficits. Treatment options in patients with BNS are limited to agents with CNS penetration. Ibrutinib can penetrate into the CNS, but data on its efficacy in BNS is lacking outside case reports.

Methods: We performed a multicenter retrospective study evaluating the efficacy of ibrutinib in patients with BNS. The diagnosis of BNS was established in patients with a clinicopathological diagnosis of WM by radiological and/or cytological evidence of CNS involvement by WM, and response was assessed based on recently published criteria. Ibrutinib was given orally at doses of 420-560 mg PO once daily until disease progression or intolerable toxicity. Response was assessed using criteria from the 8^th International Workshop for WM (Minnema et al. Haematologica 2017). Events were defined as death from any cause, progression of disease and stopping ibrutinib from any reason. Time to events was estimated using the Kaplan-Meier method.

Results: We present data on 24 patients with BNS treated with ibrutinib. The median age at diagnosis of WM was 60 years (range 38-76 years) and 14 patients (58%) were men. The median lines of therapy for WM prior to BNS diagnosis was 1 (range 0-7 lines), and 9 patients (38%) were untreated for WM at the time of BNS diagnosis. Previous WM therapies included anti-CD20 antibodies (n=15), alkylators (n=13), nucleoside analogues (n=8), proteasome inhibitors (n=3), immunomodulators (n=2), and autologous transplant (n=1). The median age at BNS diagnosis was 65 years (range 38-80). The median time from WM to BNS diagnosis was 4 years (range 0-27 years). In 2 patients, the diagnosis of BNS was made concurrently with WM diagnosis. The median number of BNS lines prior to ibrutinib was 1 (range 0-5 lines). Previous BNS therapies included intrathecal chemotherapy (n=9), high-dose methotrexate (n=6), bendamustine (n=3) and radiation therapy (n=3). In 7 patients (29%), ibrutinib was the first line of treatment for BNS. The most common symptoms at BNS presentation were cognitive deficits (n=10), sensory deficits (n=8), ataxia/falls (n=8), motor deficits (n=6), headache (n=5) and seizures (n=5). MRI findings included leptomeningeal enhancement (n=16) and brain masses (n=5). Cerebrospinal fluid (CSF) flow cytometry confirmed the presence of clonal CD19+ in 19 patients (79%). Biopsies were performed in 5 patients (21%) and confirmed presence of WM cells. 4 patients had normal MRI but had abnormal CSF cytology and/or flow cytometry. Tissue was not obtained in 1 patient in whom MRI showed leptomeningeal enhancement. Interestingly, 2 patients were diagnosed with lymphoplasmacytic lymphoma secreting IgG paraprotein. The median serum IgM (n=20) prior to ibrutinib initiation was 1,294 mg/dl (range 125-5,938 mg/dl), and the median hemoglobin level was 11.9 g/dl (7.7-15.2 g/dl). Ten patients (42%) received ibrutinib 560 mg PO once daily, and 14 (58%) received ibrutinib 420 mg PO once daily. At best response, median serum IgM and hemoglobin levels were 340 mg/dl (82-3,330 mg/dl) and 14.6 g/dl (range 9.2-16.0 g/dl). Based on consensus BNS response criteria, complete response was attained in 2 patients (8%), partial response in 14 (58%) and clinical improvement in 3 patients (13%). With a median follow-up time of 13 months (95% CI 8-21 months), 5 patients have stopped ibrutinib, 3 due to BNS progression, 1 due to grade 3 muscle cramps and 1 due to arrhythmia, and 3 patients have died, 2 from infection and 1 from BNS progression. The median event-free survival (EFS) from ibrutinib initiation was not yet reached. The 1-year and 2-year EFS rates were 71% (95% CI 46-86%) and 52% (23-75%), respectively.

Conclusion: Ibrutinib is a safe and effective treatment option for patients with BNS.