High‐dose therapy with autologous stem cells transplantation in Bing‐Neel syndrome: A retrospective analysis of 14 cases
Authors: Laurence Simon, Richard Lemal, Luc‐Matthieu Fornecker, Olivier Tournilhac, Véronique Leblond
Journal: American Journal of Hematology (2019)

To the Editor: Bing-Neel syndrome (BNS) is a rare complication in Waldenström macroglobulinemia (WM), defined by a central nervous system (CNS) involvement with lymphoplasmacytic cells. The symptoms or signs that led to the diagnosis of BNS are heterogeneous. BNS should be considered in the context of any unexplained neurological symptoms associated with WM. The most frequent symptoms being disturbed gait (ataxia or dizziness), cranial nerve involvement, cognitive impairment, sensory or motor deficit, headache, and pain.1 The diagnostic approach is based on the findings of a lumbar puncture and MRI imaging of the brain and spinal cord. The cytological examination of the cerebrospinal fluid (CSF) should be associated with immunophenotyping by flow cytometry in order to confirm the monotypy and the B-cell origin of the malignant cells and to demonstrate an immunophenotypic profile compatible with a WM proliferation. In retrospective surveys1, 2 no clear evidence emerged for a preferred treatment strategy. Most of the patients receive systemic chemotherapy.3 High-dose methotrexate and high-dose cytarabine, standard dose fludarabine, and bendamustine can be used in the front-line setting. Rituximab is mostly combined with chemotherapy. Intrathecal treatment may be combined with systemic treatment. Ibrutinib, a Brutons's tyrosine kinase inhibitor, used for WM, has also recently been used for BNS. First-line use of radiotherapy is not recommended and should be reserved for patients failing other treatment options.3 Autologous stem-cell transplantation (ASCT) is a therapeutic option in eligible patients with a chemosensitive WM relapse improving overall survival and progression free survival in WM patients previously treated.4 Favorable results were reported with ASCT in patients with primary CNS lymphoma confirming the efficacy of this strategy in CNS lymphoma localization.5, 6 There are few data regarding the role of ASCT in BNS treatment, and no recommendation for its use in first line. In this retrospective, observational, study, we describe 14 patients with BNS who received ASCT, in five French centres, between 1999 and 2018. BNS diagnosis was defined as a nonambiguous cytological or histopathological evidence of CNS involvement by a lymphoplasmacytic proliferation, concomitant with a diagnosis of systemic WM according to the Second International Workshop on WM. We use the response criteria from the task force on BNS established during the Eighth International Workshop on WM3: Median age at BNS diagnosis was 61 years (range, 52-68 years), and median time from BNS diagnosis to ASCT was 6 months (range, 3-76 months). The majority of the BNS patients (13/14) had a diffuse form of the disease. Clinical, biological, and imaging characteristics were the same as those described in the retrospective studies for BNS.1, 2 Clinical characteristics include ataxia, cranial nerve involvement, cognitive impairment, sensory or motor deficit, headache, pain, and convulsions. The search for the MYD88 mutation in the CSF was not systematic. BNS treatments were heterogeneous (Table 1) and consisted in systemic and intrathecal chemotherapy in 13 patients. In these 13 patients, high-dose cytarabine or methotrexate based chemotherapy was used in 11 patients (in association with R-CHOP, R-Fludarabine, or R-Bendamustine for four patients), and R-CHOP alone in two patients. Intrathecal chemotherapy was used alone in one patient. Rituximab-Cytarabine HD, intrathecal chemotherapy R-DHAC, intrathecal chemotherapy R-DHAC, intrathecal chemotherapy R-CHOP-MTX HD, intrathecal chemotherapy CHOP, intrathecal chemotherapy R-DHAC, intrathecal chemotherapy R-DHAC, intrathecal chemotherapy R-DHAC, intrathecal chemotherapy R-CHOP/R-DHAC, intrathecal chemotherapy R-CHOP-MTX HD/DHAP, iIntrathecal chemotherapy Death during ASCT (pneumonia) At the time of ASCT, all patients had sensitive disease. ASCT was performed directly after the first line of BNS treatment in 11 patients and in second BNS remission in 3 patients. Conditioning regimens were BEAM (carmustine or bendamustine, etoposide, cytarabine, melphalan) in seven patients, total body irradiation with melphalan in one patient, and thiotepa-based regimen in six patients (with busulfan, cyclophosphamide/melphalan, or carmustine (BCNU)). With a median follow-up period of living patients of 35 months after ASCT (range, 1, 7 to 208 months), only one patient relapsed with BNS (3 years after ASCT). This patient has been treated with Ibrutinib after relapse and is now in partial remission. All others patients are still in remission for BNS. One patient relapsed with WM (without CNS involvement) 3 year after ASCT. The overall survival rate after BNS diagnosis was 84% at 5 years and 63% at 10 years. The progression free survival rate after BNS diagnosis was 65% at 10 years. Three patients died, from causes other than BNS evolution (One due to treatment toxicity, one due to infection, a year after the ASCT, and one due to WM transformation in diffuse large B-cell lymphoma). There are few data regarding the role of ASCT in BNS treatment. In the literature, we found five case reports for ASCT in BNS, showing good responses. In our study, the majority of patients had ASCT in first line (11/14) with good results (only one relapse 3 years after ASCT), with a median follow-up period of living patients of 35 months after ASCT. ASCT is a good option in first line, in fit and eligible patients with BNS, and show long-term responses. The optimum conditioning therapy has not been clarified, but in patients with primary central nervous system lymphoma (PCNSL), high-dose thiotepa-based conditioning (thiotepa, BCNU or thiotepa, busulfan, and cyclophosphamide), is recommended over BEAM (BCNU, etoposide, cytarabine, and melphalan) by the European Association for Neuro-Oncology.7 This study has limitations, including the small sample size, its retrospective nature, and the fact that no patient experienced Ibrutinib before ASCT. Ibrutinib showed good results for BNS, possibly due to its ability to cross the blood-brain barrier.8, 9 Recently, a retrospective study of 28 patients, showed that ibrutinib monotherapy, administered at a dose of 420 or 560 mg orally once daily, in the frontline and relapsed settings, can induce durable responses with acceptable toxicity in patients with BNS.10 It is difficult to define the role of ASCT in the era of Ibrutinib treatment. Nevertheless, ASCT remains a good option in fit patients once a complete or partial response is obtained.