Bing-Neel Syndrome – a Case Series of 46 Patients from the United Kingdom

Background

Central nervous system involvement with Waldenstrom’s Macroglobulinaemia (WM) or lymphoplasmacytic lymphoma (LPL) is termed Bing-Neel syndrome (BNS). An infrequent complication, it nevertheless causes significant morbidity. Optimum treatment sequencing remains to be established, with traditional CNS-penetrating chemotherapy agents and novel Bruton Tyrosine Kinase inhibitors (BTKis) employed. We describe features and treatment outcomes at our WM centre.

Methods

A retrospective cohort analysis was undertaken using the UCLH WM patient registry.

Results

BNS was diagnosed in 59 patients between years 2012 and 2024; 46 had adequate data. Median follow up was 50 months (1-150m). Median duration from BNS symptom onset to diagnosis 5m (range 0-60). Median age at diagnosis was 66.5 (48-85) years and 26 (52.5%) were male.

A preceding diagnosis of WM/LPL was present in 34/46 (73.9%) (WM in 31, IgG LPL 2, IgA LPL 1). Median time from WM diagnosis to BNS was 55m (0-265m). BNS occurred as part of systemic progression in 15 and CNS-only in 19. No prior history of WM/LPL in 12/46 (26.1%) cases; a systemic condition was established in 8 (5 LPL, 3 IgM MGUS) whereas isolated BNS occurred in 4 patients.

Presenting symptoms included sensory and/or motor deficits in 21 (45.7%), cognitive change 8 (17.4%), cranial nerve deficits 5 (10.9%), headaches 4 (8.7%), seizures 3 (6.5%), hearing loss 3 (6.5%) and ocular/orbital involvement in 2 (4.3%). On magnetic resonance imaging (MRI), leptomeningeal enhancement present in 33 (71.7%) and parenchymal lesions in 12 (26.1%), with intracranial findings in 24 (52.2%) and spinal/cauda equina in 27 (58.7%). No pathological MRI findings were present in 7 (15.2%) patients.

Diagnosis was made using brain biopsy in 2 and cerebrospinal fluid (CSF) studies in 44 (cytology 1, immunophenotyping 27, PCR 16). CSF MYD88^L265P detected in 29/30 patients; 3 others had IgH rearrangements detected. Lack of surface immunoglobulin expression on immunophenotyping in 16 patients, but with PCR-proven clonality. Median CSF leucocyte count 15.5 cells/mm³(1-153), CSF protein 1.40 (0.25-4.69) g/L, CSF IgM 4.13 (0.147-475)g/L. Other extramedullary disease was present in 14/46 (30.4%). Median bone marrow burden 20% (0-80%), with MYD88^L265 detected in 27/28 (96.4%) and CXCR4^WHIM in 1/6 (16.7%).

Prior treatment for WM had been given in 21/46 patients, median 1 prior line (range 0-4). Frontline (1L) therapy for BNS administered in 44/46 (95.6%), with high-dose methotrexate (MTX)-cytarabine-rituximab regimens in 37 and BTKi in 5 (4 Zanubrutinib, 1 Ibrutinib 2). BCNU/Thiotepa autologous stem cell transplant (ASCT) consolidation in 3 and BTKi consolidation in 15. Intrathecal-only chemotherapy was given in 2. Median post-treatment CSF WCC 4 (0-297) and protein 0.78 (0.34-6.03).

Median 1L overall survival (OS) was not reached, 1- and 3-year rates 93% (84-100%). Median 1L PFS 49m (26-63m), with 1-, 3-year and 5-year PFS 87% (76-100%), 56% (40-78%) and 30% (16-55%). Attainment of frontline negative CSF PCR for MYD88^L265 and/or IgH PCR occurred in 13/16 evaluable patients; none of who subsequently relapsed. Residual disease following MTX-based therapy was present in 15/37 (40.6%), who initiated BTKi consolidation. PFS following 1L MTX-based therapy was only 81.3% (64.2-100) at 1 year and 49.9% (29-85.7%) at 3 years; MTX-based therapy followed by BTKi consolidation 100% at 1- and 3 years; and BTKi-only therapy 100% at 1 year.

2L therapy was given in 23/46 (50%) patients, 21 with BTKi (15 Ibrutinib, 6 Zanubrutinib) and 2 with chemoimmunotherapy. Median PFS following 2^nd line BTKi therapy not reached, with 1- and 3-year PFS 89% (79-100%). Attainment of 2L CSF negativity by MYD88 or IgH PCR occurred in 6/9 evaluable patients, all on BTKis; none subsequently relapsed. 3L therapy was given in 3 patients.

Conclusion

Symptoms of BNS are heterogenous and a quarter of patients have no history of LPL/WM when presenting with BNS. Over half of cases with known WM occur as CNS-only progression, without progressive systemic disease. Isolated BNS is seen, but is rare. Patients who attained CSF MYD88^L265 or IgH PCR-negativity did not subsequently relapse from BNS in this cohort. High-dose MTX based therapy has excellent response rates, but subsequent BNS disease progression occurs in a majority of patients. Regimens incorporating BTKi-based therapy appears to result in excellent PFS rates.