Bing Neel Syndrome: Retrospective Australasian Experience of a Rare Treatable Complication of Waldenström Macroglobulinaemia/ Lymphoplasmacytic Lymphoma

Introduction and aims: Bing Neel syndrome (BNS) is a rare complication of Waldenström Macroglobulinaemia (WM)/ Lymphoplasmacytic Lymphoma (LPL). It is a clinicopathological entity characterised by central nervous system involvement with malignant cells. It presents with diverse symptoms and can be difficult to recognise. However, it is a treatable condition amenable to systemic and intrathecal treatment. We present the Australasian experience of this rare entity.

Methods: Inclusion in the study was based on cytologically or histologically confirmed presence of lymphoplasmacytic cells in the CSF or brain biopsy. Ten patients were included from 9 sites in Australia and New Zealand. Relevant retrospective data was extracted after obtaining consent from patients or next of kin.

Results: Seven of the 10 patients were males with overall mean age of 63.5 years (range: 49-78 years); 4 patients were < 60 years old. Four patients (40%) did not have a prior diagnosis of WM; the remaining 6 patients were diagnosed ~ 11 years post diagnosis of WM (range: 3 -26 years) and received 1 line of treatment (except for 2 patients who received 2 lines of treatment). Treatment regimens received included R-CVP, chlorambucil-prednisolone, DRC, FCR, oral fludarabine, and RFM.

At diagnosis of BNS, IgM and/or PP levels ranged between 3 - 70 g/L with 6 (60%) patients having levels < 10 g/L. One patient had a diagnosis of lymphoplasmacytic lymphoma with IgG paraprotein.

Symptoms at presentation of BNS varied from headache, ptosis/ophthalmoplegia, memory loss, subacute hemiplegia, cognitive defects, hearing loss, and sensory or motor neuropathy. None of the patients had B symptoms. Lymphadenopathy was noted in 4 (40%) cases, splenomegaly in 1 (10%) and ECOG performance status ranged from 0-4 with 3 (30%) patients having an ECOG of > 2.

Brain +/- spine MRI was done in all cases with 5 (50%) showing leptomeningeal involvement. Orbital infiltration or enhancement of optic or ophthalmic nerves was noted in 3 cases (30%), and 3 patients (30%) had focal signs/masses. 1 had cortical atrophy, and 3 had normal MRI. CSF analysis was abnormal in all cases on cytology with demonstration of abnormal lymphocytes. Where immunophenotyping was performed, it showed presence of CD5, CD10 negative B cells. MYD88 L265P was detected in 3 patients (30%).

Treatment of BNS included systemic chemoimmunotherapy in 30%, CNS penetrating intravenous agents in 40%, Ibrutinib in 50%, intrathecal chemotherapy in 30%, and radiotherapy in 10%. More than 1 modality of treatment was used in 40% of patients. Ibrutinib was administered as frontline treatment in combination with high dose MTX or IT chemotherapy in 3 patients, and as single agent monotherapy in 1 patient. Ibrutinib was used as second line treatment in 2 patients with both achieving CR. The number of cycles administered were 2.6 (range 1-9).

Response data was available in 9 patients with ORR in 6 (1 CR, 5 PR) and non-response in 3. All patients except the one treated with Ibrutinib monotherapy had at least PR. With a median follow-up time of 20 months, 3 patients have died. The median overall survival of patients was not reached. The 1-year and 3-year OS rates were 80% (95% CI 41-95%) and 60% (16-87%), respectively (Figure 1).

Conclusion: BNS should be suspected in WM patients who develop focal or nonspecific neurological symptoms. It can be readily diagnosed on radiological scans i.e. brain and spinal MRI, and/or on CSF analysis. It can be treated with a number of systemic and intrathecal drugs including Ibrutinib, which crosses the blood brain barrier.