Clinical Characteristics and Treatment Outcome Of CNS Involvement (Bing-Neel Syndrome) In Waldenstrom’s Macroglobulinemia

Waldenstrom’s Macroglobulinaemia (WM) is an IgM secreting lymphoplasmocytic lymphoma characterized by involvement mainly in the bone marrow, and occasionally in the lymph nodes and spleen. Central nervous system involvement of WM, known as Bing-Neel syndrome (BNS), is very uncommon and as such the clinical characteristics and treatment outcomes remain to be clarified.

We evaluated the incidence, clinical characteristics, and treatment outcome of BNS among patients with WM who were diagnosed at our Institution.

We identified 13 patients with BNS from our database of 1,523 patients diagnosed with WM from 1999 -2013. The median age at diagnosis of BNS was 60 (range 51-75 years). The median time to development of BNS after WM diagnosis was 6.3 (range 0.3-11.9 years). Patients presented with a variety of neurological signs and symptoms including seizures, hearing loss, cognitive impairment, gait instability and lower extremity weakness. The diagnosis of BNS was confirmed by MRI in 11, and by examination of the CSF in 12 patients. CSF cytopathologic analysis demonstrated definitive evidence of malignant lymphoplasmacytic cells in 6 patients, and was suspicious for malignant cells in 2 patients. CSF flow cytometry was positive in 8, and a clonal immunoglobulin heavy chain gene rearrangement was identified in 6 patients. MYD88 L265P was identified in CSF sample of two patients in whom this examination was undertaken, and who demonstrated malignant disease by flow cytometry and cytological examination. Seven patients were treated with high-dose methotrexate (HD-MTX), 2 with intrathecal liposomal cytarabine, 1 with rituximab and intrathecal methotrexate, and 1 with rituximab and bendamustine. One patient was recommended treatment with HD-MTX and was lost to follow-up, 1 has been initiated on HD-MTX. Of 11 patients, 5 had a response in CSF and/or MRI, 4 had stable disease and 1 progressed following therapy. Of the responders, 2 patients had received HD-MTX, 2 intrathecal liposomal cytarabine and 1 rituximab-bendamustine. Four patients with stable disease had received HD-MTX. One patient who received intrathecal MTX developed treatment related “chemical meningitis”, and was subsequently treated with HD-MTX to which she had a CSF response. The median overall survival was not reached. Eleven patients are alive, 1 died and 1 was lost to follow-up.

BNS is an uncommon late complication of WM. MYD88 L265P may help in the diagnosis of BNS, and may represent a novel approach for targeted therapy of WM. HD-MTX is active in the treatment of BNS, though prospective studies are required to standardize treatment and improve outcomes.

No relevant conflicts of interest to declare.