Neither the patient nor the physician could see anything: Atypical Bing-Neel syndrome

International audienc

Neither the patient nor the physician could see anything: Atypical Bing-Neel syndrome

International audienc

Prognostic Impact Of Somatic NOTCH2 Mutation In Splenic Marginal Zone Lymphoma

Abstract Introduction New insights in the pathogenesis of the splenic marginal zone lymphoma (SMZL) has been recently enlightened by next generation sequencing technology discovering recurrent mutations in several genes implicated in major signalling pathways. In 2 recent reports (JEM 2012), mutations in NOTCH2, a gene encoding a protein required for marginal zone B-cell development, were identified in nearly 25% of the patients, with controversial impact on clinical outcome. The aim of our analysis was to analyse the incidence and the prognostic impact of somatic NOTCH2 mutations in a large cohort of patients with SMZL homogeneously treated. Methods A series of 105 consecutive SMZL patients requiring treatment and referred in 2 expert centers was analysed. Genomic DNA was extracted from frozen tumor samples of involved spleen or blood or bone marrow obtained at diagnosis. Tumor cell clonality was established by amplification of the rearranged IGH genes. Targeted sequencing of the NOTCH2 C-terminal coding exons 26, 27 and 34 was performed using Sanger sequencing and primers described by Kiel MJ et al (J.Exp.Med.209:9,2012). All mutations were verified in at least two independent PCR amplification and sequencing reactions. Log-rank tests were used to compare survival times -overall survival (OS) and progression-free survival (PFS)- between patients with mutated NOTCH2 and patient with wild-type NOTCH2. We controlled the effects of prognostic factors on outcome using multivariate Cox model analysis. Results The median follow-up was 7 years. At diagnosis, median age was 63 years. Sex ratio was M/F 1:1.35. Nearly all patients presented with a disseminated disease and a good performance status. Forty-four percent of the patients had a high LDH level. A monoclonal component was detected in 31% of the patients. An immunological event such as haemolytic anemia, thrombocytopenia, neutropenia, coagulation disorder, and cryoglobulinemia, was observed in 27% of the patients. None of the patients was infected with hepatitis C virus. Patients were scored according to the age-adjusted International Prognostic Index (n=95), and to the IIL score system (n=76). Splenectomy was realized in 97% of the patients. Three patients were treated with R-Bendamusine without splenectomy. Adjuvant treatment after splenectomy was proposed for 24% of the patients, and included CHOP+/-R (n=16), HLX-VP16 (n=1), chlorambucil (n=4), and rituximab alone (n=1). Five and 10-year OS was estimated at 82% and 69%, respectively. Five and 10-year PFS was estimated at 61% and 46%, respectively. Age&gt;60 was significantly associated to a shorter OS (p=0.0135). We identified NOTCH2 mutations in 10 (10%) of the patients. The detected mutations occurred only within the exon 34 (TAD and PEST domains) and represented mostly truncating or insertional events leading to frameshift mutations (8 of the 10 cases) (also 1 nonsense and 1 missense mutations). Comparison of the clinical characteristics at diagnosis between patients with or without NOTCH2 mutations did not show any significant differences. Patients with NOTCH2 mutations were characterized by a significantly worse OS (at 5 years, 32% vs 87%, p&lt;0.0001). Presence of NOTCH2 mutations was also significantly associated with a shorter PFS (at 5-years, 16% vs 66%; p=.0008), and with a shorter time to histological transformation (at 5 years, 26% vs 6%; p=0.0051). NOTCH2 mutational status did not influence the time to first treatment. Multivariate analysis showed an independent prognostic impact of NOTCH2 mutational status on OS (RR 4.7, p=0.02). Conclusion NOTCH2 mutation was identified in 10% of the SMZL patients in our series. Our data demonstrate also, as described, than patients with NOTCH2 mutations have a significant poorer prognosis than patients without NOTCH2 mutations, with a shorter PFS and a shorter OS. NOTCH2 mutational status seems to be an independent prognostic factor. This needs to be confirmed in prospective trials in the context of new therapeutics. CA and GB equally contributed Disclosures: Coiffier: Millennium Pharmaceuticals : Consultancy. </jats:sec

Interim-Positron Emission Tomography with [18F]Fluorodeoxyglucose (interim-PET) Evaluation In Mediastinal Lymphoma Including Hodgkin Lymphoma (HL) and Primary Mediastinal Large B-Cell Lymphoma (PMBL)

Abstract Abstract 2860 Introduction. Histological lymphoma diagnosis of adult patients with bulky mediastinal mass is either HL or PMBL, two distinct diseases with a specific outcome. PET interpretation is often difficult for mediastinal lymphoma because of the volume of the tumor and the presence of blood pool. No specific criteria for interpretation of interim-PET have yet been defined in this clinical entity. The purpose of this study was to investigate the prognostic value of qualitative and semiquantitative evaluations of interim-PET in mediastinal lymphoma. Methods. We retrospectively included 72 patients with either HL (n=48) or PMBL (n=24), previously untreated, aged under 60 at diagnosis and who underwent at least one interim-PET evaluation. Patients with sub-diaphragmatic or medullar localisations of lymphoma were excluded. All PET scans were reviewed. Qualitative evaluation included global visual evaluation (GVE) (positive or negative) and 5 points-scale (5PS). Semiquantitative evaluation consisted in maximum standardized uptake value (SUVmax) and SUVmax reduction between the baseline PET (PET0) and the evaluation performed after two (PET2) or four (PET4) cycles of chemotherapy. Prognostic impact was evaluated on the event-free survival (EFS), defined as disease progression/first relapse (n=18) or death (n=2). ROC (Receiver Operating Characteristic) curve was used to assess the value of SUVmax reduction in discriminating future deaths or relapses, based on area under the curve (AUC). The “best“ cut-off that provides both the lowest false positive and the lowest false negative rates was computed. Results. Median age was 29 (24 - 35), 60% male. Tumoral mass was more than 7.5 cm in 70% of the patients, and M/T ratio&gt;= 0.35 in 79%. Median SUVmax at baseline, PET2 and PET4 were 12.8 (4.1;33.2), 1.9 (1.7;3.1), and 2.4 (1.7;3.1), respectively. With a median follow-up at 24 months, 2-year event-free survival (EFS) was 67%, without significant difference between HL and PMBL (p=0.98). Except for ECOG performance status in PMBL, neither clinical nor biological feature was predictive for EFS. Using GVE, a negative PET2 (n=36/59) and PET4 (n=24/34), were achieved in 61% and 71%, respectively. GVE and 5PS have a significant negative predictive value (NPV) at PET2 (HR=3.2, 95%CI: 1.2–8.2; p=0.012, and HR=1.9, 95%CI: 1.1–3.3, p=0.01) and at PET4 (HR=13.9, 95%CI: 3.5–55; p=0.0001, and 2.6, 95%CI: 1.5–4.7, p=0.001 respectively), with a 2-year estimated EFS of 69% for PET2-negative patients versus 51% for PET2-positive patients (p=0.012), and of 86% for PET4-negative patients versus 20% for PET4-positive patients (p=0.001). An optimal cut-off of 81% SUVmax reduction from PET0 to PET2 or PET4 yielded a 2-year estimated EFS of 70% in patients with reduction of more than 81%, versus 47% in those with reduction of 81% or less (p=0.004). In the HL subgroup, GVE and SUVmax reduction higher than 81% at PET2 (p=0.0001, p=0.015, respectively) and PET4 (p=0.004, p=0.015, respectively) showed significant prognostic values for EFS. In the PMBL subgroup, neither qualitative nor semiquantitative evaluation at PET2 was predictive for EFS. At PET4, GVE and 5PS were strongly predictive for EFS (p=0.005, p=0.0001). Patients with SUVmax reduction higher than 81% between PET0 and PET4 reached a 67% 2-year EFS, while patients with lower SUVmax reduction had only a 33% 2-year EFS (p=0.13). Conclusion. The cut-off value of SUVmax reduction estimated for predicting EFS with best accuracy in mediastinal lymphoma was 81%. Although the SUV semiquantification helps to reduce the number of false positives, visual global analysis had a significant negative predictive value in interim-PET in mediastinal lymphoma, with a possible very early prediction, as early as PET2 in HL, and a better prediction at PET4 than PET2 in PMBL. Disclosures: No relevant conflicts of interest to declare. </jats:sec

Interest of Negative Minimal Residual Disease Estimated by Flow Cytofluorometry After Allogeneic Stem Cell Transplantation for B-Cell Chronic Lymphocytic Leukemia

Abstract Abstract 2547 Introduction. Minimal residual disease (MRD) eradication in patients with chronic lymphocytic leukemia (CLL) treated by standard chemo-immunotherapy regimens correlates with improved outcome. However, there is limited information about the interest of negative MRD after allogeneic stem cell transplantation (allo-SCT). In this study we investigated whether blood phenotypic remission could impact post-transplant outcome in patients with CLL. Methods. We retrospectively included patients who underwent allo-SCT for CLL and with post-transplant MRD monitored by four or six-colour flow cytofluorometry in blood samples (sensitivity≥10−4). Prognostic impact was evaluated on overall survival (OS) and progression-free survival (PFS). Each of these parameters was evaluated according to the best response and to the 12 month-MRD status, using log-rank test. Results. Thirty-three patients from 4 hematology departments were included. Median age at transplant was 54 years (range, 41 to 66 years). The median number of prior chemotherapy regimens was 3 (range, 1 to 6) including autologous stem cell transplantation in 48% of the patients. Status at transplant was available in 27 patients and 11% of them had negative MRD, 26% haematological complete response (CR), 59.% partial response (PR) and 4% had refractory disease. Twenty-two patients (67%) received a reduced intensity conditionning regimen. Conditioning regimen included serotherapy (antithymoglobulin n = 10, alemtuzumab n = 1, rituximab n = 1) in 12 patients. Twenty-two patients (67%) were transplanted with HLA identical sibling donor. The median number of MRD evaluations after transplant was 5 (range, 1 to 23). Response to transplant: After transplant, 16 patients achieved negative MRD, 15 patients achieved haematological CR, 1 PR and 1 did not respond to transplant. Among the 16 patients with phenotypic remission, negativation of MDR was obtained before the cessation of immunosuppressive therapy for 15 of them (94%) and median time to negativation was 7 months (range, 2 to 20 months). In patients achieving phenotypic remission chronic GVHD rate was 75% versus 44% in patients with post-transplant detectable MRD. Post-transplant outcomes: With a median follow-up of 27 months, the 2-y OS and the 2-y PFS were respectively 84% and 53%. Cause of death (n = 8) was progression in 4 cases and transplant related mortality in 4 cases. Impact of phenotypic remission: The achievement of phenotypic remission (whatever the time of evaluation) correlates with better PFS: 2-y PFS was 85% in these patients versus 27% in the other patients (p = 0.012). Considering the 19 patients with MRD evaluation available at 12 months after transplant, 2-y PFS was 100% in 12-month-negative-MRD patients (n = 10) versus 17% in positive-MRD patients at that date (p = 0.003) No relapse was observed in the group of patients who achieved phenotypic remission at 12 months post-transplant (figure). Conclusion. These data suggest that achievement of post transplant negative MRD in patients with CLL is associated with a long-term control of the disease and better PFS. In our series, no relapse occurred in patients with negative MRD at 12 months post transplant. These results could lead to decrease immunotherapy and to administrate donor lymphocytes to patients with post-transplant persistent positive MRD. Disclosures: Leblond: ROCHE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MUNDIPHARMA: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. </jats:sec

To Dose or Not to Dose: Are IL-10 and IL-6 Accurate Biomarkers to Detect Leptomeningeal Involvement in Small B-Cell Lymphoproliferation?

Abstract Identifying the etiology of neurological symptoms in hematological malignancies is still a challenging issue. Lymphomatous meningitis (LM) is mainly described in aggressive systemic B-cell lymphomas (diffuse large B-cell (DLBCL) and Burkitt lymphomas), and is associated with poor prognosis. Leptomeningeal involvement in small B-cell lymphoproliferation is a rare, poorly described condition, mentioned only in case reports. The diagnosis relies on the combination of non-specific central nervous system (CNS) symptoms (headaches, paraplegia, etc.) or psychiatric symptoms, and the cytological detection of tumor cells in the cerebrospinal fluid (CSF). However, cell analysis has a low sensitivity here due to the small drawn volumes of CSF samples, their poor cellularity and cell viability. Soluble biomarkers can be measured by multiplex techniques on small sample volumes, hence can overcome cytological limitations and seem fairly interesting for further investigations. The aim of the present study was to evaluate the diagnostic value of interleukin (IL)-10 and IL-6 quantification combined with the IL-10:IL-6 ratio in CSF of patients suffering from LM secondary to systemic small B-cell lymphoproliferations. Seventeen patients suffering from LM were included in the study: 4 with chronic lymphocytic leukemia (CLL), 2 with mantle-cell lymphoma (MCL) and 11 with Waldenström's macroglobulinemia (WM). All patients presented CNS symptoms associated with documented LM (revealed either by conventional cytology and/or flow cytometry) at the diagnostic stage and before intrathecal chemotherapy. IL-10 and IL-6 quantifications were performed in CSF using the quantitative Cytometric Bead Array® technique (human IL-10 CBA kit and human IL-6 CBA kit; BD BiosciencesTM) on a FACSCanto II flow cytometer (BD BiosciencesTM) following the manufacturer's recommendations, with a limit of detection of 2.5 pg/ml. All CLL and MCL patients displayed an undetectable level of IL-10 (&lt;2.5 pg/ml) along with undetectable (&lt;2.5 pg/ml) or low level of IL-6 (n=6; range &lt;2.5-14 pg/ml) in the CSF. These results suggest that IL-10 and IL-6 are not increased in secondary LM in these two malignancies. WM patients had a more heterogeneous distribution and are divided into 2 groups: undetectable IL-10 (n=4) or positive IL-10 (n=7; range 4-39 pg/ml with a median value of 18 pg/ml). We therefore calculated the IL-10:IL-6 ratio in this group, setting the threshold at 1 as firstly described in primary vitroretinal lymphomas and more recently in primary central nervous system lymphoma (PCNSL). Two patients displayed a ratio &gt;1; one had WM transformed into DLBCL in CNS (IL-10= 21pg/ml; IL-6= 7pg/ml; IL-10:IL-6= 3), and the other had a PCNSL simultaneously diagnosed in CSF (IL-10= 18pg/ml; IL-6= 4pg/ml; IL-10:IL-6= 4.5). Other patients with a ratio &lt;1 have a documented Bing Neel syndrome (BNS) and an absence of any other aggressive B-cell lymphoma. Furthermore, IL-6 levels were higher in CSF of BNS patients (n=9; range 4-540 pg/ml with a median value of 32 pg/ml) than in CLL and MCL patients. Our findings demonstrate the need of IL-10 and IL-6 quantification with the use of IL-10:IL-6 ratio at diagnosis of LM in small B-cell lymphoproliferations to exclude any other aggressive B-cell malignancy. Further investigation of IL-6 concentration may be useful in BNS diagnosis regardless of the ratio because some data demonstrate a central role of IL-6 in WM pathophysiology. Besides, it has already been reported that CCL5 production by tumor microenvironment in WM leads to IL-6 and IgM secretion through the JAK/STAT signaling pathway. In conclusion, we describe for the first time that IL-10 concentration in the CSF is not increased in small B-cell lymphoproliferations with LM. However, we report its usefulness in revealing more aggressive lymphomas in the context of either a transformation or when associated with another "hidden" lymphoma such as PCNSL. Supplementary data will be prospectively collected to confirm our preliminary results. On one hand, it seems important to study CLL cases with or without Richter syndrome, and on the other hand to further explore the role of IL-6 in BNS. Disclosures Choquet: Roche: Consultancy; Janssen: Consultancy. Leblond:Gilead: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Mundipharma: Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau. </jats:sec

Immunochemotherapy versus rituximab in anti-MAG neuropathy: a report of 64 patients

International audienceMonoclonal immunoglobulin M (IgM) anti-myelin-associated glycoprotein (MAG) neuropathy is a rare disabling condition, most commonly treated with rituximab monotherapy (R), which leads to neurological improvement in only 30%-50% of patients. The combination of rituximab plus chemotherapy has been proven to improve the level of responses. We studied the outcomes of anti-MAG neuropathy patients treated either by R, or by immunochemotherapy (ICT) in our centre, focusing on the incidence of the first neurological response evaluated by the modified Rankin Scale (mRS). From 2011 to 2018, 64 patients were studied: 34 were treated with R and 30 with ICT. According to our treatment decisionmaking process, the median mRS was higher in the ICT group (mRS 2) compared to the R group (mRS 1). At 1 year, mRS improvement rates were 46% and 18% of the ICT and R groups of patients respectively, with a median time to response of 8 and 13 months (p=0.023). Adverse effects were higher in the ICT group: 62% vs 15% (p˂0.01) all grades included. One secondary acute leukaemia occurred 5 years after treatment by ICT. In conclusion, ICT may be used as a valid option for patients with rapidly progressive and/or severe anti-MAG neuropathy symptoms

Cerebrospinal fluid interleukin (IL)-10 and IL-10:IL-6 ratio as biomarkers for small B-cell lymphoproliferations with leptomeningeal dissemination

International audienceWe here report for the first time that low levels of interleukin (IL)-10 do not exclude lymphomatous meningitis (LM) in B-cell lymphoproliferative disorders (CLPD). Unexpectedly, IL-10 levels and IL-10:IL-6 ratio in CLPD differed from the levels observed in diffuse large B-cell lymphoma (DLBCL). We report the usefulness of adding the IL-10:IL-6 ratio in order to potentially reveal more aggressive lymphomas: either a transformation or an association with another “hidden” lymphoma such as primary CNS lymphoma (PCNSL)