Rare case of Bing-Neel syndrome treated successfully with ibrutinib

Abstract

Waldenstrom’s macroglobulinaemia (WM) is a lymphoproliferative disorder of the B cell origin. It is characterised by the presence of IgM paraprotein in the serum and lymphoplasmacytic lymphoma cells in the bone marrow with extranodal involvement relatively uncommon. Bing-Neel syndrome (BNS) is a neurological complication of WM that results from infiltration of the central nervous system by malignant lymphoplasmacytic cells. We present an interesting case of BNS that responded remarkably to ibrutinib monotherapy.

Background

Bing-Neel syndrome (BNS) is a rare manifestation of Waldenstrom’s macroglobulinaemia (WM) with neurological complications. It results from infiltration of the central nervous system (CNS) by lymphoplasmacytic cells. Due to non-specific clinical presentation, diagnosis is often a challenge and requires testing for certain characteristic mutations that not only have diagnostic value, but also predict excellent response to targeted therapy.

Case presentation

A 64-year-old White woman with a known history of hypertension presented with gradually worsening headaches, right ear hearing deficit and recurrent sinusitis of 3 months duration. She also experienced profound fatigue, intermittent non-drenching night sweats and unexplained weight loss of 100 pounds over the preceding 2 years.

Investigations

Given recurrent headaches, patient underwent MRI brain which showed multiple peripherally enhancing lesions in the right cerebral hemisphere, subdural empyema with midline shift and leptomeningeal enhancement (figure 1). Given concerns for underlying brain infection and raised intracranial pressure, patient underwent frontal and temporal lobe craniotomy for evacuation of abscesses. Biopsy specimen from frontal lobe craniotomy was consistent with Streptococcus angiosus abscesses as well as infiltration with B cell non-Hodgkin lymphoma cells (CD20+, PAX5+, CD5−, C10−). CT chest, abdomen and pelvis revealed multiple enlarged but non-bulky lymph nodes above and below diaphragm with no evidence of hepatosplenomegaly. Excisional biopsy of a right inguinal lymph node revealed B cell non-Hodgkin lymphoma with immunohistochemical staining pattern similar to the previous brain tissue specimen (CD20+, PAX5+, CD5−, C10−). Further workup revealed complete blood count (CBC) with a haemoglobin 85 g/L, white blood cell count of 6.5 x 10⁹/L and platelet count of 300 x 10⁹/L, IgM level 1241 mg/dL, beta-2 microglobulin 7.4 mg/dL, serum protein electrophoresis and immunofixation with IgM 1.4 g/dL, kappa light chain 727 mg/L, lambda light chain 19.2 mg/L and kappa lambda light chain ratio of 37.9. Skeletal survey was without evidence of lytic lesions. Cerebrospinal fluid (CSF) analysis revealed protein levels elevated at 72 mg/dL, 5 lymphocytes/mm³ and no evidence of malignant lymphocytes on cytology or flow cytometry analysis.

Figure 1.

MRI at diagnosis showing right frontal and temporal parenchymal enhancing lesions (arrows).

Differential diagnosis

Although the patient had a histological specimen from the brain raise strong suspicion for lymphoplasmacytic lymphoma, possibility of other differential diagnoses for a CD5−, CD10− lymphoma including marginal zone lymphoma with lymphoplasmacytic differentiation could not be entirely excluded based on immunohistochemistry or morphological features only. Hence, PCR-based DNA sequencing was conducted on the lymph node tissue and confirmed MYD88 (L265P) mutation. Testing for MYD88 mutation was helpful not only in establishing a conclusive diagnosis, but also guiding treatment in this case

Treatment

Once diagnosis was established, treatment was initiated with ibrutinib 560 mg daily. A baseline ECG was obtained prior to initiation of therapy and revealed normal sinus rhythm.

Outcome and follow-up

Within 2 weeks of starting treatment with ibrutinib, patient noticed clinical improvement with resolution of headaches and right ear hearing deficit. On follow-up after 2 months of therapy, CBC revealed haemoglobin 125 g/L and MRI revealed significant interval resolution of previously rim enhancing lesions (figure 2). Patient was continued on ibrutinib 560 mg daily without experiencing any adverse events.

Figure 2.

MRI after 2 months of ibrutinib therapy with resolution of peripherally enhancing lesions.

Discussion

Waldenstrom’s macroglobulinaemia (WM) is a B cell lymphoproliferative disorder characterised by the presence of an IgM paraprotein in the serum and infiltration of the bone marrow with lymphoplasmacytic cells.¹ Although the disease is primarily localised to the bone marrow, 15%–20% of patients have extramedullary involvement with lymphadenopathy and/or splenomegaly. BNS is a rare neurological manifestation of WM resulting from infiltration of the CNS by the lymphoplasmacytic cells. CNS involvement occurs in two forms with majority of the patients developing diffuse leptomeningeal enhancement on imaging and tumorous form with one or more parenchymal lesions seen less commonly.^{2 3} Clinical presentation is nonspecific with most common neurological manifestations including gait disturbances (48%), cranial nerve (II and VII) involvement (36%), cognitive impairment and memory loss (27%). Symptoms are generally slow onset and gradually progressive in weeks to months. Age greater than 65, thrombocytopaenia with platelet count less than 100×10⁹/L and treatment for WM prior to BNS diagnosis are factors associated with poor outcome.² Diagnostic workup includes MRI of the brain±spinal cord and CSF analysis by flow cytometry. Definitive diagnosis of BNS requires morphological and immune histochemical evaluation of cerebral or meningeal tissue or the presence of a clonal B cell population with a typical WM phenotype (CD5−, CD10−, CD20+, CD79+) in the CSF.⁴ Somatic mutation in MYD88 gene is seen in 90% of the patients with WM and leads to substitution of leucine with proline at position 265.⁵ Using quantitative-PCR and Sanger sequencing, Paulain et al detected MYD88 L265P mutation in both CSF and bone marrow of three BNS patients.⁶

Intrathecal chemotherapy with or without intravenous high-dose methotrexate and systemic chemo-immunotherapies including FCR (fludarabine, cyclophosphamide, rituximab) and BR (bendamustine, rituximab) have been historically used to treat BNS. Based on one study, overall response rate of 70% is seen after first-line treatment with chemo-immunotherapy with a median progression-free survival of 26 months and an overall survival of 71% at 5 years and 59% at 10 years.³ Due to enhanced neurotoxicity and cognitive impairment, radiotherapy should only be considered for patients failing other treatment options.⁴ Ibrutinib causes irreversible inhibition of Bruton’s tyrosine kinase pathway leading to decreased malignant B cell proliferation and survival. When used in previously untreated patients with WM, it has an overall response rate of 90% with a 2-year progression free survival of 70%.⁷ At 560 mg daily dose, adequate blood and CSF concentration of ibrutinib have been seen.⁸ However, based on recently reported study, good clinical responses have been seen with a lower dose of 420 per day.⁹

Learning points.

• For patients with Bing-Neel syndrome (BNS), testing for MYD88 mutation is helpful not only in establishing a conclusive diagnosis, but also guiding treatment.

• As compared with more intensive chemoimmunotherapies, treatment with Ibrutinib monotherapy in well tolerated in older and frail patients with BNS.

• Presence of MYD88 mutation predicts excellent response to ibrutinib and hence if present, ibrutinib monotherapy should be the preferred first line of treatment for patients with BNS.

• Although 560 mg daily dose of ibrutinib was used in our patient, lower doses of 420 mg daily have shown clinical benefit. Optimal dose of ibrutinib for BNS needs to be evaluated in a larger cohort of patients.