Successful treatment with <scp>R</scp>ituximab and <scp>B</scp>endamustine in a patient with newly diagnosed <scp>W</scp>aldenström's <scp>M</scp>acroglobulinemia complicated by <scp>B</scp>ing‐<scp>N</scp>eel syndrome
Authors: Marzia Varettoni, Enrico Marchioni, Maurizio Bonfichi, Anna Picchiecchio, Luca Arcaini, Carla Arbasino, Manuel Gotti, Matteo Da Vià, Mariella Delmonte, Roberta Sciarra, Mario Cazzola
Journal: American Journal of Hematology (2015)

Bing-Neel syndrome (BNS), defined as central nervous system involvement from lymphoplasmacytic lymphoma/Waldenstrom's Macroglobulinemia (WM), is a rare and usually late complication of the disease and is associated with a dismal prognosis. Treatment options for BNS include intrathecal chemotherapy, systemic chemotherapy (mainly with alkylating-based regimens or with purine analogs), and brain irradiation. The outcome reported with these treatments, often used in combination, is extremely variable and durable remissions have been only anedoctically reported. Here, we report the case of a patient with newly diagnosed WM complicated by BNS, who was successfully treated with Rituximab and Bendamustine. A 64-year old man was admitted to hospital for confusion, cognitive decline, memory loss, blurred speech, and ataxia. Magnetic resonance imaging (MRI) showed communicating normal pressure hydrocephalus and both subtentorial and hemispheric leptomeningeal enhancement after gadolinium. CSF analysis revealed a high white blood cell count (196/mm3), increased proteins (67 mg/dL), and normal glucose levels (73 mg/dL). The microscopic evaluation of the cerebrospinal fluid (CSF) showed the presence of lymphocytes, which were B CD19+, CD20+, CD22+, sIgk+, CD5+, CD10–, CD23–, FMC7+, CD79b+ at flow cytometric studies. Serum electrophoresis and immunofixation revealed a small IgMk paraprotein (3 g/L). Blood counts showed a mild neutrophilic leukocytosis, with normal levels of hemoglobin and platelets. Bone marrow biopsy showed an interstitial infiltration by lymphoplasmacytic lymphoma (30%). The MYD88 (L265P) mutation was detectable with allele-specific PCR on bone marrow CD19+ mononuclear cells. Total body computed tomography revealed multiple bone lesions in the pelvis, and 18-Fluorodeoxyglucose Positron Emission Tomography (18-FDG-PET) showed an abnormally high uptake in the pelvis, with a maximum standardized uptake value (SUV) of 7.6. The histologic examination of the largest bone lesion showed a lymphoplasmacytic infiltration. The final diagnosis was WM, low-risk according to the international prognostic system for WM (ISSWM). The patient's ECOG performance status was 3. Immunochemotherapy with R-HyperC-VAD (rituximab plus high-dose methotrexate and cytarabine alternating with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) was started, but treatment was withheld after the first dose of methotrexate due to acute renal failure and worsening of patient's clinical conditions. Three weekly intrathecal administrations of methotrexate 15 mg were given. The patient was considered ineligible to further intensive chemotherapy and then switched to Rituximab and Bendamustine (28-day cycles with Rituximab 375 mg/m2 i.v. on day 1 and Bendamustine 90 mg/m2/day i.v. on days 1–2) associated with intrathecal Methotrexate 15 mg at each cycle. At the end of treatment, the patient's clinical conditions were markedly improved (ECOG performance status: 0). Serum paraprotein after therapy was 0.5 g/L. MRI of the brain showed persistence of communicating hydrocephalus and almost complete disappearance of the leptomeningeal enhancement. CSF analysis and flow cytometric studies were negative. Bone marrow biopsy showed the complete regression of lymphoplasmacytic infiltration. MYD88 (L265P) mutation was undetectable on bone marrow CD19+ mononuclear cells. MRI of the pelvis showed a reduction of bone lesions, with a normal uptake at 18-FDG-PET. Three months after the end of immunochemotherapy the patient underwent hematopoietic stem cells mobilization with the aim to consolidate the good response achieved with autologous stem cell-supported high-dose chemotherapy. The case here described provides the first evidence that the combination of Rituximab and Bendamustine may represent a suitable treatment option for patients with WM complicated by BNS, especially for those who are not eligible to intensive treatment due to advanced age, comorbidities or poor performance status. Marzia Varettoni1*, Enrico Marchioni2, Maurizio Bonfichi1, Anna Picchiecchio2, Luca Arcaini,3, Carla Arbasino4, Manuel Gotti1, Matteo Da Vià1, Mariella Delmonte5, Roberta Sciarra1, Mario Cazzola,3 1Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy 2Fondazione IRCCS C. Mondino, Institute of Neurology, Pavia, Italy 3Department of Molecular Medicine, University of Pavia, Pavia, Italy 4Division of Neurology, Ospedale Civile Di Voghera, Italy 5Radiology and Neuroradiology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy