Efficacy of ibrutinib as first-line treatment of tumoral Bing–Neel syndrome

Bing–Neel syndrome (BNS) is a rare disease manifestation of Waldenstr€ om’s macroglobulinemia (WM) that results from infiltration of the central nervous system (CNS) by malignant lymphoplasmacytic cells [1]. Given that literature on BNS is limited to case reports and small case series, the treatment approaches are nonstandardized [2]. Ibrutinib, a Bruton’s tyrosine kinase inhibitor, has shown efficacy in WM and became the first drug to receive approval by the FDA for the treatment of patients with WM [3]. Recently, two publications reported efficacy of ibrutinib in relapsed/refractory BNS with pharmacodynamic proof of cerebrospinal fluid (CSF) diffusion [4,5]. Herein, we report a case of a patient treated with ibrutinib as first-line treatment of BNS. The patient, a 71-year-old male, presented in November 2016 somnolence and frontal syndrome. Brain magnetic resonance imaging (MRI) showed a right frontal mass with voluminous vasogenic edema (Figure 1). A brain biopsy was performed and the pathology report indicated a low-grade lymphoplasmacytic proliferative process. Immunoglobulin gene rearrangement analysis established the clonal character of the lymphoid B-cell population. CSF analysis revealed slightly increased CSF protein of 1g/L and normal glucose level, leukocyte cell count and differentiation. Multiparameter flow cytometry (MFC) in CSF did not detect a clonal B-cell population. Protein electrophoresis was not performed in the CSF. Complete blood count showed a platelet level of 80000/ mm3, without hemoglobin or white blood cells abnormalities. LDH level was normal. Hepatic and renal function was adequate. Serum IgM level was 5335mg/dL, with a 4.5 g/dL IgM spike. Bone marrow aspiration detected 44% lymphoplasmacytic lymphoma cells and MFC confirmed the presence of a malignant B-cell clone (CD5 , CD10 , CD19þ, CD20þ, CD22þ, FMC7 and CD23 , with kappa light chain restriction) in the marrow. L265P MYD 88 mutation was not found in in cellular fractions from bone marrow and in the brain biopsy. Positon emission tomography (PET) scanner did not show evidence of extra cerebral neoplastic lesion. Ibrutinib (420mg/d) and steroids (prednisone 60mg/d with rapid decrease) were initiated. Within 7 days, we observed significant clinical improvement. After 3 months of ibrutinib and 2 months of stopping steroids, platelet level improved to 155,000/mm, IgM spike decreased to 3.4 g/L and MRI showed decreased nodular enhancement along the right frontal floor with vasogenic edema extinction. At 6 months repeat MRI showed decreased IgM spike (2.1 g/L) and frontal mass continuation (Figure 1). After 11 months from starting ibrutinib the patient continues to do well and remains on treatment. Consensus recommendations for treatment approach of BNS suggest purine analogs or bendamustine or ibrutinib or high-dose methotrexate or cytarabine-based regimens as first-line treatment for symptomatic BNS [6]. However, at the best of our knowledge, this case is the first one showing efficacy of ibrutinib as first-line treatment for a patient with BNS. Two categories of CNS involvement in BNS can be distinguished by MRI imaging: the diffuse form and the tumoral form [7]. Unlike previously reported cases of ibrutinib efficacy in BNS our patient had a tumoral form, without CSF involvement. Despite this case fulfill WHO and consensus criteria for the diagnosis of Waldentrom macroglobulinemia and Bing–Neel syndrome [6,8], MYD 88 L265P mutation was not found in in cellular fractions from bone marrow and in the brain biopsy. Indeed, MYD88 L265P is a somatic point mutation detected in approximately 90% of WM cases and is a useful biomarker in distinguishing WM from other lymphomas with IgM secretion [9,10]. Diagnostic ambiguity exists between MYD88 wildtype WM and other MYD88 wild-type IgM secreting entities, but in this case, clinical pathological and laboratory studies are sufficient for the diagnosis of BNS [11]. Unfortunately, CXCR4 mutations detection was not available in our institution and was not performed in the