Efficacy of ibrutinib in the treatment of <scp>B</scp>ing–<scp>N</scp>eel syndrome
Authors: Aurélie Cabannes‐Hamy, Richard Lemal, Lauriane Goldwirt, Stéphanie Poulain, Sandy Amorim, Renan Pérignon, Juliette Berger, Pauline Brice, Eric De Kerviler, Jacques‐Olivier Bay, Helene Sauvageon, Kheira Beldjord, Samia Mourah, Olivier Tournilhac, Catherine Thieblemont
Journal: American Journal of Hematology (2015)

To the Editor :Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare low-grade lymphoproliferative disorder of B-cell origin characterized by serum monoclonal M immunoglobulin (IgM) and bone marrow involvement with lymphoplasmacytic cells. WM represents approximately 2% of monoclonal gammapathies, with neurological complications occurring in 25–47% of cases. Polyneuropathies due either to IgM deposition, IgM with anti-MAG activity, IgM reacting with other gangliosides or cryoglobulinemic neuropathy are the most frequent. Central nervous system (CNS) manifestations are rare and mostly related to serum hyperviscosity syndrome. Direct malignant lymphoid infiltration of the CNS constitutes a pretty rare and poorly defined entity known as Bing–Neel syndrome (BNS) 1: about 100 cases have been so far reported, including 44 patients recently collected and analyzed by the French Innovative Leukemia Organization 2. Diagnosis of BNS is suspected in patients with CNS symptoms, which are heterogeneous and mainly represented by balance disorder or disturbed gait. BNS is the first manifestation of WM in up to 36% of cases, or follows the WM diagnosis with a median delay of 8.9 years. BNS frequency has been reported with a male predominance (8/10 cases), and a median age at diagnosis of 63 years. Brain magnetic resonance imaging (MRI) is abnormal in 78% of the cases. Cerebrospinal fluid (CSF) analysis usually shows an increased protein level (95% of the cases), and evidence for CNS infiltration by WM monotypic tumor cells. Moreover, BNS CSF-infiltrating tumor cells have recently been shown to carry the MYD88 L265P mutation, adding this molecular tool in our diagnostic arsenal 3. Due to the small number of available data in the literature, no consensus exists for BNS treatment. Remission has been reported either with intrathecal and/or systemic chemotherapies, including high-dose methotrexate or cytarabine, due to their good blood–brain barrier penetration. Front-line intensification with autologous stem-cell transplantation seems to be associated with long-term remissions. Rituximab has been used in about half of the patients of the largest series 2, with no effect on response rate nor survival, consistent with its presumed low blood–brain barrier penetration. Whole brain radiation therapy (20–40 Gy), alone or in combination with chemotherapy, also could bring some responses with short duration. Ibrutinib, a Bruton's tyrosine kinase inhibitor, has shown remarkable efficacy in WM, especially in MYD88 L265P carrying WM 4, and has recently been approved by the FDA (January 29, 2015) and the EMEA (October 17, 2015) for WM. Recently, ibrutinib has been shown to penetrate through the blood–brain barrier and to induce response in some CNS lymphoid tumor infiltrations 5. Herein, we report the first two cases of patients with a refractory/relapsed MYD88 L265P BNS, in whom control of neurological symptoms was achieved with ibrutinib. A 72-year-old man was diagnosed with WM/LPL on an axillary lymph node biopsy associated with bone marrow infiltration by a lymphoplasmacytic monoclonal population with MYD88 L265P mutation and serum monoclonal IgM kappa at 13.1 g/l. The patient achieved a very good partial response (VGPR) after six cycles of R-CHOP regimen (every 21 days). Ten months later, he developed general weakness, weight loss, impaired memory, sphincter disorders, disturbed gait, and falls. Serum IgM kappa was measured at 2.7 g/l and CSF analysis revealed a WBC count of 26/mm3 with monotypic CD20+ lymphocytes and an elevated protein level at 3.57 g/l (normal <0.45) (Fig. 1A,B). Brain and spinal cord MRI revealed periventricular edema and T2 hypersignal lesions with contrast enhancement at C2–C3 level consistent with the diagnosis of Bing–Neel syndrome (Fig. 1C). Six cycles of Rituximab (375 mg/m2) and high-dose methotrexate (3 g/m2) were administered every 21 days, with four intrathecal injections of liposomal cytarabine. We observed a rapid decrease of CSF WBC count and CSF protein level, but intrathecal IgM synthesis persisted, neurological symptoms incompletely improved and post-treatment MRI showed persistence of lesions consistent with a partial response. Biological and neuroimaging evolution under ibrutinib. A. Biological parameters before and after ibrutinib. B. Graphical representation of CSF protein level and ibrutinib CSF concentration. The normal CSF protein threshold is represented by the dotted line (0.45 g/l). Left axis corresponds to the CSF protein level (g/l); right axis corresponds to the CSF ibrutinib concentration for the patient 1 (ng/ml). Ibrutinib plasma exposure (area under the curve) were calculated using the trapezoidal rule, and reached during follow-up a median AUC of 1750 ng h mL−1 (790–3758) and 531 ng (280–781) in patients 1 and 2, respectively. C. MRI of the two patients with BNS treated with ibrutinib. Patient 1: Sagittal contrast-enhanced T1-weighted MRI images demonstrate significant decrease in the periventricular and corpus callosum contrast-enhancement at 1, 3, and 6 months after ibrutinib introduction; axial T1 sequences with gadolinium show progressive disappearance of the cerebral white matter lesion and complete resolution of the periventricular contrast enhancement at 1, 3, and 6 months after ibrutinib initiation. Patient 2: Coronal short T1 inversion recovery and fat-saturated contrast-enhanced T1-weighted sequences reveal complete healing of the brachial plexus polyradiculonevritis at 3 and 6 months after ibrutinib ignition; axial fat-saturated contrast-enhanced T1-weighted MRI prove the whole recovery of cauda equine contrast-enhancing thickening and agglutination at 3 and 6 months from beginning of ibrutinib. MRI = magnetic resonance imaging. After a 10 months follow-up, neurological symptoms exacerbated, spinal MRI revealed a new corpus callosum lesion, and CSF protein was at 1.11 g/l with intrathecal monoclonal IgM synthesis. After four cycles of high-dose aracytine (2 g/m2/day for 2 days), BNS was refractory. Following its recent FDA approval, we started ibrutinib at 420 mg/day. Within 8 days, we observed significant clinical improvement, promptly decreasing of CSF protein level until normalization persisting at 6 months, and remarkable improvement of MRI lesions lasted at 6 months (Fig. 1). A 56-year-old woman was diagnosed with WM and achieved a PR after first-line treatment with chlorambucil (8 mg/m2/day, 10 consecutive days monthly, 12 cycles). Five years later, she presented bilateral and very intensive burning pain, mostly in extremities. Brain and spinal cord MRI and electromyography were normal. CSF analysis revealed 1/WBC count of 11/mm3 with monotypic CD20+ lymphocytes 2/elevated protein level at 4.04 g/l (Nl < 0.45), consistent with the diagnosis of BNS. The patient received six cycles of R-DHAC plus 2 R IV infusions. We observed neurological improvement, no cell in CSF, and CSF protein level at 1.2 g/l. The planned intensification was finally impossible because of repeated mobilization failure. After a 10 months follow-up, the same pain reappeared and rapidly worsened, concomitantly with a WM general relapse. MRI showed a diffuse infiltrative polyradiculonevritis. CSF protein level was at 1.64 g/l associated with a pauci-cellularity and the detection of a CSF MYD88 L265P mutation. Within 10 days of ibrutinib administration, the patient experimented dramatical improvement, with complete pain disappearance. At 6 months of ibrutinib, CSF MYD88 L265P mutation was no more detected. MRI evaluation at 3 and 6 months showed a progressive ad integrum restitution (Fig. 1). For both patients, ibrutinib quantification in plasma and CSF was performed using a liquid chromatography coupled with mass tandem spectrometry. Ibrutinib was able to cross blood–neuromeningeal barrier with a 1–7% CSF/plasma ratio, without any adverse effect observed in the two cases (Fig. 1B). To the best of our knowledge, these cases are the first reports of efficacy of ibrutinib in BNS. We observed objective sustainable responses and pharmacodynamic proof of ibrutinib CSF diffusion. Our reports confirm that ibrutinib has good neuromeningeal distribution and provide a rationale to prospectively study its use in BNS. CT is supported by the Nelia and Amadeus Barletta Foundation. The authors thank Prof. C. Dumontet for helpful discussions. ACH, RL, OT, and CT designed the research. ACH, RL, LG, SP, EDK, SA, PB, KH, SM, OT, and CT analyzed data. ACH, RL, OT, and CT wrote the paper. ACH, RL, LG, SP, EDK, SA, RP, JB, PB, HS, KH, SM, OT, and CT reviewed the manuscript. Aurélie Cabannes-Hamy,1,2, Richard Lemal,3,4 Lauriane Goldwirt,5 Stéphanie Poulain,6,7 Sandy Amorim,1,2 Renan Pérignon,8 Juliette Berger,9 Pauline Brice,1 Eric De Kerviler,10 Jacques-Olivier Bay,3,4 Helene Sauvageon,5 Kheira Beldjord,11 Samia Mourah,5 Olivier Tournilhac,3,4 Catherine Thieblemont1,2,11* 1APHP, Department of Hemato-Oncology, Hopital Saint-Louis, Paris, France; 2Université Paris Diderot, Sorbonne Paris Cité, Paris, France; 3CHU Clermont-Ferrand, Service D'hématologie Clinique Adulte Et De Thérapie Cellulaire, Clermont-Ferrand 63003, France; 4Clermont Université, Université D'auvergne, EA7283, CIC501, BP, Clermont-Ferrand 10448, 63000, France; 5APHP, Department of Pharmacology, Hopital Saint-Louis, Paris, France; 6Centre Hospitalier De Valenciennes, Service d'Hématologie-Immunologie-Cytogénétique, Valencia, France; 7Centre De Biologie Et Pathologie, Laboratoire D'hématologie, INSERM UMR 1172, IRCL, CHRU De Lille, Lille, France; 8CHU Clermont-Ferrand, Pôle De Radiologie, Clermont-Ferrand 63003, France; 9Hématologie Biologique, Centre De Ressources Biologiques D'auvergne, CHU Clermont-Ferrand, Clermont-Ferrand 63003, France; 10APHP, Department of Radiology, Hopital Saint-Louis, Paris, France; 11EA7324, Paris Descartes Université, Sorbonne Paris Cité, Paris, France