Effective treatment of Bing Neel Syndrome with oral fludarabine: a case series of four consecutive patients
Venue: British journal of haematology

Direct central nervous system (CNS) involvement of WaldenstrEUR om macroglobulinaemia (WM) is very rare and is referred to as Bing Neel syndrome (BNS) (Bing Neel, 1936; Ly et al, 2011) The incidence of BNS is unknown, but in a retrospective cohort of 1523 WM patients only 13 patients with BNS were identified. (Kulkarni et al, 2013) The prognosis has typically been poor. Less than 50 cases have been published, mostly in a setting of relapsed WM (Malkani et al, 2010; Abdallah et al, 2013; Poulain et al, 2014) There is no consensus on the best treatment strategy and, thus far, there are no systematic reports on treatment in Bing Neel Syndrome. Purine analogues (fludarabine, cladribine) are widely used and considered very effective in the treatment of WM (Leblond et al, 2013) Fludarabine is thought to cross the blood brain barrier based on animal studies, and has induced remissions in CNS involvement of B CLL.  in Patient one after the second cycle of fludarabine. Patient one presented with a 1 year history of symptomatic tonic clonic seizures and cognitive complaints. She was first treated with i.t. methotrexate (MTX) without response. Monotherapy with oral fludarabine resulted in a complete remission (CR) of both the BNS and WM in the bone marrow and a full neurological recovery. BNS and WM relapsed 5 years later, with complaints of double vision. Treatment with rituximab fludarabine resulted in a second haematological and neurological partial remission (PR) with residual slight cognitive disturbances. A second relapse 2 years later was refractory to rituximab cladribine. The patient achieved a third CR following radiotherapy (40 Gy) and remained in a stable clinical condition for 10 years after BNS was first diagnosed. She died due to a traumatic subdural haematoma. Patient two presented with bradyphrenia, dysarthria and a rapidly progressive tetraparesis. He was treated with rituximab fludarabine combined with i.t MTX (15 mg) A haematological CR combined with an impressive and fast full neurological recovery was reached: after only one cycle he went from tetraplegic to fully ambulatory. The MRI response for this patient is shown in Fig 1. On neurological examination only a slight bipyramidal syndrome remained. He has remained stable since then, with a follow up of 3.5 years. Patient three presented with a 5 year history of mild paresthesias in the hands. IgM related polyneuropathy was excluded based on the neurological evaluation. The CSF demonstrated infiltration of monotypic B cells. Treatment with rituximab fludarabine resulted in a haematological PR with neurological improvement. She has remained stable since then, with a follow up of 1.5 years. Patient four presented with a bilateral paresis of the upper extremity. Treatment with rituximab fludarabine resulted in a haematological PR and clear neurological improvement. She has remained stable with a follow up of 1.5 year. To our knowledge this is the first consecutive case series of patients with BNS treated with a systematic therapeutic approach. There is no established first line therapy for BNS. Based on the available case reports, i.t. MTX alone does not seem to be very effective, as was also the case in Patient 1. Radiotherapy seems effective in reversing neurological symptoms and achieving a MRI response, but there is concern about the long term neurotoxicity and it also leaves the WM activity in the bone marrow untreated. High dose systemic chemotherapy using MTX and cytarabine, analogous to the treatment of the aggressive primary CNS lymphoma, has lead to good responses, including CRs correspondence